50 results on '"Jorge E. Cortes"'
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2. Supplementary Figures 1 - 8 from Reversal of Acquired Drug Resistance in FLT3-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies
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Michael Andreeff, Abhijit Ramachandran, Farhad Ravandi, Jorge E. Cortes, Gautam Borthakur, Rodrigo O. Jacamo, Ye Chen, Marina Konopleva, Chen Gao, and Weiguo Zhang
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PDF file - 468K, S1. Sorafenib-resistant murine AML (Ba/F3-ITD-Res) and parental cells (Ba/F3-ITD) were treated with indicated concentrations of sorafenib for 72 hours. Cell apoptosis induction was analyzed by measuring the percentage of annexin V-positive cells using flow cytometry. S2. Ba/F3-D835G, Ba/F3-D835Y and Ba/F3-FLT3 wild type cells were treated with crenolanib for 72 hours and their EC50s for apoptosis induction were determined by measuring percentage of annexin V-positive cells using flow cytometry. S3. Isobologram and combination index (CI) analyses were performed on sorafenib resistant cells after 48 hours combination treatment with crenolanib and sorafenib . S4. Isobologram and combination index (CI) analyses were performed on sorafenib resistant cells Ba/F3-ITD+676/842 after 48 hours combination treatment with vary combination strategies of type I and type II tyrosine kinase inhibitors. S5. Ba/F3-FLT3 wild type cells were treated with vary combination strategies of type I and type II tyrosine kinase inhibitors for 48 hours and apoptosis induction were determined by measuring percentage of annexin V-positive cells using flow cytometry. Creno: crenolanib; sora: sorafenib; PKC: PKC412; MLN: MLN518. S6. Normal bone marrow cells were exposed to indicated agents for 48 hours and apoptosis induction was determined by measuring the percentage of Annexin V-positive cells using flow cytometry. S7. FLT3 wild type AML patient blasts were exposed to crenolanib and/or sorafenib at physiologically achievable concentrations (i.e. Crenolanib @ 2 microM and sorafenib @ 5 microM) for 48 hours and apoptosis induction was determined by measuring the percentage of Annexin V-positive cells by gating CD33/CD34 positive population using flow cytometry. * Specific apoptosis (%) was calculated as follow: 100 X (drug-induced apoptosis − spontaneous apoptosis)/(100 − spontaneous apoptosis). S8. Sorafenib-resistan cells Ba/F3-ITD+676/842 were cultured in normoxic (21% oxygen) or hypoxic (1% oxygen) condition in the presence/absence of mesenchymal stem cells (MSC) feeder for 6 hours and phosphorylation levels of FLT3 and its downstream signaling ERK and AKT were determined using Western blotting.
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- 2023
3. Supplemental Figures 1-6 from Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models
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Marina Konopleva, Michael Andreeff, Charles P. Hart, Jorge E. Cortes, James A. Bankson, R. Eric Davis, Joseph R. Marszalek, Pratip K. Bhattacharya, Jaehyuk Lee, Hong Mu, Marina Protopopova, Andrei Volgin, Teresa McQueen, Sergej Konoplev, Helen Ma, Rodrigo Jacamo, Polina Matre, Yue-xi Shi, Hongbo Lu, Karine G. Harutyunyan, Juliana Velez, Niki Zacharias Millward, Marc S. Ramirez, and Juliana Benito
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Supplementary Figure S1. TH-302 has potent antitumor activity in a 3D in vitro co-culture system of leukemia cells and bone marrow-derived mesenchymal stromal cells that recapitulates the multidimensional BM niche Supplementary Figure S2. Hypoxia is present in spheroids as indicated by PIMO positive staining in spheroids incubated with PIMO for 3hr before harvesting Supplementary figure S3. In vitro synergistic activity of TH-302 in combination with chemotherapy and demethylating agents Supplementary Figure S4. TH-302 has anti-leukemia activity in an in vivo primary AML xenograft murine model. Supplementary figure S5. In vitro synergistic activity of TH-302 in combination with sorafenib Supplementary figure S6 A, B. Assessment of BM hypoxia in AML/ETO bearing mice treated with TH-302 or chemotherapy
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- 2023
4. Supplemental Methods and Tables from Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models
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Marina Konopleva, Michael Andreeff, Charles P. Hart, Jorge E. Cortes, James A. Bankson, R. Eric Davis, Joseph R. Marszalek, Pratip K. Bhattacharya, Jaehyuk Lee, Hong Mu, Marina Protopopova, Andrei Volgin, Teresa McQueen, Sergej Konoplev, Helen Ma, Rodrigo Jacamo, Polina Matre, Yue-xi Shi, Hongbo Lu, Karine G. Harutyunyan, Juliana Velez, Niki Zacharias Millward, Marc S. Ramirez, and Juliana Benito
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Supplemental Methods and Tables 1) mRNA Hybridization and Gene-expression Profiling. 2) Gene expression analysis by Nanostring technology. 3) Hyperpolarized Magnetic Resonance Spectroscopy. 4) In Vitro 1-13C Pyruvic Acid Feeding Studies and High Resolution Nuclear Magnetic Resonance (NMR) Experiments 5) Three-dimensional spheroids 6) Murine tumor models 7) Immunohistochemistry Supplementary Table S1. Cell line characteristics Supplementary Table S2. Patient characteristics Supplemental Table S3. List of upregulated DEPs in hypoxia. Supplemental Table S4. 1-13C pyruvate uptake and 1-13C lactate production in cell culture. Supplemental Table S5. TH-302 cytotoxic activity against leukemia cell lines
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- 2023
5. Data from Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models
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Marina Konopleva, Michael Andreeff, Charles P. Hart, Jorge E. Cortes, James A. Bankson, R. Eric Davis, Joseph R. Marszalek, Pratip K. Bhattacharya, Jaehyuk Lee, Hong Mu, Marina Protopopova, Andrei Volgin, Teresa McQueen, Sergej Konoplev, Helen Ma, Rodrigo Jacamo, Polina Matre, Yue-xi Shi, Hongbo Lu, Karine G. Harutyunyan, Juliana Velez, Niki Zacharias Millward, Marc S. Ramirez, and Juliana Benito
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Purpose: To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models.Experimental Design: Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models.Results: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a “hypoxia index” compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo. In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells.Conclusions: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. Clin Cancer Res; 22(7); 1687–98. ©2015 AACR.
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- 2023
6. Supplemental Figure 1 from Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Renata Pasqualini, Wadih Arap, Erkki Koivunen, George A. Calin, Jorge E. Cortes, Hagop M. Kantarjian, Susan O'Brien, Amado J. Zurita, Cecilia Rietz, Marina Cardó-Vila, Wouter H.P. Driessen, Akihiko Kuniyasu, Yan Sun, Laura Bover, Carlos Bueso-Ramos, Diana E. Jaalouk, and Katja Karjalainen
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Supplemental Figure 1. Cell surface expression of IL-11R in AML patient derived samples and hematopoietic cells from healthy bone marrow as analyzed by flow cytometry.
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- 2023
7. Supplemental Table 1 from Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Renata Pasqualini, Wadih Arap, Erkki Koivunen, George A. Calin, Jorge E. Cortes, Hagop M. Kantarjian, Susan O'Brien, Amado J. Zurita, Cecilia Rietz, Marina Cardó-Vila, Wouter H.P. Driessen, Akihiko Kuniyasu, Yan Sun, Laura Bover, Carlos Bueso-Ramos, Diana E. Jaalouk, and Katja Karjalainen
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Supplemental Table 1. Features of synthesized analogs of BMTP-11 for drug-lead optimization.
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- 2023
8. Data from Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-Risk MDS
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Jorge E. Cortes, Geoffrey Chan, Ashleigh O'Connell, Mirjana Zeremski, A. Douglas Laird, M. Naveed Shaik, Weidong Wendy Ma, Hagop M. Kantarjian, James McCloskey, Jeffrey Lancet, Mark A. Schroeder, Vivian G. Oehler, Wendy Stock, Daniel A. Pollyea, and Michael R. Savona
- Abstract
Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D).Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting.Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294–303. ©2018 AACR.
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- 2023
9. Data from Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Renata Pasqualini, Wadih Arap, Erkki Koivunen, George A. Calin, Jorge E. Cortes, Hagop M. Kantarjian, Susan O'Brien, Amado J. Zurita, Cecilia Rietz, Marina Cardó-Vila, Wouter H.P. Driessen, Akihiko Kuniyasu, Yan Sun, Laura Bover, Carlos Bueso-Ramos, Diana E. Jaalouk, and Katja Karjalainen
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Purpose: The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.Experimental Design and Results: First, we show that the IL11R protein is expressed in a variety of human leukemia– and lymphoma–derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand–receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.Conclusions: These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases. Clin Cancer Res; 21(13); 3041–51. ©2015 AACR.
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- 2023
10. SuppData from Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-Risk MDS
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Jorge E. Cortes, Geoffrey Chan, Ashleigh O'Connell, Mirjana Zeremski, A. Douglas Laird, M. Naveed Shaik, Weidong Wendy Ma, Hagop M. Kantarjian, James McCloskey, Jeffrey Lancet, Mark A. Schroeder, Vivian G. Oehler, Wendy Stock, Daniel A. Pollyea, and Michael R. Savona
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Additional Methods: MTD determination; Biomarker analyzed Supplementary Table S1. Patient disposition by treatment group Supplementary Table S2. Treatment-related AEs reported in >10% of patients in arm A Supplementary Table S3. Treatment-related AEs reported in in {greater than or equal to}2 patients in arm B Supplementary Table S4. Treatment-related AEs reported in >20% of patients in arm C Supplementary Table S5 Median treatment duration and dose reductions/delays by treatment group Supplementary Table S6. Treatment discontinuations by treatment group Supplementary Table S7. Glasdegib pharmacokinetic parameters at the RP2D Supplementary Table S8. Best overall response in patients with AML by treatment arm Supplementary Table S9. Selected baseline characteristics including gene mutations and response to treatment Supplementary Figure S1. Potential associations of MMP-3 and SDF-1 with response in patients administered glasdegib plus cytarabine/daunorubicin
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- 2023
11. Supplemental Figure 3 from Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Renata Pasqualini, Wadih Arap, Erkki Koivunen, George A. Calin, Jorge E. Cortes, Hagop M. Kantarjian, Susan O'Brien, Amado J. Zurita, Cecilia Rietz, Marina Cardó-Vila, Wouter H.P. Driessen, Akihiko Kuniyasu, Yan Sun, Laura Bover, Carlos Bueso-Ramos, Diana E. Jaalouk, and Katja Karjalainen
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Supplemental Figure 3. Drug activity of BMTP-11 and BMTP#4 on a panel of established leukemia and lymphoma cell lines.
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- 2023
12. Data from Reversal of Acquired Drug Resistance in FLT3-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies
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Michael Andreeff, Abhijit Ramachandran, Farhad Ravandi, Jorge E. Cortes, Gautam Borthakur, Rodrigo O. Jacamo, Ye Chen, Marina Konopleva, Chen Gao, and Weiguo Zhang
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Purpose: FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (FLT3-ITD) mutations are common in patients with acute myeloid leukemia (AML). These patients regularly develop resistance to FLT3 inhibitors suggesting that targeted combination drug strategies are needed to enhance AML therapy efficacy.Experimental Design: Acquired point mutations of FLT3-ITD gene were screened using cDNA-based sequencing approach in vitro sorafenib-resistant cells, which were developed by long-term exposure of Ba/F3-ITD to increasing doses of sorafenib, and in FLT3-ITD mutated AML patients, who developed relapse following sorafenib therapy. Drug effects (e.g., proliferation inhibition, apoptosis induction, and changes in signal transduction protein expression) were assessed in AML cells harboring the point mutations in vitro and in FLT3-ITD–mutated AML patient samples.Results: We identified several acquired point mutations in the tyrosine kinase domains (TKD) of the FLT3 gene in sorafenib-resistant murine leukemia cell line carrying human FLT3-ITD mutations, which were also detected in two of four sorafenib-resistant patient samples. Engineering these point mutations into Ba/F3-ITD cells generated sublines that demonstrated varying degrees of sorafenib [a type II tyrosine kinase inhibitor (TKI)] resistance. A similar pattern of resistance could be observed by exposing these sublines to the other type II TKIs AC220 and MLN518. However, these sublines retained sensitivity to the type I TKIs PKC412 or crenolanib. The combination of crenolanib with sorafenib demonstrated marked cytotoxic effects in all of the sorafenib-resistant sublines.Conclusions: These combination strategies could be clinically important in reversing acquired resistance to FLT3 inhibition in AML. Clin Cancer Res; 20(9); 2363–74. ©2014 AACR.
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- 2023
13. Supplemental Figure Legends from Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Renata Pasqualini, Wadih Arap, Erkki Koivunen, George A. Calin, Jorge E. Cortes, Hagop M. Kantarjian, Susan O'Brien, Amado J. Zurita, Cecilia Rietz, Marina Cardó-Vila, Wouter H.P. Driessen, Akihiko Kuniyasu, Yan Sun, Laura Bover, Carlos Bueso-Ramos, Diana E. Jaalouk, and Katja Karjalainen
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Supplemental Figure Legends
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- 2023
14. Supplemental Figure 2 from Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Renata Pasqualini, Wadih Arap, Erkki Koivunen, George A. Calin, Jorge E. Cortes, Hagop M. Kantarjian, Susan O'Brien, Amado J. Zurita, Cecilia Rietz, Marina Cardó-Vila, Wouter H.P. Driessen, Akihiko Kuniyasu, Yan Sun, Laura Bover, Carlos Bueso-Ramos, Diana E. Jaalouk, and Katja Karjalainen
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Supplemental Figure 2. Cell membrane and cytoplasmic expression of IL-11R.
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- 2023
15. Supplementary Methods and Figures and Table from KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors
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Michael W. Deininger, Brian J. Druker, Jorge E. Cortes, Paul W. Manley, Christopher A. Eide, Tian Y. Zhang, Anthony D. Pomicter, Jamshid S. Khorashad, Anna M. Eiring, Ira L. Kraft, Zhimin Gu, Thomas O'Hare, and Amie S. Corbin
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PDF file, 421K, Supplementary Figure 1: Specificity of imatinib, dasatinib, PPY-A, BAW667, and a SCF-blocking antibody on Mo7ep210BCR-ABL1 cells. Supplementary Figure 2: Comparison of CFU-GM colony formation upon sole BCR-ABL1 inhibition (PPY-A), sole KIT inhibition or dual BCR-ABL1/KIT inhibition. Supplementary Figure 3: Inhibition of KIT in human cells through use of a lentiviral vector for simultaneous expression of shKIT and GFP . Supplementary Figure 4: Analysis of CML CFU-GM colony growth following removal of the individual cytokines. Supplementary Figure 5: BCR-ABL1 and KIT signaling influence activation of AKT associated with a reduction of Foxo3A. Supplementary Table 1. Activity profile of BAW667.
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- 2023
16. Data from KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors
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Michael W. Deininger, Brian J. Druker, Jorge E. Cortes, Paul W. Manley, Christopher A. Eide, Tian Y. Zhang, Anthony D. Pomicter, Jamshid S. Khorashad, Anna M. Eiring, Ira L. Kraft, Zhimin Gu, Thomas O'Hare, and Amie S. Corbin
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Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34+38− cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34+38+ cells, SCF strongly induced pAKTS473 in a phosphoinositide 3-kinase (PI3K)–dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKTS473 levels remained low in CD34+38− cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34+38− compared with CD34+38+ CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells. Cancer Res; 73(18); 5775–86. ©2013 AACR.
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- 2023
17. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study
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Guillermo Garcia-Manero, Marina Konopleva, Sherry Pierce, Michael Andreeff, Farhad Ravandi-Kashani, Tauna Gordon, Naveen Pemmaraju, Graciela M. Nogueras-Gonzalez, Hagop M. Kantarjian, Jorge Blando, Jorge E. Cortes, Jeffrey L. Jorgensen, Carlos E. Bueso-Ramos, Sreyashi Basu, Zainab Al-Hamal, Jing Ning, Prajwal Boddu, Tapan M. Kadia, Naval Daver, Mansour Alfayez, Padmanee Sharma, Courtney D. DiNardo, Wilmer Flores, James P. Allison, Keyur P. Patel, Elias Jabbour, and Steven M. Kornblau
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0301 basic medicine ,medicine.medical_specialty ,Myeloid ,business.industry ,Azacitidine ,Salvage therapy ,Phases of clinical research ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Hypomethylating agent ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Bone marrow ,Nivolumab ,business ,medicine.drug - Abstract
Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22–90) and the median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)–naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. Significance: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305
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- 2019
18. Disruption of Wnt/β-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
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Marina Konopleva, Wenjing Tao, Rongqing Pan, Peter P. Ruvolo, Qifa Liu, Xuejie Jiang, Teresa McQueen, Michael Andreeff, Bing Z. Carter, Jared K. Burks, Steven M. Kornblau, Jorge E. Cortes, Weiguo Zhang, Po Yee Mak, Hong Mu, Duncan H. Mak, Qi Zhang, and Hongsheng Zhou
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0301 basic medicine ,Cancer Research ,Cell signaling ,Cell Survival ,Antineoplastic Agents ,Apoptosis ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,fluids and secretions ,Cell Line, Tumor ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Gene Silencing ,Progenitor cell ,Protein Kinase Inhibitors ,Wnt Signaling Pathway ,Cell Proliferation ,Quizartinib ,Cell growth ,Cell Cycle ,Wnt signaling pathway ,Myeloid leukemia ,Drug Synergism ,hemic and immune systems ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,Protein Transport ,Leukemia ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,Oncology ,chemistry ,Catenin ,Mutation ,embryonic structures ,Neoplastic Stem Cells ,Cancer research ,Female - Abstract
Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro. The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR.
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- 2018
19. Abstract 784: Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML)
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Li-An Xu, Cedric E. Dos Santos, Alexander E. Perl, Nigel H. Russell, Jorge E. Cortes, Hiroyuki Sumi, Derek E. Mires, Alwin Krämer, Mark J. Levis, Ken C. Chang, Flora Berisha, Aziz Benzohra, Yuhu Yan, Giovanni Martinelli, Kazunobu Kato, Samer K. Khaled, Arnaud Lesegretain, Sergey Korkhov, Takeshi Isoyama, Siddhartha Ganguly, and Tobias Günnel
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Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,Myeloid ,business.industry ,Salvage treatment ,Population ,Hazard ratio ,Myeloid leukemia ,Cancer ,Variant allele ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Internal medicine ,medicine ,business ,education ,Quizartinib - Abstract
Introduction: We evaluated the impact of baseline (BL) co-mutations and FLT3-ITD VAF on overall survival (OS) and response (composite complete remission [CRc]) to quizartinib and SC in the phase III QuANTUM-R trial. Methods: We analyzed 37 recurrently mutated genes in AML in BL samples from 304 patients (pts) (83% of ITT population) with R/R FLT3-ITD-positive AML using next-generation sequencing and a customized Archer® Core Myeloid panel. Positive mutation status was defined as ≥1 mutation detected in the gene region using a VAF cutoff of 2.7%. FLT3-ITD VAF was measured by the Navigate BioPharma FLT3 Mutation Assay (polymerase chain reaction-based, VAF cutoff of 3%). Low and high FLT3-ITD VAF were defined as ≤25% and >25%, respectively. Results: In addition to FLT3-ITD, the prevalence of key BL co-mutations were 59.9% for DNMT3Amut and 55.3% for NPM1mut. Pts with DNMT3Amut treated with quizartinib had significantly longer OS vs SC (6.3 and 5.4 mos, respectively; hazard ratio [HR], 0.652), p Conclusions: Key co-mutations identified here potentially affect treatment response and OS with quizartinib vs SC. Our results suggest that molecular subsets of R/R AML pts may particularly derive clinical benefit from quizartinib. TableCRc, %Median OS, monthsQuizartinibSCQuizartinibSCHR95% CIITT Population (N = 367)a48276.24.70.760.58-0.98Single Gene Analyses (n = 304)bDNMT3Amut (n = 182)52376.35.40.6520.44-0.97DNMT3Awt (n = 122)40246.04.60.8490.53-1.37NPM1mut (n = 168)48395.14.70.9540.63-1.44NPM1wt (n = 136)47218.55.10.4850.31-0.76TET2mut (n = 98)34326.22.90.6640.38-1.16TET2wt (n = 206)54306.35.40.7280.51-1.05CEBPAmut (n = 46)44428.58.71.9220.80-4.62CEBPAwt (n = 258)48296.24.50.6130.45-0.84IDH1/2mut (n = 49)32275.53.70.4270.20-0.92IDH1/2wt (n = 255)51316.55.10.750.54-1.04Double Gene Analyses (n = 304)NPM1wt/DNMT3Amut (n = 44)61279.04.50.2390.09-0.61NPM1mut/DNMT3Amut (n = 138)50405.45.40.8370.52-1.34FLT3-ITD VAF AnalysesFLT3-ITD high VAF50195.53.90.6890.51-0.93FLT3-ITD low VAF43467.96.10.8570.53-1.40FLT3-ITD VAF Analyses in Selected MutationsDNMT3Amut high VAF53215.82.70.6260.40-0.98DNMT3Amut low VAF526910.26.40.7370.36-1.51NPM1wt/DNMT3Amut high VAF6409.01.50.01790.002-0.16NPM1wt/DNMT3Amut low VAF555011.36.20.3720.11-1.23aN = 367; quizartinib, n = 245; SC, n = 122bBaseline bone marrow samples were available and viable from 304 of 367 pts in the ITT population Citation Format: Alexander E. Perl, Jorge E. Cortes, Siddhartha Ganguly, Samer K. Khaled, Alwin Krämer, Giovanni Martinelli, Nigel H. Russell, Ken C. Chang, Kazunobu Kato, Yuhu Yan, Li-An Xu, Sergey Korkhov, Tobias Günnel, Hiroyuki Sumi, Arnaud Lesegretain, Flora Berisha, Derek Mires, Aziz Benzohra, Takeshi Isoyama, Cedric Dos Santos, Mark J. Levis. Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 784.
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- 2020
20. Reversal of Acquired Drug Resistance in FLT3-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies
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Marina Konopleva, Gautam Borthakur, Ye Chen, Jorge E. Cortes, Farhad Ravandi, Weiguo Zhang, Chen Gao, Michael Andreeff, Abhijit Ramachandran, and Rodrigo Jacamo
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Niacinamide ,Sorafenib ,Cancer Research ,Cell Survival ,medicine.drug_class ,DNA Mutational Analysis ,Antineoplastic Agents ,Apoptosis ,Drug resistance ,Biology ,Pharmacology ,Article ,Tyrosine-kinase inhibitor ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,Gene Duplication ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Point Mutation ,Protein Interaction Domains and Motifs ,Protein Kinase Inhibitors ,neoplasms ,Dose-Response Relationship, Drug ,Phenylurea Compounds ,Point mutation ,Membrane Proteins ,Myeloid leukemia ,Drug Synergism ,Leukemia, Myeloid, Acute ,fms-Like Tyrosine Kinase 3 ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Tandem Repeat Sequences ,Mutation ,Fms-Like Tyrosine Kinase 3 ,Cancer research ,Tyrosine kinase ,Signal Transduction ,medicine.drug ,Crenolanib - Abstract
Purpose: FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (FLT3-ITD) mutations are common in patients with acute myeloid leukemia (AML). These patients regularly develop resistance to FLT3 inhibitors suggesting that targeted combination drug strategies are needed to enhance AML therapy efficacy. Experimental Design: Acquired point mutations of FLT3-ITD gene were screened using cDNA-based sequencing approach in vitro sorafenib-resistant cells, which were developed by long-term exposure of Ba/F3-ITD to increasing doses of sorafenib, and in FLT3-ITD mutated AML patients, who developed relapse following sorafenib therapy. Drug effects (e.g., proliferation inhibition, apoptosis induction, and changes in signal transduction protein expression) were assessed in AML cells harboring the point mutations in vitro and in FLT3-ITD–mutated AML patient samples. Results: We identified several acquired point mutations in the tyrosine kinase domains (TKD) of the FLT3 gene in sorafenib-resistant murine leukemia cell line carrying human FLT3-ITD mutations, which were also detected in two of four sorafenib-resistant patient samples. Engineering these point mutations into Ba/F3-ITD cells generated sublines that demonstrated varying degrees of sorafenib [a type II tyrosine kinase inhibitor (TKI)] resistance. A similar pattern of resistance could be observed by exposing these sublines to the other type II TKIs AC220 and MLN518. However, these sublines retained sensitivity to the type I TKIs PKC412 or crenolanib. The combination of crenolanib with sorafenib demonstrated marked cytotoxic effects in all of the sorafenib-resistant sublines. Conclusions: These combination strategies could be clinically important in reversing acquired resistance to FLT3 inhibition in AML. Clin Cancer Res; 20(9); 2363–74. ©2014 AACR.
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- 2014
21. Abstract CT184: Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial
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Alexander E. Perl, Richard A. Larson, Nikolai A. Podoltsev, Stefania Paolini, Antonio Di Stasi, Wen-Chien Chou, Amir T. Fathi, Andreas Neubauer, Margaret Kasner, Xuan Liu, Francesco Fabbiano, Giovanni Martinelli, Celalettin Ustun, Timothy S. Pardee, Sung-Soo Yoon, Mark J. Levis, Maria R. Baer, Je-Hwan Lee, Ellin Berman, Pau Montesinos, Hisayuki Yokoyama, Christian Recher, Chaofeng Liu, Fabio Ciceri, Erkut Bahceci, Robert K. Stuart, Rebecca L. Olin, Jorge E. Cortes, and Naoko Hosono
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Cancer Research ,medicine.medical_specialty ,Population ,Salvage therapy ,01 natural sciences ,Gastroenterology ,010104 statistics & probability ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Idarubicin ,030212 general & internal medicine ,Midostaurin ,0101 mathematics ,education ,education.field_of_study ,business.industry ,Induction chemotherapy ,medicine.disease ,Fludarabine ,Oncology ,chemistry ,Cytarabine ,business ,Febrile neutropenia ,medicine.drug - Abstract
Introduction: Gilteritinib is a potent/selective oral inhibitor of FMS-like tyrosine kinase 3 (FLT3). Based upon interim analysis response rates from the ADMIRAL Phase III study of gilteritinib vs salvage chemotherapy (SC) in patients (pts) with R/R FLT3mut+ AML (NCT02421939), gilteritinib became the first FLT3 inhibitor approved as single agent therapy in this population. Here we present the final results of this pivotal trial. Methods: Adults with confirmed FLT3mut+ AML (FLT3-ITD and/or FLT3-TKD D835 or I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive continuous 28-day cycles of 120 mg/day gilteritinib or pre-randomization selected SC: low-dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA). Prior FLT3 inhibitor use, other than midostaurin or sorafenib, was excluded. Overall survival (OS) and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary endpoints. Secondary endpoints were event-free survival (EFS) and CR rate; safety/tolerability was also examined. Results: A total of 371 pts were randomized: 247 to gilteritinib and 124 to SC (MEC, 25.7%; FLAG-IDA, 36.7%; LoDAC, 14.7%; AZA, 22.9%). Median age was 62 years (range, 19-85). Baseline FLT3 mutations were: FLT3-ITD, 88.4%; FLT3-TKD, 8.4%; both FLT3-ITD and FLT3-TKD, 1.9%; unconfirmed, 1.3%. Overall, 39.4% of pts had refractory AML and 60.6% had relapsed AML. Patients randomized to gilteritinib had significantly longer OS (9.3 months) than SC (5.6 months; hazard ratio [HR] for death = 0.637; P=0.0007); 1-year survival rates were 37.1% and 16.7%, respectively. The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively (P=0.0001); CR rates were 21.1% and 10.5% (2-sided P=0.0106). Median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively (HR 0.793, P=0.0830). Common adverse events (AEs) in all randomized pts were febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Common grade ≥3 AEs related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%). Adjusted for exposure duration, serious treatment-emergent AEs per patient year were less common with gilteritinib (7.1%) than SC (9.2%). Conclusions: In patients with R/R FLT3mut+ AML, the potent, selective FLT3 inhibitor gilteritinib resulted in significantly longer OS and higher response rates compared with chemotherapy and had a favorable safety profile. These results change the treatment paradigm for salvage therapy of R/R FLT3mut+ AML and establish gilteritinib as the new standard of care. Citation Format: Alexander E. Perl, Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Stefania Paolini, Pau Montesinos, Maria R. Baer, Richard A. Larson, Celalettin Ustun, Francesco Fabbiano, Antonio Di Stasi, Robert Stuart, Rebecca Olin, Margaret Kasner, Fabio Ciceri, Wen-Chien Chou, Nikolai Podoltsev, Christian Recher, Hisayuki Yokoyama, Naoko Hosono, Sung-Soo Yoon, Je-Hwan Lee, Timothy Pardee, Amir T. Fathi, Chaofeng Liu, Xuan Liu, Erkut Bahceci, Mark J. Levis. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT184.
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- 2019
22. Abstract CT102: Phase Ib safety, preliminary anti-leukemic activity and biomarker analysis of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory acute myeloid leukemia
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Amer M. Zeidan, Pamela S. Becker, Maya Ridinger, Tara L. Lin, Michaela L. Tsai, Mark G. Erlander, Prapti A. Patel, Alexander I. Spira, Jorge E. Cortes, Sandra L Silberman, and Gary J. Schiller
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Decitabine ,Myeloid leukemia ,Cancer ,medicine.disease ,01 natural sciences ,010104 statistics & probability ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Pharmacodynamics ,medicine ,Cytarabine ,Biomarker (medicine) ,030212 general & internal medicine ,0101 mathematics ,Adverse effect ,business ,medicine.drug - Abstract
Background: Despite recent advances in the understanding of the biology and development of new agents for patients with acute myeloid leukemia (AML), prognosis remains poor with most patients (pts) succumbing to their disease. PLK1 is a serine/threonine kinase, a master regulator of cell-cycle progression, and is overexpressed in numerous cancer types including AML. Onvansertib is a third generation, orally active and highly selective PLK1 inhibitor with a ~24-hour half-life that demonstrates activity in preclinical AML models both as a single agent and in combination with low-dose cytarabine (LDAC). A Phase I study showed that Onvansertib was well tolerated in pts with solid tumors. Methods: The goal of this Phase Ib (NCT03303339) study is to test the safety of Onvansertib in combination with either LDAC or Decitabine in relapsed or refractory AML. Efficacy, pharmacokinetics and pharmacodynamics of the combination are secondary endpoints. Pts are treated with Onvasertib for 5 days in combination with either LDAC (20 mg/m2 SC qd x 10d) or Decitabine (20 mg/m2 IV qd x 5d) over a flexible 21 to 28-day cycle, with the next cycle initiated based on recovery of cell counts. Each arm follows a standard dose escalation design with 50% increments in successive cohorts of 3 pts. Dose limiting toxicity (DLT) is evaluated during the 1stcycle. As of January 2, 2019, 21 pts have enrolled. The starting dose of Onvansertib was 12mg/m2 and was escalated to 18, 27 and 40mg/m2 in subsequent cohorts. In both arms, no treatment-related serious adverse events and deaths or DLTs occurred at the first 3 doses and treatment at 40mg/m2 is ongoing. Additional objectives include pharmacokinetics, preliminary anti-leukemic activity and correlative biomarker and pharmacodynamics analyses. Assessment of PLK1 inhibition is being determined in pts by changes in phosphorylation status of the translationally controlled tumor protein (TCTP), which is a PLK1 substrate, and is being evaluated not only in terms of response to treatment, but also as a potentially identifiable marker ex vivo for pts that may be more responsive to therapy. Genomic and gene expression analysis are assessed to identify biomarkers that may also be associated with response to treatment. Citation Format: Amer M. Zeidan, Pamela Becker, Alexander I. Spira, Prapti A. Patel, Gary J. Schiller, Michaela L. Tsai, Tara L. Lin, Maya Ridinger, Mark Erlander, Sandra L. Silberman, Jorge E. Cortes. Phase Ib safety, preliminary anti-leukemic activity and biomarker analysis of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT102.
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- 2019
23. Abstract LB-009: Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or nonintensive chemotherapy in patients with acute myeloid leukemia (AML)
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Michael Heuser, Keith A. Ching, Jorge E. Cortes, Panpan Wang, Jillian G. Johnson, Catriona Jamieson, Geoffrey Chan, Akil Merchant, and Thomas O’Brien
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Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Cancer ,Myeloid leukemia ,Gene mutation ,medicine.disease ,Cytokine ,Internal medicine ,medicine ,FOXM1 ,Cytarabine ,B-cell activating factor ,business ,medicine.drug - Abstract
Background: The Smoothened inhibitor glasdegib (GLAS) was recently approved in combination with low-dose cytarabine (LDAC) in adults with AML when intensive chemotherapy is not an option. GLAS in combination with intensive chemotherapy has also been well tolerated and shown clinical activity, and is undergoing further evaluation. This analysis aimed to identify molecular drivers that predict overall response (OR) and OS with GLAS. Materials and Methods: We included AML patients receiving LDAC alone or with GLAS 100 mg QD (nonintensive arm) or GLAS 100 mg QD & 7+3 (intensive arm) from Phases 1b and 2 of a multicenter study (NCT01546038). We assessed correlation of OS/OR with mRNA expression of 19 genes, expression levels of 38 cytokines, and mutations in 109 genes. For correlation analyses, a cut-off < or ≥ the median was used for gene expression and cytokine levels and mutated or not for gene mutations. Results: Within the nonintensive arm (LDAC + GLAS, n=68; LDAC, n=30), improved OS with GLAS + LDAC correlated with lower FOXM1 and MSI2, and higher BCL2 and CCND2 expression. For cytokines, lower levels of 6CKINE, BAFF, ICAM-1, MIP-1α, MIP-1β and MMP-3 correlated with improved OS. The low number of responders in the LDAC arm (n=2) prevented correlation analysis of mRNA or cytokines; however, within the LDAC + GLAS arm, OR correlated with high PTCH1 levels, and high EOTAXIN but low BAFF levels. In the intensive arm (GLAS & 7+3, n=59), higher PTCH1 expression correlated with improved OS (median OS 10.8 vs 39.5 months) but no significant correlations were found with OR; no cytokines correlated with OS or with OR. For gene mutation, in the nonintensive arm (LDAC + GLAS, n=65; LDAC alone, n=25), OS differed with PLEKHH1 and STAG2 mutation status, but no genes correlated with OR. In the intensive arm (n=55), mutations in FLT3, TP53, CEP170, PHF6, and ANKRD26 correlated with OS. Patients in this arm with FLT3 mutations (including ITD) responded better vs wild type FLT3 (median OS 13.4 months vs unreached for FLT3 mutant). We also examined mRNA expression and cytokine levels at various times after starting treatment: statistically significant changes included modulation of SMO, BDNF, ITAC, and IL-23 levels in the nonintensive arm, and SMO, MYCN, CDKN1A, and a number of cytokines including IL-8, TNF-α and IL-5 in the intensive arm. Conclusions: In this analysis, expression levels of a select number of genes and circulating cytokines implicated in AML appear to correlate with OS and OR. The improved response with FLT3 mutations and high PTCH1 expression levels in the intensive arm, along with the analysis appearing to indicate modulation of select genes (eg SMO) and cytokines in both arms while on treatment, deserves further investigation. These preliminary findings will need to be verified in larger randomized trials, which are on-going. Citation Format: Akil Merchant, Catriona Jamieson, Michael Heuser, Geoffrey Chan, Panpan Wang, Keith A. Ching, Jillian Johnson, Thomas O’Brien, Jorge E. Cortes. Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or nonintensive chemotherapy in patients with acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-009.
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- 2019
24. KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors
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Jamshid S. Khorashad, Christopher A. Eide, Amie S. Corbin, Tian Y. Zhang, Ira L. Kraft, Brian J. Druker, Anna M. Eiring, Paul W. Manley, Michael W. Deininger, Zhimin Gu, Anthony D. Pomicter, Thomas O'Hare, and Jorge E. Cortes
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Cancer Research ,Stromal cell ,Cellular differentiation ,Blotting, Western ,Fusion Proteins, bcr-abl ,CD34 ,Fluorescent Antibody Technique ,Antigens, CD34 ,Apoptosis ,Stem cell factor ,Biology ,Real-Time Polymerase Chain Reaction ,Piperazines ,Article ,Mice ,Phosphatidylinositol 3-Kinases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,RNA, Messenger ,Progenitor cell ,Protein Kinase Inhibitors ,Cell Proliferation ,Phosphoinositide-3 Kinase Inhibitors ,Stem Cell Factor ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Differentiation ,Imatinib ,Flow Cytometry ,medicine.disease ,Molecular biology ,Proto-Oncogene Proteins c-kit ,Pyrimidines ,Oncology ,Drug Resistance, Neoplasm ,Benzamides ,Imatinib Mesylate ,Neoplastic Stem Cells ,Cancer research ,Stromal Cells ,Tyrosine kinase ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34+38− cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34+38+ cells, SCF strongly induced pAKTS473 in a phosphoinositide 3-kinase (PI3K)–dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKTS473 levels remained low in CD34+38− cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34+38− compared with CD34+38+ CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells. Cancer Res; 73(18); 5775–86. ©2013 AACR.
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- 2013
25. Abstract 16: Genomic landscape of adult mixed phenotype acute leukemia (MPAL)
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Marina Konopleva, Latasha Little, Rebecca Thornton, Guillermo Garcia-Manero, Xingzhi Song, Marisela Mendoza, Koichi Takahashi, Samantha Tippen, Carlos E. Bueso-Ramos, Michael Andreeff, Abdallah Abou Zahr, Farhad Ravandi, Marcus Coyle, Feng Wang, Andrew Futreal, Elias Jabbour, Steven M. Kornblau, Courtney D. DiNardo, Kiyomi Morita, Hagop M. Kantarjian, Chang-Jiu Wu, Jianhua Zhang, Curtis Gumbs, Keyur P. Patel, and Jorge E. Cortes
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Cancer Research ,Mixed phenotype acute leukemia ,Oncology ,Cancer research ,Biology - Abstract
Background: Mixed phenotype acute leukemia (MPAL) is a rare subgroup of acute leukemia characterized by blasts that express antigens of both myeloid and lymphoid lineage to such a degree that it is not possible to assign the leukemia to any one lineage with certainty. MPAL poses both diagnostic and therapeutic challenges in clinic and has a poor prognosis. The genetic basis of MPAL is not well studied. Aim: Our aim in this study is to perform comprehensive molecular characterization of adult MPAL and lay the groundwork for future personalized therapy in MPAL. Methods: We studied 31 patients with adult MPAL (median age 53) that met 2008 WHO classification criteria. Pretreatment bone marrow samples were studied by targeted capture exome sequencing of 295 genes that are recurrently mutated in hematologic malignancies (median 393x coverage, N = 31), RNA sequencing (N = 24), and Infinium methylation EPIC array (Illumina, N = 31). Mutational landscape was compared to that of 194 AML, 71 B-ALL, and 6 T-ALL cases of which pretreatment samples were sequenced internally with the same platform. Promoter CpG methylation pattern was compared to the data from 194 AML (data derived from The Cancer Genome Atlas Project), 505 B-ALL and 101 T-ALL cases (data shared by Nordlund et al. Genome Biology 2013). Copy number variation was inferred from methylation array data. Results: Of the 31 MPAL cases, 18 (58%) had myeloid-T and 13 (42%) had myeloid-B phenotype. Four cases had Philadelphia chromosome (Ph), 1 had 11q23 abnormality, and 8 cases had complex karyotype. MPAL had similar numbers of mutations (median 2 [range: 0-6]) with AML (median 3 [range: 0-7], P = 0.79) or T-ALL (median 3 [range: 1-4], P = 0.92) but had significantly higher number of mutations than B-ALL (median 0 [range: 0-4]). Both AML-type and ALL-type mutations were detected in MPAL, which is consistent with the mixed immunophenotypic features. However, NPM1 mutation was specific to AML and was not found in MPAL cases. Myeloid-T and myeloid-B showed distinct patterns of somatic mutations, in which mutations in DNMT3A, IDH2, NOTCH1, IL7R, and FBXW7 were enriched in myeloid-T whereas RUNX1 mutations were enriched in myeloid-B. Myeloid-T and myeloid-B showed distinct patterns of promoter CpG methylation. Overall, myeloid-T had more hypermethylated CpG loci than myeloid-B in all different CpG locations (island, shore, shelf, and others). Genes that are essential in T-cell receptor (TCR) signaling (CD3D, CD7, CD247, LCK, PRKCQ, CCR9, and TCL1A) were differentially methylated and consequently differentially expressed between myeloid-T and myeloid-B. RNA sequencing revealed several known translocations such as NSD1-NUP98, and KMT2A-MLLT4, in addition to the novel translocations such as FOXP1-DNAJC15, FLI1-IFT46, and ITPR2-ARID5B. Unsupervised hierarchical clustering of all MPAL, AML, B-ALL and T-ALL by promoter CpG methylation pattern revealed that myeloid-T consistently showed similar methylation pattern with T-ALL, while myeloid-B showed random similarity with either B-ALL or AML. Conclusion: MPAL is a genetically heterogeneous disease and myeloid-T and myeloid-B shows distinct patterns of mutation landscapes, methylation, and gene expressions. Genomic classification of MPAL may provide a clue to personalization of therapy for MPAL. Citation Format: Koichi Takahashi, Feng Wang, Kiyomi Morita, Keyur Patel, Carlos Bueso-Ramos, Abdallah Abou Zahr, Curtis Gumbs, Latasha Little, Samantha Tippen, Rebecca Thornton, Marcus Coyle, Jianhua Zhang, Xingzhi Song, Marisela Mendoza, Chang-Jiu Wu, Steven Kornblau, Courtney DiNardo, Guillermo Garcia-Manero, Elias Jabbour, Michael Andreeff, Farhad Ravandi, Hagop Kantarjian, Jorge Cortes, Marina Konopleva, Andrew Futreal. Genomic landscape of adult mixed phenotype acute leukemia (MPAL) [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 16.
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- 2017
26. Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells
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Wendy D. Schober, Duncan H. Mak, Wenjing Chen, Hagop M. Kantarjian, Jorge E. Cortes, Michael Andreeff, Marina Konopleva, and Bing Z. Carter
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Cancer Research ,CD34 ,Imatinib ,Biology ,Triptolide ,medicine.disease ,chemistry.chemical_compound ,Imatinib mesylate ,Oncology ,chemistry ,hemic and lymphatic diseases ,medicine ,Cancer research ,Stem cell ,Progenitor cell ,neoplasms ,medicine.drug ,K562 cells ,Chronic myelogenous leukemia - Abstract
The advent of Bcr-Abl tyrosine kinase inhibitors (TKI) has revolutionized the treatment of chronic myelogenous leukemia (CML). However, resistance evolves due to BCR-ABL mutations and other mechanisms. Furthermore, patients with blast crisis CML are less responsive and quiescent CML stem cells are insensitive to these inhibitors. We found that triptolide, a diterpenoid, at nanomolar concentrations, promoted equally significant death of KBM5 cells, a cell line derived from a Bcr-Abl–bearing blast crisis CML patient and KBM5STI571 cells, an imatinib-resistant KBM5 subline bearing the T315I mutation. Similarly, Ba/F3 cells harboring mutated BCR-ABL were as sensitive as Ba/F3Bcr-Ablp210wt cells to triptolide. Importantly, triptolide induced apoptosis in primary samples from blast crisis CML patients, who showed resistance to Bcr-Abl TKIs in vivo, with less toxicity to normal cells. Triptolide decreased X-linked inhibitor of apoptosis protein, Mcl-1, and Bcr-Abl protein levels in K562, KBM5, and KBM5STI571 cells and in cells from blast crisis CML patients. It sensitized KBM5, but not KBM5STI571, cells to imatinib. More importantly, triptolide also induced death of quiescent CD34+ CML progenitor cells, a major problem in the therapy of CML with TKIs. Collectively, these results suggest that triptolide potently induces blast crisis CML cell death independent of the cellular responses to Bcr-Abl TKIs, suggesting that triptolide could eradicate residual quiescent CML progenitor cells in TKI-treated patients and benefit TKI-resistant blast crisis CML patients. [Mol Cancer Ther 2009;8(9):2509–16]
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- 2009
27. Proteasome Enzymatic Activities in Plasma as Risk Stratification of Patients with Acute Myeloid Leukemia and Advanced-Stage Myelodysplastic Syndrome
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Elihu H. Estey, Wanlong Ma, Benjamin N. Bekele, Hagop M. Kantarjian, Zhong J. Zhang, Maher Albitar, Jorge E. Cortes, Amber C. Donahue, Zeev Estrov, Francis J. Giles, Susan O'Brien, Xi Zhang, and Michael J. Keating
- Subjects
Adult ,Male ,Oncology ,Proteasome Endopeptidase Complex ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Biology ,Article ,Young Adult ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Chymotrypsin ,Humans ,Trypsin ,Risk factor ,Survival analysis ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Proportional hazards model ,Beta-2 microglobulin ,Myelodysplastic syndromes ,Cancer ,Myeloid leukemia ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Leukemia, Myeloid ,Caspases ,Myelodysplastic Syndromes ,Acute Disease ,Multivariate Analysis ,Immunology ,Biomarker (medicine) ,Female - Abstract
Purpose: Cytogenetic abnormalities are currently the most important predictors of response and clinical outcome for patients with acute myeloid leukemia (AML) or advanced-stage myelodysplastic syndrome (MDS). Because clinical outcomes vary markedly within cytogenetic subgroups, additional biological markers are needed for risk stratification. Experimental Design: We assessed the utility of measuring pretreatment proteasome chymotrypsin-like, caspase-like, and trypsin-like activities in plasma to predict response and survival of patients with AML (n = 174) or advanced-stage MDS (n = 52). Results: All three enzymatic activities were significantly (P < 0.001) increased in the plasma of patients with AML and MDS compared with normal controls. Both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, correlated with outcome. Chymotrypsin-like and caspase-like activities, but not trypsin-like activity, predicted response in univariate analysis (P = 0.002). However, only chymotrypsin-like activity was independent predictor of response from age grouping ( Conclusions: Measuring plasma chymotrypsin-like activity may provide a powerful biomarker for risk stratification in patients with AML and advanced-stage MDS, including those with normal karyotype.
- Published
- 2009
28. BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations
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Maher Albitar, Hagop M. Kantarjian, Jorge E. Cortes, Tai-Sung Lee, Wanlong Ma, Xi Zhang, and Francis J. Giles
- Subjects
Cancer Research ,ABL ,Alternative splicing ,Imatinib ,Biology ,medicine.disease ,Molecular biology ,Fusion protein ,Frameshift mutation ,Imatinib mesylate ,Oncology ,Protein kinase domain ,hemic and lymphatic diseases ,medicine ,neoplasms ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Rare cases of chronic myelogenous leukemia (CML) express high levels of alternatively spliced BCR-ABL mRNA with a 35-bp insertion (35INS) between ABL kinase domain exons 8 and 9. This insertion results in a frameshift leading to the addition of 10 residues and truncation of 653 residues due to early termination. Sensitive PCR-based testing showed that 32 of 52 (62%) imatinib-resistant CML patients in chronic phase and 8 of 38 (21%) in accelerated or blast crisis expressed varying levels of the alternatively spliced BCR-ABL mRNA. A three-dimensional structural model of the 35INS ABL kinase domain complexed with imatinib was built using homology modeling, followed by molecular dynamics simulations. Simulation results showed that the new residues cause a significant global conformational change, altering imatinib binding in a way similar to that of the T315I mutation and, therefore, providing resistance to imatinib that depends on the level of expression. [Mol Cancer Ther 2008;7(12):3834–41]
- Published
- 2008
29. Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia
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Alfonso Quintás-Cardama and Jorge E. Cortes
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Clinical Trials as Topic ,Cancer Research ,Antineoplastic Agents ,Imatinib ,Protein-Tyrosine Kinases ,Pharmacology ,Biology ,medicine.disease ,Dasatinib ,Leukemia ,Myelogenous ,Oncology ,Nilotinib ,Drug Resistance, Neoplasm ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Mutation ,medicine ,Humans ,Kinase activity ,Protein Kinase Inhibitors ,Tyrosine kinase ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of resistance continues to challenge the treatment of this disease. Mutations within the kinase domain of BCR-ABL1 constitute the most frequent mechanism of resistance in patients with chronic myelogenous leukemia treated with imatinib or the second generation tyrosine kinase inhibitors nilotinib and dasatinib. Of particular concern is the substitution of the threonine residue at the highly conserved gatekeeper residue 315 with a bulkier hydrophobic isoleucine amino acid. This mutation causes steric hindrance precluding the access ATP-competitive inhibitors to the ATP-binding pocket. To expedite the identification of strategies to override the resistance imposed by the T315I mutation, several strategies have been pursued, including the exploitation of BCR-ABL1 kinase sites distant from the ATP-binding pocket to cripple the kinase activity of the enzyme and inhibiting signaling pathways downstream from BCR-ABL1. Recent insights gained regarding the structural biology of T315I have led to the development of a variety of compounds against this mutant. We herein summarize the most clinically promising anti-T315I therapies.
- Published
- 2008
30. Phase II Study of Dasatinib in Philadelphia Chromosome–Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis
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Guillermo Garcia-Manero, Deborah A. Thomas, Cem Akin, Animesh Pardanani, Hagop M. Kantarjian, Srdan Verstovsek, Jorge E. Cortes, Susan O'Brien, Stefan Faderl, Ayalew Tefferi, and Taghi Manshouri
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Dasatinib ,Antineoplastic Agents ,Philadelphia chromosome ,Article ,Mastocytosis, Systemic ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Philadelphia Chromosome ,Systemic mastocytosis ,Aged ,business.industry ,Myelodysplastic syndromes ,Remission Induction ,Myeloid leukemia ,Imatinib ,Middle Aged ,medicine.disease ,Mast cell leukemia ,Leukemia, Myeloid, Acute ,Thiazoles ,Leukemia ,Pyrimidines ,Treatment Outcome ,Immunology ,Female ,business ,medicine.drug - Abstract
Purpose: Molecular characterization of Philadelphia chromosome–negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and platelet-derived growth factor receptor β TKs, and is active against cells carrying the mutant KIT-D816V gene. Experimental Design: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph− myeloid disorders, including SM (n = 33; 28 KIT-D816V positive). Results: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. Conclusion: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.
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- 2008
31. The Prognostic Significance of Serum β2 Microglobulin Levels in Acute Myeloid Leukemia and Prognostic Scores Predicting Survival: Analysis of 1,180 Patients
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Sherry Pierce, Emil J. Freireich, Elihu H. Estey, Michael J. Keating, Hagop M. Kantarjian, Charles Koller, Jorge E. Cortes, Apostolia Maria Tsimberidou, William G. Wierda, Sijin Wen, Susan O'Brien, and Mark Brandt
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Fluorodeoxyglucose F18 ,Predictive Value of Tests ,Internal medicine ,Remission Induction Therapy ,Biomarkers, Tumor ,medicine ,Humans ,Survival analysis ,Aged ,Retrospective Studies ,Performance status ,business.industry ,Beta-2 microglobulin ,Myeloid leukemia ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Leukemia, Myeloid, Acute ,ROC Curve ,Positron-Emission Tomography ,Multivariate Analysis ,Immunology ,Cytarabine ,Tomography, X-Ray Computed ,beta 2-Microglobulin ,business ,medicine.drug - Abstract
Purpose: Serum β2 microglobulin (β2M) is prognostic in other hematologic malignancies; therefore, we evaluated its prognostic significance in acute myeloid leukemia (AML).Experimental Design: Multivariate analyses were used to examine the effect of pretreatment serum β2M levels on clinical outcomes in patients with AML. β2M was associated with poorer survival in older but not younger patients. We thus fit separate Cox survival models in patients above and below age 60 years treated with remission induction therapy containing high-dose cytarabine (n = 1,280). In each age group, 50% of the patients were used to develop the model, which was tested in the other 50%. Resampling methods were also used to validate the independent prognostic significance of covariates.Results: In patients 60 years or older (n = 591), poorer risk cytogenetics; poorer performance status; and higher levels of β2M, uric acid, and lactate dehydrogenase were each found to independently predict shorter survival and formed the basis of a scoring system. A similar approach was used in patients younger than 60 years (n = 589), with poorer risk cytogenetics, poorer performance status, older age, higher hemoglobin level, and higher leukocyte count predicting a shorter survival and forming the basis of the scoring system. Higher β2M levels were an adverse independent factor for response, survival, relapse-free survival, and event-free survival in older but not in younger patients.Conclusions: Serum β2M levels can help predict outcome in patients ≥60 years with untreated AML, and their use is strongly encouraged.
- Published
- 2008
32. A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic Malignancies
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Glen Laird, Farhad Ravandi, Patricia Rae, Margaret Dugan, Eric Masson, Thomas Fischer, Joachim Beck, Francis J. Giles, Guillermo Garcia-Manero, Sunil Sharma, Hagop M. Kantarjian, Jorge E. Cortes, Maher Albitar, and Kapil N. Bhalla
- Subjects
Adult ,Cancer Research ,Indoles ,Maximum Tolerated Dose ,medicine.drug_class ,Apoptosis ,Pharmacology ,Hydroxamic Acids ,Drug Administration Schedule ,Histones ,Structure-Activity Relationship ,chemistry.chemical_compound ,Predictive Value of Tests ,Panobinostat ,Acute lymphocytic leukemia ,Biomarkers, Tumor ,medicine ,Humans ,Enzyme Inhibitors ,Aged ,Cell Proliferation ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Histone deacetylase inhibitor ,Area under the curve ,QTcF Prolongation ,Myeloid leukemia ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Hypokalemia ,Histone Deacetylase Inhibitors ,Leukemia ,Treatment Outcome ,Oncology ,chemistry ,Cinnamates ,Leukemia, Myeloid ,Myelodysplastic Syndromes ,Acute Disease ,Injections, Intravenous ,Immunology ,medicine.symptom ,business ,Follow-Up Studies - Abstract
Purpose: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle. Experimental Design: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m2): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasma LBH589 concentrations were assayed. Results: Four dose-limiting toxicities (grade 3 QTcF prolongation) were observed, four at 14.0 mg/m2 and one at 11.5 mg/m2. QTcF prolongation was asymptomatic and reversed on LBH589 discontinuation. Other potentially LBH589-related toxicities included nausea (40%), diarrhea (33%), vomiting (33%), hypokalemia (27%), loss of appetite (13%), and thrombocytopenia (13%). In 8 of 11 patients with peripheral blasts, transient reductions occurred with a rebound following the 7-day treatment period. H3 acetylation increase was significant in B-cells (CD19+; P = 0.02) and blasts (CD34+; P = 0.04). The increase in H2B acetylation was highest in CD19+ and CD34+ cells [3.8-fold (P = 0.01) and 4.4-fold (P = 0.03), respectively]. The median acetylation of histones H2B and H3 in CD34+ and CD19+ cells significantly increased on therapy as did apoptosis in CD14+ cells. Area under the curve increased proportionally with dose with a terminal half-life of ∼11 hours. Conclusion: Intravenous administration of LBH589 was well tolerated at doses
- Published
- 2006
33. Phase I Study of Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, Combined with Cytarabine in Patients with Refractory Leukemia
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Stanton L. Gerson, Hagop M. Kantarjian, Elias Jabbour, Steven M. Kornblau, Jorge E. Cortes, Farhad Ravandi, Ann Cahill, Deborah A. Thomas, Mario Sznol, Maher Albitar, Susan O'Brien, Francis J. Giles, Guillermo Garcia-Manero, Stefan Faderl, Karen W.L. Yee, Verena Karsten, Alessandra Ferrajoli, and Srdan Verstovsek
- Subjects
Adult ,Male ,Alkylating Agents ,Cancer Research ,medicine.medical_specialty ,Time Factors ,DNA Repair ,Base Pair Mismatch ,medicine.drug_class ,Antineoplastic Agents ,Antimetabolite ,Gastroenterology ,Cohort Studies ,O(6)-Methylguanine-DNA Methyltransferase ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Aged ,Sulfonamides ,Leukemia ,business.industry ,Cytarabine ,Myeloid leukemia ,DNA ,Middle Aged ,medicine.disease ,Surgery ,Phase i study ,Regimen ,Hydrazines ,Models, Chemical ,Oncology ,Disease Progression ,Leukocytes, Mononuclear ,Female ,business ,medicine.drug - Abstract
Purpose: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-β-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease. Design: Ara-C was given i.v. at a fixed dose of 1.5 gm/m2/d by continuous infusion for 4 days (patients ages Results: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of ≥400 mg/m2 in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P ≤ 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m2 of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule. Conclusion: The recommended cloretazine dose schedule for future studies is 600 mg/m2 combined with 1.5 gm/m2/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.
- Published
- 2005
34. Phase I Evaluation of a 40-kDa Branched-Chain Long-Acting Pegylated IFN-α-2a With and Without Cytarabine in Patients with Chronic Myelogenous Leukemia
- Author
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Ashok Rakhit, Karen Rittweger, Moshe Talpaz, Leon Hooftman, Susan O'Brien, Hagop M. Kantarjian, Jorge E. Cortes, and Scott Fettner
- Subjects
Adult ,Male ,Cancer Research ,Maximum Tolerated Dose ,Interferon alpha-2 ,Pharmacology ,Drug Administration Schedule ,Polyethylene Glycols ,chemistry.chemical_compound ,Pharmacokinetics ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Dosing ,Aged ,Drug Carriers ,business.industry ,Cytarabine ,Interferon-alpha ,Neopterin ,Middle Aged ,Recombinant Proteins ,Drug Combinations ,Oncology ,chemistry ,Tolerability ,Pharmacodynamics ,Toxicity ,Immunology ,Female ,business ,Complete Hematologic Response ,medicine.drug - Abstract
Purpose: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-α-2a in which IFN-α is attached to a branched methoxypolyethylene glycol (PEG) moiety of large molecular weight (40 kDa). Such molecular modification results in sustained absorption after s.c. drug administration and a prolonged half-life. A phase I study of PEG-IFN was conducted in patients with chronic myelogenous leukemia (CML) who were previously treated with IFN-α to evaluate the effect of sustained exposure to IFN on patients with CML. Experimental Design: Twenty-seven patients with long-term or IFN-refractory CML were enrolled in cohorts of three or six patients. PEG-IFN was given once weekly by s.c. injections starting at a dose of 270 μg/wk to a maximum dose of 630 μg/wk. Sixteen additional patients were treated with escalating doses of PEG-IFN ranging from 450 to 540 μg/wk in combination with two different schedules of low-dose cytarabine (1-β-d-arabinofuranosylcytosine, ara-C). Serial venous blood samples were collected to evaluate the pharmacokinetic and pharmacodynamic characteristics of PEG-IFN in these patients. Results: The dose-limiting toxicity (DLT) as defined by the protocol was not achieved at the highest dose tested of 630 μg/wk. With the addition of ara-C, the DLT was reached at 540 μg/wk. The safety profile was similar to that of unmodified IFNs. Of 27 patients treated with PEG-IFN, 14 (52%) achieved or maintained a complete hematologic response and three (11%) achieved a complete cytogenetic response. Among 16 patients treated with the combination of PEG-IFN and ara-C, 11 (69%) achieved or maintained complete hematologic remission and two (13%) achieved complete cytogenetic remission. The mean serum peak concentration (Cmax) of PEG-IFN increased from 9.4 to 28 ng/mL as the dose increased from 270 to 450 μg/wk, with no further increases in Cmax at higher dose levels. Serum concentration reached peak value starting about 48 hours after drug administration and was maintained at close to peak value throughout the dosing interval. The mean ± SD area under the serum concentration-time curve (AUC) calculated after the first dose also increased from 1,022 ± 694 to 3,343 ± 2,728 ng hour/mL as dose was increased from 270 to 450 μg/wk, showing a dose-related increase in systemic exposure of PEG-IFN. As with Cmax, the AUC did not increase at higher dose levels. The maximum induction (Emax) of neopterin, the surrogate marker of the pharmacodynamic activity of PEG-IFN, increased from 120% to 361% over baseline values as the dose was increased from 270 to 540 μg/wk. On the once-weekly multiple dosing schedule, both the PEG-IFN and neopterin concentration seemed to reach steady state by week 5 and the steady-state values were maintained with chronic dosing over 6 months. Conclusion: Pegasys provided a significant advantage over standard IFN-α by enabling once-weekly dosing while maintaining acceptable safety, tolerability, and activity profiles. This branched 40-kDa PEG-IFN was well tolerated both as a monotherapy as well as in combination with ara-C. Demonstration of its sustained exposure, pharmacodynamic activity, hematologic response, and evidence of cytogenetic response in several patients in this limited study with either IFN-refractory or INF-intolerant patients provides a promise for further investigation in combination with new agents like imatinib.
- Published
- 2005
35. Molecular Responses in Patients with Chronic Myelogenous Leukemia in Chronic Phase Treated with Imatinib Mesylate
- Author
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Stefan Faderl, Moshe Talpaz, Rajyalakshmi Luthra, Jenny Shan, Dan Jones, Hagop M. Kantarjian, Jorge E. Cortes, Francis J. Giles, Guillermo Garcia-Manero, Mary Beth Rios, Srdan Verstovsek, and Susan O'Brien
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Adolescent ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Piperazines ,Myelogenous ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Child ,Proto-Oncogene Proteins c-abl ,In Situ Hybridization, Fluorescence ,Aged ,Aged, 80 and over ,Chromosome Aberrations ,ABL ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Remission Induction ,breakpoint cluster region ,Imatinib ,Middle Aged ,Protein-Tyrosine Kinases ,Prognosis ,medicine.disease ,Leukemia ,Pyrimidines ,Treatment Outcome ,Imatinib mesylate ,Child, Preschool ,Molecular Response ,Benzamides ,Immunology ,Imatinib Mesylate ,business ,Follow-Up Studies ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Purpose: To determine the clinical significance of molecular response and relapse among patients with chronic myelogenous leukemia (CML) treated with imatinib. Experimental Design: We analyzed the results of quantitative PCR in 280 patients with CML in chronic phase who achieved complete cytogenetic remission with imatinib (117 after IFN-α failure and 163 previously untreated). Median follow-up was 31 months (range, 3-52 months). Results: Median BCR-ABL/ABL ratio before the start of therapy was 39.44 (range, 0.252-170.53). A major molecular response (BCR-ABL/ABL ratio 1-log reduction in transcript levels after 3 months of therapy predicted for an improved probability of achieving a major molecular response at 24 months. Increasing levels of BCR-ABL transcripts predicted for a loss of cytogenetic remission only among patients who did not achieve a major molecular response. Conclusions: Achieving a major molecular response, particularly within the first year of therapy, is predictive of a durable cytogenetic remission and may be the future goal of therapy in CML.
- Published
- 2005
36. A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia
- Author
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Michael Andreeff, Guillermo Garcia-Manero, Francis J. Giles, Deborah A. Thomas, Mario Sznol, Alessandra Ferrajoli, Srdan Verstovsek, Stefan Faderl, Miloslav Beran, Ann Cahill, Hagop M. Kantarjian, Jorge E. Cortes, Caroline Clairmont, Charles Koller, and Sima Jeha
- Subjects
Adult ,Alkylating Agents ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Metabolic Clearance Rate ,Vomiting ,Pharmacology ,Gastroenterology ,Pharmacokinetics ,Refractory ,Internal medicine ,medicine ,Humans ,Adverse effect ,Aged ,Aged, 80 and over ,Sulfonamides ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,Nausea ,Middle Aged ,medicine.disease ,Survival Analysis ,Thrombocytopenia ,Leukemia ,Hydrazines ,Treatment Outcome ,Oncology ,Leukemia, Myeloid ,Area Under Curve ,Myelodysplastic Syndromes ,Acute Disease ,Cohort ,Toxicity ,business - Abstract
Purpose: VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS). Experimental Design: VNP40101M was given as a single i.v. infusion over 15–70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m2 was escalated by ∼33% in cohorts of 3–6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8. Results: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m2 for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m2 was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m2 and 1 with acute myeloid leukemia treated with 600 mg/m2, achieved complete remission. Conclusions: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.
- Published
- 2004
37. Abstract CT147: Phase I studies of AZD1208, a PIM kinase inhibitor, in patients with recurrent or refractory acute myelogenous leukemia or advanced solid tumors
- Author
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Janet Elizabeth Pease, Geoffrey L. Uy, Hagop M. Kantarjian, Robert Godin, Jorge E. Cortes, Karen Keating, Kristen McEachern, Daniel J. DeAngelo, Mark D. Minden, Johann S. de Bono, Kenji Tamura, David Lorente, Karthick Vishwanathan, and Emma Dean
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Nausea ,Cancer ,medicine.disease ,030226 pharmacology & pharmacy ,Gastroenterology ,Rash ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,Refractory ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,Pharmacodynamics ,Immunology ,Medicine ,medicine.symptom ,business - Abstract
AZD1208 is a potent oral ATP-competitive, pan-PIM kinase inhibitor. Here we report the results of 2 Phase 1, open-label, multi-center dose escalation studies, recruiting patients with recurrent or refractory AML or advanced solid tumors including malignant lymphoma. The studies examined the safety, tolerability, pharmacokinetics and preliminary efficacy of AZD1208 in patients including evaluation of pharmacodynamic biomarkers in the AML study. The AML study was a first-in-patient study where 32 patients were treated and the range of treatment duration ranged from 15 to 27 days. In patients with heavily treated AML, AZD1208 was generally well tolerated up to doses of 700 mg QD, but was not tolerated at the 900 mg dose. The most common AEs reported likely to be associated with AZD1208 were nausea (37.5%), diarrhea (21.9%), vomiting (18.8%) and fatigue (18.8%). Three DLTs were reported including 1 case of Guillain-Barré syndrome at the 700mg dose and 2 cases of rash at the 900mg dose. Although there were no AML responses to AZD1208 treatment, reductions in peripheral blasts were seen in 5 patients. Modulation of PIM mediated biomarkers was observed with a greater than 50% reduction in pBAD in 14 out of 20 patients and a reduction in p4EBP1 in 6 out of 14 patients. There was no correlation of biomarker modulation and peripheral blast reduction. The solid tumor study recruited 35 patients with a median treatment duration of 41 days (range of 10-357 days). The best objective response was stable disease. Similar AEs to those seen in the AML study were observed in the solid tumor study. DLTs were reported in 4 patients including 2 patients with fatigue (800mg), increased GGT (240mg) and vomiting (540mg). In this study, AZD1208 was well tolerated as monotherapy at doses up to 700 mg QD, but was not tolerated at 800 mg QD. The MTD of AZD1208 was not determined in either study due to termination of development, however was below 900 mg in the AML study and below 800 mg in the solid tumor study. The PK of AZD1208 in both studies showed similar characteristics and was highly variable and generally dose proportional across the range of 120 mg to 900 mg. In the solid tumor study the absorption following multiple dosing was rapid, exposure showed time-dependent PK and interestingly, the accumulation ratios of exposure decreased with increasing doses. One possible mechanism for the decreased exposure is through increased CYP3A4 activity, demonstrated from a 4β-hydroxycholesterol assay showing that AZD1208 increased CYP3A4 activity after continuous dosing resulting in increased clearance of AZD1208 and perhaps resulting in decreased clinical activity. Overall, AZD1208 was generally well tolerated; however, there was no clear evidence of anti-tumor activity from AZD1208 monotherapy treatment. Citation Format: Jorge Cortes, Kenji Tamura, Daniel J. DeAngelo, Johann de Bono, David Lorente, Mark Minden, Geoffrey L. Uy, Hagop Kantarjian, Karen Keating, Kristen McEachern, Karthick Vishwanathan, Robert E. Godin, Janet Elizabeth Pease, Emma Dean. Phase I studies of AZD1208, a PIM kinase inhibitor, in patients with recurrent or refractory acute myelogenous leukemia or advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT147.
- Published
- 2016
38. Abstract 3205: Defining the immune checkpoint landscape of acute myeloid leukemia (AML)
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Carlos E. Bueso-Ramos, Michael Andreeff, Steven M. Kornblau, William G. Wierda, James P. Allison, Tapan M. Kadia, Srdan Verstovsek, Jairo Matthews, Naval Daver, Nitin Jain, Narmeen Somani, Hagop M. Kantarjian, Padmanee Sharma, Jorge E. Cortes, Marina Konopleva, Hui Yang, Gautam Borthakur, Guillermo Garcia-Manero, Peter P. Ruvolo, Wilmer Flores, Jorge Blando, Farhad Ravandi, and Sreyashi Basu
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,T cell ,FOXP3 ,Myeloid leukemia ,Immune checkpoint ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Medicine ,Cytotoxic T cell ,Bone marrow ,business ,Interleukin-7 receptor ,CD8 - Abstract
Introduction: The expression of co-stimulatory (costim) receptors/ligands in the bone marrow (BM) and peripheral blood (PB) in patients (pts) with AML has not been defined. Identification of immune-checkpoint pathways that dominate in AML will guide the rational selection of specific antibodies for clinical trials. Methods: Between March, 2015 and October 2015 we performed 17-color multi-parameter flow-cytometry (MFC) on 15 untreated AML and 25 relapsed AML to assess expression of costim ligands (4-1BBL, B7-1, B7-2, ICOSL, PDL-1, PDL-2, OX40L) on leukemic blasts and costim receptors (4-1BB, CTLA-4, ICOS, PD-1, OX40, GITR, LAG-3, TIM-3) on T cell subsets: CD4 T effector cells [Teff]: CD3+CD4+CD127lo/+Foxp3−, CD4 T regulatory cells [Treg]: CD3+CD4+CD127−Foxp3+, and CD8 T cells: CD3+CD8+. Four healthy human BMs were used as control. Expression is denoted by percentage of specific T-cell subset or gated AML blasts positive for the marker indicated. PB mononuclear cells (PBMCs) and blasts were evaluated at the same time-point. Results: OX40+ Teffs and OX40+ CD8 cells were higher in untreated AML BM as compared to healthy donor BM (median [med]: 7.2% versus [vs] 0.26%; P = 0.0005 and med: 2.03% vs 0.06%; P = 0.07, respectively). PD1+ Tregs and OX40+ Tregs were also higher in untreated AML BM as compared to healthy donor BM (med: 19.7% vs 7.5%; P = 0.03 and med: 10.3% vs 0.5%; P = 0.02, respectively). PD1+ Teffs, OX40+ Teffs, and ICOS+ Teffs were higher in relapsed AML BM as compared to healthy donor BM (med: 17.7% vs 6.7%; P = 0.047, med: 12% vs 0.27%, P = 0.002, and med: 13.3% vs 1.1%; P = 0.07, respectively). OX40+ CD8 cells, ICOS+ CD8 cells, TIM3+ CD8 cells (med: 5.0% vs 0.07%; P = 0.04, med: 18.5% vs 2.6%; P = 0.09, and med: 2.7% vs 0.7%; P = 0.01, respectively) and OX40+ Tregs (med: 15.5% vs 0.5%; P Conclusions: Clinically targetable checkpoint receptors including PD1, OX40, and ICOS appear to be overexpressed in the BM of pts with AML as compared to healthy donor BM. Relapsed AML had higher expression of costim receptors than untreated AML. Three anti-PD1 based clinical trials for pts with AML are enrolling at our institution (NCT02397720, NCT02464657, NCT02532231). Citation Format: Naval Daver, Sreyashi Basu, Guillermo Garcia-Manero, Jorge Cortes, Farhad Ravandi, Steven Kornblau, Marina Konopleva, Michael Andreeff, Gautam Borthakur, Nitin Jain, William Wierda, Srdan Verstovsek, Peter Ruvolo, Tapan Kadia, Jairo Matthews, Wilmer Flores, Hui Yang, Carlos Bueso-Ramos, Narmeen Somani, Jorge Blando, James Allison, Hagop Kantarjian, Padmanee Sharma. Defining the immune checkpoint landscape of acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3205.
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- 2016
39. Abstract CT307: Phase I/II study of vosaroxin and decitabine in older patients (pts) with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS)
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Tapan M. Kadia, Guillermo Garcia Manero, Nitin Jain, Naval Daver, Naveen Pemmaraju, Courtney D. DiNardo, G. Borthakur, Hagop M. Kantarjian, Jorge E. Cortes, Farhad Ravandi, and Craig Adam
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Performance status ,business.industry ,medicine.medical_treatment ,Decitabine ,medicine.disease ,Gastroenterology ,Vosaroxin ,Surgery ,Regimen ,chemistry.chemical_compound ,Oncology ,chemistry ,Internal medicine ,medicine ,Mucositis ,business ,Myeloproliferative neoplasm ,Lenalidomide ,medicine.drug - Abstract
Background: Vosaroxin (formerly voreloxin), is a quinolone derived DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein and has limited toxicity; it is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ≥ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. The treatment regimen included vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. Vosaroxin dose was reduced to 70 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the complete remission (CR) rate. Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 12 pts (9 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-76) have been enrolled; 11 were older than 60 years. They included 6 (50%) pts with diploid cytogenetics, 4 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 2 (16%) with other miscellaneous abnormalities. 4 (34%) pts with AML had antecedent hematological disorders (AHD) including 1 (8%) with MDS, 1 (8%) with myeloproliferative neoplasm and 2 (17%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1) and lenalidomide (n=1). RAS mutations were identified in 4 (34%) and IDH2 mutations in 2 (16%) pts. Median bone marrow blast %, median white blood cell, hemoglobin, & platelet counts were 29% (11-73), 3.7 x 109/L (1.0-127.1), 9.5 g/dL (8.2-10.8), and 92 x 109/L (11-361), respectively. 9 pts were evaluable for response; 5 (42%) achieved CR, 1 (8%) CRp, and 2 (17%) CRi, for an overall response rate of 89%. 1 pt had no response after cycle 1 and is currently undergoing re-induction. Three are too early for response assessment. Pts have received a median of 2 (1-3) treatment cycles with median number of cycles to response being 1 (1-2) and median time to achieving response, 26 days (21-74 days). The median duration of CR/CRp/CRi is 53+ days (6-89+ days). One pt has proceeded to allogeneic stem cell transplant. No pts died during induction. One pt died on study on day 47 from sepsis and acute myocardial infarction. The regimen is well tolerated with the main grade ≥ 3 toxicity being mucositis in 3 (25%) pts. Conclusion: Combination of vosaroxin and decitabine is effective and well tolerated in older patients with AML and high-risk MDS. Enrollment is ongoing. Citation Format: Naval Daver, Hagop M. Kantarjian, Guillermo Garcia - Manero, Naveen Pemmaraju, Tapan Kadia, Courtney DiNardo, Nitin Jain, Gautum Borthakur, Jorge Cortes, Craig Adam, Farhad Ravandi. Phase I/II study of vosaroxin and decitabine in older patients (pts) with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT307. doi:10.1158/1538-7445.AM2014-CT307
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- 2014
40. Abstract 4768: Novel peptidic CXCR4 antagonist LY2510924 disrupts the SDF-1α/CXCR4 axis resulting in anti-AML efficacy in vivo
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Marina Protopopova, Byung Sik Cho, Joe Marszalek, Michael Andreeff, Zhihong Zeng, Marina Konopleva, Sheng-Bin Peng, Jorge E. Cortes, Donald Thornton, Teresa McQueen, and Hong Mu
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Cancer Research ,CXCR4 antagonist ,business.industry ,Plerixafor ,Myeloid leukemia ,Pharmacology ,medicine.disease ,CXCR4 ,Leukemia ,medicine.anatomical_structure ,Oncology ,In vivo ,Cytarabine ,Medicine ,Bone marrow ,business ,medicine.drug - Abstract
Disruption of the SDF-1α/CXCR4 axis by CXCR4 inhibitors has been proven to be an attractive investigational therapeutic approach for acute myeloid leukemia (AML). Moreover, the addition of CXCR4 inhibitor plerixafor to cytotoxic chemotherapy in a phase 1/2 study was associated with increased response rates in relapsed AML (Blood 2012:119;3917). However, plerixafor as a single agent induces only 2- to 4-fold mobilization of leukemic blasts, and this is thought to be due to incomplete inhibition of the SDF-1α/CXCR4 axis and short half-life. LY2510924 is a selective peptidic CXCR4 antagonist that blocks SDF-1α from binding to the receptor. Flow cytometry using OCI-AML3 cells showed that LY2510924 inhibited binding of anti-CXCR4 antibody 12G5 to surface CXCR4 in a concentration-dependent fashion. LY2510924 was 100 times more potent compared to plerixafor (normalized surface expression, LY2510924 at 1 nM, 10.7±0.27%; plerixafor at 1 nM and 100 nM, 74.6±1.23% and 11.0±0.29%, respectively). The action of LY2510924 started as early as 1 minute and continued up to 72 hours at 10 nM. SDF-1α induced migration of OCI-AML3 and primary AML cells, which was abolished by 1 nM LY2510924 but not suppressed by 1 nM plerixafor. LY2510924 inhibited SDF-1α-induced AKT and/or ERK phosphorylation in AML cell lines (OCI-AML3 and U937) and primary AML cells as shown by immunoblotting and multi-parameter phospho-flow cytometry. To test the efficacy of LY2510924 in vivo, we injected OCI-AML3/luc/mCherry cells into sub-lethally irradiated NSG mice. Twelve days after cell injection, mice were randomized into 4 groups: control, cytarabine, LY2510924, and LY2510924 plus cytarabine. On day 21 after cell injection, we observed a 3.4±1.4-fold increase of circulating leukemic cells at 3 hours and a 24.1±15.4-fold mobilization at 24 hours after LY2510924 injection. Bioluminescence imaging demonstrated that mice treated with LY2510924 had lower leukemia burden than cytarabine-treated and control mice. On day 39, the combination group showed less luciferase activity than the LY2510924 group (P=0.034). Hematoxylin-eosin and immunohistochemical staining with human CD45 antibody demonstrated that the LY2510924-treated groups had a significant decrease in leukemic infiltration of bone marrow, spleen, liver, and lung. This anti-leukemia effect translated into a significant prolongation of survival in LY2510924-treated mice (40 days vs. 26 days, P In summary, in vitro data showed that a novel peptidic CXCR4 antagonist, LY2510924, could effectively disrupt the SDF-1α/CXCR4 axis in AML cells and was more potent than plerixafor. In vivo data showed anti-leukemia effects of LY2510924 as a single agent. LY2510924's stronger potency than plerixafor, rapidity of action, and prolonged CXCR4-inhibitory effects will likely translate into a higher anti-leukemia potency than that of plerixafor in future clinical applications. Citation Format: Byung Sik Cho, Zhihong Zeng, Hong Mu, Teresa McQueen, Marina Protopopova, Jorge Cortes, Joe Marszalek, Sheng-Bin Peng, Donald E. Thornton, Michael Andreeff, Marina Konopleva. Novel peptidic CXCR4 antagonist LY2510924 disrupts the SDF-1α/CXCR4 axis resulting in anti-AML efficacy in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4768. doi:10.1158/1538-7445.AM2014-4768
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- 2014
41. Abstract B277: Polymutant BCR-ABL1 proteins during chronic myeloid leukemia therapy: Novel mechanisms of resitance from clinical, in vitro, and in silico evidence
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Paola Storici, Maurizio Fermeglia, Moshe Talpaz, Don L. Gibbons, Barbara Giabbai, Nicholas J. Donato, Erik Laurini, Paola Posocco, Sabrina Pricl, Alfonso Quintás-Cardama, Jorge E. Cortes, and Hunshi Sun
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Cancer Research ,ABL ,business.industry ,Ponatinib ,Myeloid leukemia ,Cancer ,Imatinib ,medicine.disease ,Dasatinib ,chemistry.chemical_compound ,Oncology ,Nilotinib ,chemistry ,hemic and lymphatic diseases ,Immunology ,Cancer research ,Medicine ,business ,Tyrosine kinase ,medicine.drug - Abstract
The acquisition of mutations within the BCR-ABL1 kinase domain is frequently associated to imatinib failure among patients with chronic myeloid leukemia (CML). Typically, patients failing imatinib undergo sequential therapy with second line tyrosine kinase inhibitors (TKIs) such as nilotinib or dasatinib. To investigate the prevalence of BCR-ABL1 mutations and the mechanisms of acquired TKI resistance during sequential therapy, we used a sensitive cloning technique in a cohort of chronic-phase patients failing imatinib therapy that subsequently received dasatinib. The analysis revealed that most patients failing imatinib carry BCR-ABL1 mutations, many with polymutant BCR-ABL1 alleles, and that there is progressive exhaustion of the pool of unmutated BCR-ABL1 alleles over the course of treatment. Detailed modeling of the structural effects on the ABL1 kinase domain of the various mutations and of clinically available/experimental TKIs against some of the most frequent polymutants found in our patient cohort indicates that the accumulation of more than one BCR-ABL1 mutation within the same allele promotes a higher than expected level of TKI resistance compared to that of each single mutation alone. Some polymutants exhibited levels of resistance to imatinib/dasatinib remarkably higher than those of the highly resistant T315I mutation, suggesting that the generation of polymutant BCR-ABL1 alleles represents a powerful mechanism of escape for CML cells exposed to TKI-induced selection pressure. Notably, the complexity of the polymutants is limited, suggesting that, in addition to increasing TKI resistance, the successive accumulation of single mutations within the same clone may compromise its fitness, the latter being a function of the number and type of single mutants involved in any given polymutant. Strategies to limit the generation of complex mutants and clinical resistance may require the use of frontline therapy with TKI combinations or with novel TKIs that cover a broad range of mutations and therefore may prevent the emergence of resistance. In addition to providing an understanding for the molecular basis of clinical TKI failure in our patient cohort, we modeled the activity of the novel TKI ponatinib against the most frequently encountered polymutants. Although all the polymutants were predicted to be highly resistant to imatinib and dasatinib, ponatinib was predicted to maintain a notable affinity for most clinically relevant BCR-ABL1 single mutants and some of the polymutants detected in our patient cohort. Ponatinib was able to accommodate the structural changes induced by these complex mutants, which suggest the possibility of polymutant kinase inhibition at doses frequently within a clinically achievable range. These findings were validated in cell-based biochemical assays, thus supporting the clinical applicability of in silico modeling as a means to predict the TKI approach with the highest probability of clinical success. It is worth noting, however, that some polymutants examined required ponatinib concentrations unlikely to be reached in humans without excessive toxicity, thus anticipating potential mechanisms of escape to ponatinib therapy through selection and expansion of clones carrying highly TKI resistant complex BCR-ABL1 mutant proteins. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B277. Citation Format: Sabrina Pricl, Don L. Gibbons, Paola Posocco, Erik Laurini, Barbara Giabbai, Paola Storici, Maurizio Fermeglia, Hunshi Sun, Jorge Cortes, Moshe Talpaz, Nicholas Donato, Alfonso Quintas-Cardama. Polymutant BCR-ABL1 proteins during chronic myeloid leukemia therapy: Novel mechanisms of resitance from clinical, in vitro, and in silico evidence. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B277.
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- 2013
42. Abstract 3516: AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML
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Patricia Mccoon, Yichen Cao, Rachel DuPont, Kristen McEachern, Lourdes Pablo, Daniel J. DeAngelo, Mark D. Minden, Jeffrey L. Brown, Jorge E. Cortes, Becker Hewes, and C. Barrett
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Clinical trial ,Cancer Research ,Oncology ,business.industry ,Kinase ,Phase (matter) ,Cancer research ,Medicine ,business - Abstract
PIM kinases have been shown to play a key role as downstream effectors of growth factor signalling pathways including Flt3 and the Jak-STAT signalling pathways in AML, NHL and other solid tumors. AZD1208 is a novel, orally bioavailable, highly selective PIM kinase inhibitor with single nanomolar potency against all three PIM kinases and is currently undergoing Phase I testing and dose escalation studies in AML. Here we describe a multiplexed biomarker strategy measuring pBAD, p4EBP1 and p-p70S6K as downstream pharmacodynamic biomarkers for PIM kinase inhibition in clinical trials. Patient bone marrow aspirates and peripheral blood samples were collected pre- and post-AZD1208 treatment in AML patients during the Phase I dose escalation and expansions. Primary patient samples were analyzed for quantitative changes in pBAD, p4EBP1 by NanoPro and MesoScale assay platforms as well as a qualitative evaluation of p-p70S6K and other exploratory endpoints. Preclinical PK-PD modeling data with AZD1208 had suggested that greater than a 50% decrease in the levels of one of these phosphorlyated substrates would be indicative of efficacy and PIM pathway inhibition. Following a single dose of AZD1208 at 120mg, the first dose level, approximately 60-70% inhibition of pBAD, S112 was seen in the bone marrow and peripheral blasts. Taken together, the data presented here provide evidence for single agent AZD1208 activity in AML patients based on quantitative reduction in these biomarkers. Correlations of these biomarker endpoints with Phase I pharmacokinetic data underscore the therapeutic potential of Pim kinase inhibition by AZD1208 for the treatment of AML, and strongly support further investigation of this agent in other indications where PIM signaling may play a role in tumorigenesis and survival. Citation Format: Kristen A. McEachern, Yichen Cao, Rachel DuPont, Lourdes Pablo, Patricia McCoon, Jorge E. Cortes, Daniel J. DeAngelo, Mark D. Minden, Becker Hewes, Jeffrey L. Brown, Carl Barrett. AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3516. doi:10.1158/1538-7445.AM2013-3516
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- 2013
43. Abstract 1050: Mechanisms of action of Pim kinase inhibitor, AZD1208, in acute myeloid leukemia cells
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Lisa S. Chen, Varsha Gandhi, and Jorge E. Cortes
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Cancer Research ,Kinase ,Cell growth ,Myeloid leukemia ,Cell cycle ,Biology ,chemistry.chemical_compound ,Histone H3 ,Oncology ,chemistry ,Cell culture ,hemic and lymphatic diseases ,Immunology ,Cancer research ,Phosphorylation ,Growth inhibition - Abstract
Pim kinase proteins (Pim-1, -2 and -3) are a family of conserved proto-oncogenes that are upregulated in leukemias and lymphomas and are involved with leukemogenesis. Pim kinase substrates include transcription, translation, cell cycle, and survival proteins. Increased Pim expression in acute myeloid leukemia (AML), especially in FLT3-ITD activating mutation, provides a rationale to evaluate Pim kinase inhibitors in AML. AZD1208 is a small molecule pan-Pim kinase inhibitor [IC50: Pim-1 (0.4 nM), Pim-2 (5.0 nM) and Pim-3 (1.9 nM)]. AZD1208 treatment resulted in growth inhibition in AML cell lines including FLT3-WT (OCI-AML-3, KG-1a, MOLM-16) and FLT3-ITD mutated (MOLM-13, MV-4-11), with greater sensitivity measured in MOLM-16, followed by KG-1a and MV-4-11. The effects of AZD1208 on cell survival were investigated and there was limited apoptosis induction ( To elucidate the mechanism of AZD1208, Pim kinase target protein phosphorylation was evaluated. With 3 μM AZD1208 for 24 h, there was a decrease in Bad (Ser112) phosphorylation relative to total Bad only in KG-1a and MOLM-16 cells. Similarly, there was significant decline in histone H3 (Ser10) phosphorylation only in MOLM-16. However, several mTOR signaling pathway proteins were modulated by AZD1208. Pim-1 target PRAS40 (Thr246) phosphorylation decreased in KG-1a, MOLM-13, MV-4-11 and MOLM-16 within 6 h of exposure to 3 μM AZD1208. Similarly, Pim-2 target 4E-BP1 (Ser65) phosphorylation decreased in all five cell lines by 24 h. Phosphorylation of downstream S6 (Ser235/236) was dramatically reduced in KG-1a and MOLM-16, and also declined in MV-4-11. Growth inhibition mediated by AZD1208 is similar in FLT3-WT (KG-1a) and FLT3-ITD (MV-4-11), however there is a varied response in Bad and S6 phosphorylation. These results indicate that although growth inhibition induced by AZD1208 is similar in cells with disparate FLT3 mutation status, the molecular events are divergent and may uncover signaling differences between Pim and FLT3-WT and FLT3-ITD. Taken together, Pim kinase inhibition by AZD1208 may be a valuable strategy to inhibit AML cell proliferation even in hard-to-treat AML with FLT3 activating mutations, and these investigations will be used to identify biomarkers during clinical trial that may be predictive of response in patients. There is a multi-center Phase I clinical trial with AZD1208 in AML currently underway and investigations are ongoing. Citation Format: Lisa S. Chen, Jorge E. Cortes, Varsha Gandhi. Mechanisms of action of Pim kinase inhibitor, AZD1208, in acute myeloid leukemia cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1050. doi:10.1158/1538-7445.AM2013-1050
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- 2013
44. Abstract 2903: Therapeutic targeting of leukemia and lymphoma with a neuropilin-1 binding pro-apoptotic peptide
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Bedrich L. Eckhardt, Erkki Koivunen, Benjamin Lichtiger, Carlos E. Bueso-Ramos, Katja Karjalainen, Renata Pasqualini, Wadih Arap, Jorge E. Cortes, Frank C. Marini, Hagob M. Kantarjian, Diana E. Jaalouk, Akihiko Kuniyasu, Amado J. Zurita, and Susan O'Brien
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Cancer Research ,business.industry ,Peptidomimetic ,medicine.disease ,Lymphoma ,Haematopoiesis ,Myelogenous ,Leukemia ,medicine.anatomical_structure ,Oncology ,Targeted drug delivery ,hemic and lymphatic diseases ,Immunology ,Neuropilin 1 ,medicine ,Cancer research ,Bone marrow ,business - Abstract
Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short cell-internalizing peptide ligands that bind to specific cell surface receptors on malignant hematopoietic cells. Such targeting motifs could also serve as vehicles for preferential delivery of cytotoxic agents to leukemias and lymphomas. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence FF/YXLRS, which bound to human leukemia and lymphoma cell lines as well as to primary human acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) bone marrow specimens obtained from patients. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, the functional relevance of this internalizing receptor was evaluated in the context of disease progression via the targeted delivery of a pro-apoptotic peptidomimetic to leukemia and lymphoma cells, and a potent anti-leukemia cell effect was observed both with cell lines and patient samples when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D(KLAKLAK)2. Markedly, the pro-apoptotic peptide did not have an effect on purified mononuclear cells from normal bone marrow cells. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with ALL or AML compared to normal bone marrow specimens. Taken together, our results indicate that NRP-1 could, potentially, be used as a target for ligand-directed therapy in human leukemias and lymphomas - as well as in many human solid tumors, which are also know to over-express NRP-1 - and that the prototype CGFYWLRSC-GG-D(KLAKLAK)2 is a promising drug candidate in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2903. doi:1538-7445.AM2012-2903
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- 2012
45. Abstract 4619: PF-04449913 reverts multi drug resistance (MDR) by a strong down-regulation of ABCA2 and BCL2 on leukemia stem cells in phase I acute myeloid leukemia and chronic myeloid leukemia treated patients
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Antonio Curti, Viviana Guadagnuolo, Todd VanArsdale, Carolina Terragna, Emanuela Ottaviani, Catriona Jamieson, Maria Chiara Abbenante, Michele Baccarani, Carmen Baldazzi, Jorge E. Cortes, Vivian G. Oehler, Simona Soverini, Karen McLachlan, Barbara Lama, Ilaria Iacobucci, Rachel Courtney, Wendy J. Levin, Lucia Toni, Giovanni Martinelli, Federica Cattina, Cristina Papayannidis, and Sandra Durante
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Cancer Research ,education.field_of_study ,biology ,Abcg2 ,Population ,Myeloid leukemia ,ABCA2 ,medicine.disease ,Fold change ,ABCF1 ,Leukemia ,Oncology ,Chronic leukemia ,Immunology ,biology.protein ,Cancer research ,medicine ,education - Abstract
PF-04449913 is a selective and potent inhibitor of the Hh pathway and leukemia self-renewal and is currently being evaluated in Phase I clinical trials. We studied leukemia stem cell population (CD34+ subpopulation) collected before and after 28 days treatment in a phase I dose escalation protocol (Clinical Trial Gov. NTC00953758) enrolling selected hematological malignancies including MF, MDS, CML, CMML and AML. We collected and separated highly purified (98%) bone marrow hematopoietic progenitor cells (CD34+ populations) in 5 AML, 1 MF and 2 CML patients, by immunomagnetic separation, and analyzed them for gene expression profile (GEP) using Affimetrix HG-U133 Plus 2.0 platform. We have observed that 1197 genes were differentially expressed between CD34+ cells collected before and after 28 days of PF-04449913 dose finding oral therapy. We demonstrated a down regulation of Bcl2 (fold change –1.03004; p value= 0.01), ABCA2 (fold change –1.08966; p value=0.03), Bcl2l13 (fold change –1,04259; p-value=0,027642), Bcl2l2 (fold change –1,17214; p-value=0,000768), Casp4 (fold change –1,06551; p-value=0,032428), Casp7 (fold change –1,01569; p-value=0,006688), Casp10 (fold-change –1,3076; p-value=0,050431), ABCF1 (fold change –1,04999; p-value=0,07213). On the contrary, ABCB1 (fold change 1,46592) and ABCG2 (fold change –1,16103) are respectively up and down regulated, with a not statistically significant p-value. Bcl2 (B-cell lymphoma 2), Bcl2l2 (Bcl2-like protein 2) and Bcl2l13 (Bcl2-like 13) are the founding members of the Bcl-2 family of apoptosis regulator proteins. Recent studies showed that Hh signals upregulate Bcl2 to promote cellular survival. Casp 4,7,10 (Caspases) are a family of cysteine proteases that play essential roles in apoptosis, necrosis, and inflammation. ABCA2 (ATP-binding cassette sub-family A member 2), ABCF1 (ATP-binding cassette sub-family F member 1), ABCB1 (ATP-binding cassette sub-family B member 1, MDR1), ABCG2 (ATP-binding cassette sub-family G member 2) belong to the superfamily of adenosine triphosphate-binding cassette (ABC) transporters. One mechanism of MDR is the increased expression of ABC drug transporters, resulting in low intracellular drug concentrations. We evaluated Gli1 and Smo expression by GEP, comparing data before and after 28 days of treatment with PF-04449913 and we observed a down regulation of both genes (fold changes –1.0775 and –1.07702 respectively). PF-04449913 is able to revert MRD mechanisms of LSC by a strong down regulation of genes (Bcl-2, Bcl-2l13, Bcl-2l2, ABCA2, and ABCF1), which are critical for chemoresistance in acute and chronic leukemia patients. Acknowledgments. Pfizer, European LeukemiaNet, FIRB 2006, AIRC, AIL, COFIN, University of Bologna and BolognAIL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4619. doi:1538-7445.AM2012-4619
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- 2012
46. Abstract 906: Gas1 and Kif27 genes are strongly up-regulated biomarkers of Hedgehog inhibition (PF-04449913) on leukemia stem cells in Phase I Acute Myeloid Leukemia and Chronic Myeloid Leukemia treated patients
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Catriona Jamieson, Todd VanArsdale, Carolina Terragna, Sandra Durante, Antonio Curti, Emanuela Ottaviani, Viviana Guadagnuolo, Federica Cattina, Wendy J. Levin, Michele Baccarani, Carmen Baldazzi, Cristina Papayannidis, Giovanni Martinelli, Karen McLachlan, Vivian G. Oehler, Rachel Courtney, Maria Chiara Abbenante, Lucia Toni, Jorge E. Cortes, Ilaria Iacobucci, Simona Soverini, and Barbara Lama
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Cancer Research ,education.field_of_study ,business.industry ,Population ,Myeloid leukemia ,Chronic myelomonocytic leukemia ,medicine.disease ,Hedgehog signaling pathway ,Fold change ,Leukemia ,homeobox A9 ,Oncology ,Cancer research ,Medicine ,Stem cell ,business ,education - Abstract
Hedgehog (Hh) pathway activation contributes to leukemia development and growth, and that targeted pathway inhibition is likely to offer an efficient therapeutic opportunity. PF-04449913, a Hh pathway inhibitor, is a new selective and potent inhibitor of leukemia self-renewal and is currently being evaluated in phase I clinical trials. In order to identify new potential clinical biomarkers for the PF-04449913, we studied CD34+ leukemia stem cell population (LSC) collected before and after 28 days treatment in a phase I dose escalation protocol (Clinical Trial Gov. NTC00953758) enrolling selected hematological malignancies. This experimental clinical trial enrolled Myelofibrosis (MF), MDS, blastic phases CML, chronic myelomonocytic leukemia (CMML) and AML patients (pts). We were able to collect and separate highly purified (98%) bone marrow CD34+ cells from 5 AML, 1 MF and 2 CML pts by immunomagnetic separation, and analysed them for gene expression profile using Affimetrix HG-U133 Plus 2.0 platform. 1197 genes were differentially expressed between CD34+ cells collected before and after 28 days of PF-04449913 dose finding oral therapy. Clustering of their expression profiles showed that mostly genes differentially expressed are mainly related to Hh signaling, this providing further evidences that PF-04449913 really therapeutically targets the Hh pathway. Regarding genes involved in Hh signaling pathway, Gas1 and Kif27 were strongly upregulated (fold change 1.0947 and 1.12757 respectively; p-value 0.01 and 0.02 respectively) in CD34+ LSC after 28 days exposure to PF-04449913 as compared to baseline, suggesting these two genes have potential as new biomarkers of activity. GAS-1 is a Sonic Hedgehog (Shh)-binding protein; it acts to sequester Shh and inhibit the Shh signalling pathway. Kif27 mainly acts as a negative regulator in the Hh signaling pathway, and inhibits the transcriptional activator activity of Gli1 by inhibiting its nuclear translocation. Other genes were differentially expressed after ‘ex- vivo’ treatment with PF-04449913 as compared to baseline: we observed a down regulation of Bcl2 (fold change -1.03004), ABCA2 (fold change -1.08966), LEF1 (fold change -1.28457), Gli1 (fold change -1.0775), Smo (fold change -1.07702), and an upregulation of Gli2 (fold change 1.08191). Conclusions: This data demonstrates that PF-04449913 specifically targets the Hh Pathway in CD34+ cells, suggesting that Hh inhibition may impair leukemia stem cell maintenance. In addition, we identify several new potential biomarkers (e.g. Gas1 and KIF27). Taken together, these data may be useful for pts selection strategies and subsequent eradication of the LSC. Acknowledgments: Work supported by Pfizer, European LeukemiaNet, FIRB 2006, AIRC, AIL, COFIN, University of Bologna and BolognAIL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 906. doi:1538-7445.AM2012-906
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- 2012
47. Abstract LB-109: BCR-ABL1 kinase activity but not its expression is dispensable for Ph+ quiescent stem cell survival which depends on the PP2A-controlled Jak2 activation and is sensitive to FTY720 treatment
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Robert Bittman, Tessa L. Holyoake, Danilo Perrotti, Joshua J. Oaks, Ravi Bhatia, Peter Hokland, Charlene Mao, Ramasamy Santhanam, Guido Marcucci, Michael A. Caligiuri, Bin Zhang, Carolyn Paisie, Anna M. Eiring, Christopher J. Walker, Ralph B. Arlinghaus, Denis-Claude Roy, Ching-Shih Chen, Jason G. Harb, Jorge E. Cortes, Yihui Ma, Paolo Neviani, Stefano Volinia, Bastianella Perazzona, and Claudia S. Huettner
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Cancer Research ,business.industry ,Protein phosphatase 2 ,Transplantation ,Haematopoiesis ,Oncology ,hemic and lymphatic diseases ,Immunology ,Cancer research ,Medicine ,CD90 ,Progenitor cell ,Stem cell ,Kinase activity ,business ,Tyrosine kinase - Abstract
Background: The success of tyrosine kinase inhibitors (TKIs) depends on the addiction of Philadelphia-positive (Ph+) CML progenitors to BCR-ABL1 kinase activity. However, CML quiescent hematopoietic stem cells (HSC) are TKI-resistant and represent an active disease reservoir. We hypothesize that this innate drug-resistance depends on inhibition of the tumor suppressor protein phosphatase 2A (PP2A). PP2A can be reactivated by FTY720, a drug that targets CML but not normal progenitors. Here we investigated the mechanism controlling survival/self-renewal of quiescent leukemic HSCs and their sensitivity to PP2A-activating drugs. Methods: HSCs from CML (n=68) and healthy (n=12) donors were FACS-isolated, and the biologic importance of PP2A inhibition and pharmacologic PP2A activation on their survival/self-renewal was assessed by BM serial transplantation; CFSE and Annexin-V staining; LTC-IC and CFC/replating assays; lentiviral shRNA/cDNA-transduction; LEF/TCF and proximity-ligation assays; Western blot, confocal microscopy and FACS analyses. Results: We observed increased BCR-ABL1 expression with impaired kinase activity in quiescent CML HSCs, in which BCR-ABL1 per se is required for induction of JAK2 that subsequently activated β-catenin and inhibited PP2A. In fact, PP2A was suppressed in CML but not normal CD34+/CD38−/CD90+ HSCs. FTY720 and/or its non-immunosuppressive (S)-FTY720-OMe derivative markedly reduced survival and self-renewal of CML but not normal quiescent HSCs through BCR-ABL1 kinase-independent and PP2A-mediated JAK2 and β-catenin inhibition. Importantly, FTY720 also strongly diminished BCR-ABL1+ LT-HSC frequency in serial BM transplantation assays. Conclusions: The pharmacologic targeting of the newly-identified BCR-ABL1 kinase-independent JAK2/β-catenin interplay in quiescent HSCs with FTY720 and its derivatives, might lead to cessation of lifelong patient dependence on TKIs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-109. doi:10.1158/1538-7445.AM2011-LB-109
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- 2011
48. Abstract 4715: Dasatinib as initial therapy for patients with chronic myeloid leukemia (CML) in early chronic phase (CP)
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Farhad Ravandi, Elias Jabbour, Susan O'Brien, Elizabeth M. Burton, Naveen Pemmaraju, Aflonso Quintas-Cardama, Brenda Walker, Gautam Borthakur, Raja Luthra, Hagop M. Kantarjian, and Jorge E. Cortes
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Cancer Research ,medicine.medical_specialty ,Pleural effusion ,business.industry ,Anemia ,Neutropenia ,medicine.disease ,Gastroenterology ,Rash ,Surgery ,Dasatinib ,Oncology ,Internal medicine ,Heart failure ,Toxicity ,medicine ,medicine.symptom ,business ,Bone pain ,medicine.drug - Abstract
Dasatinib is approximately 300 times more potent than imatinib in vitro and has significant activity in patients (pts) with CML-CP resistant or intolerant of imatinib (IM). We initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with previously untreated CML-CP within 6 mo from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. Results: 82 pts have been enrolled (49 on the QD schedule, 33 BID). Median age was 47 years (yrs) (range 18-76 yrs). Median follow-up is 29 mo (range, 0 to 54 mo). All 72 pts who were not in CHR at the start of therapy achieved CHR. Among 75 pts followed for at least 3 mo, 73 (97%) achieved complete cytogenetic response (CCyR). Major molecular response (MMR) has been achieved in 64 (86%), including 19 (26%) with complete molecular response. The CCyR rate at different timepoints compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily. MMR was observed in 81% and 82% of the QD and BID patients respectively. However, the 12 mo MMR trended slightly higher with the BID dosing schedule compared to the QD schedule: 81% and 71% (p=0.384) respectively. Grade 3-4 non-hematologic toxicity included pain (muscle or joint) (13%), fatigue (11%), dyspnea (7%), neuropathy (6%), memory impairment, headache (5% each), diarrhea, pleural effusion, musculoskeletal complaints (2% each) and rash, prolonged QTC, weight gain and pruritus (1% each). Pleural effusion occurred in 16% evaluable pts. Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 13%, neutropenia 25%, and anemia 9%. Fifty-two (63%) of 82 pts required transient treatment interruptions. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3-4 toxicity by treatment schedule but there was a trend for less pleural effusion with QD (13%) vs BID (22%; p=0.267). Five pts lost CCyR:(including 2 because of non-compliance). The 24-month probability of event-free survival (EFS) is 88%. There have been no transformations on study, and only one patient has died (metastatic pancreatic cancer). Ten patients have discontinued therapy (3 patient choice, 5 toxicity 2 pleural effusion, 1 prolonged thrombocytopenia, 1 bone pain, 1 congestive heart failure, and 2 for loss of MCyR) Conclusion: Rapid CCyR occurs in nearly all patients with previously untreated CML-CP treated with frontline dasatinib therapy; the MMR rate at 24 months was 93%, with a favorable toxicity profile. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4715. doi:10.1158/1538-7445.AM2011-4715
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- 2011
49. Abstract 1950: Suppression of RISC-independent decoy and RISC-mediated RNA-pairing activities of microRNA-328 is required for maturation-arrest and enhanced survival of blast crisis CML progenitors
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Heiko Becker, Carlo M. Croce, Joshua J. Oaks, Denis C. Roy, Jason C. Chandler, Raul Andino, Christopher Hickey, Guido Marcucci, Peter Hokland, Sebastian Schwind, Ramiro Garzon, Michael A. Caligiuri, Riccardo Spizzo, Danilo Perrotti, Jason G. Harb, Jorge E. Cortes, Stephen A. Liebhaber, Anna M. Eiring, Shujun Liu, Paolo Neviani, Ravi Bhatia, Claudia S. Huettner, Ramasamy Santhanam, and George A. Calin
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Cancer Research ,ABL ,RISC complex ,biology ,Chemistry ,Cellular differentiation ,breakpoint cluster region ,medicine.disease ,Cell biology ,Oncology ,hemic and lymphatic diseases ,CEBPA ,microRNA ,medicine ,biology.protein ,Chronic myelogenous leukemia ,Dicer - Abstract
MicroRNAs (miRs) and heterogeneous ribonucleoproteins (hnRNPs) are post-transcriptional gene regulators that bind to mRNA in a sequence-specific manner. We showed that hnRNP-E2 inhibits myeloid maturation of bone marrow (BM) progenitors from chronic myelogenous leukemia patients in myeloid blast crisis (CML-BC) by suppressing CEBPA mRNA translation. We report here that loss of miR-328 is induced by BCR/ABL and specifically occurs in CML-BC, and its restored expression rescues differentiation and impairs clonogenic potential of BCR/ABL+ BM progenitors. Accordingly, miR-328 increases during granulocytic differentiation of human CD34+ and mouse LSK BM stem/progenitor cells. Mechanistically, BCR/ABL uses the MAPK-hnRNP-E2 pathway to suppress C/EBPα and miR-328 expression as pharmacologic inhibition of and/or shRNAs against these molecules efficiently restore miR-328 expression. Interestingly, two functional C/EBPα binding sites are present in the miR-328 promoter and positively regulate its transcription. We also show that maturation of differentiation-arrested BCR/ABL+ blasts requires direct interaction of hnRNP-E2 with the miR-328 C-rich regions. Moreover, imatinib treatment restores miR-328 expression, thus allowing its direct binding to hnRNP E2 independent from the RISC complex. Importantly, physiological miR-328 expression decreased hnRNP E2 binding to the uORF/spacer region of endogenous CEBPA mRNA (decoy activity). This, in turn, releases CEBPA mRNA from hnRNP E2 translation inhibition and allows in vitro and in vivo BCR/ABL+ cell differentiation. Although hnRNP E2 was not found in complex with the basic RISC components in BCR/ABL+ cells, miR-328 was found associated to Dicer and Ago2, suggesting that miR-328 also acts through base-pairing with the 3′UTR of mRNA targets in a RISC-dependent manner. In fact, miR-328 suppresses PIM1 protein but not mRNA expression and this effect requires the integrity of the PIM1 3′UTR. Indeed, forced expression of a wild type, but not a kinase-deficient, PIM1 lacking the 3′UTR into miR-328-expressing cells fully rescues BCR/ABL clonogenicity, suggesting that miR-328-induced inhibition of PIM1 accounts for reduced survival of miR-328-infected CML-BCCD34+ blasts. To demonstrate that miR-328 acts on PIM1 in a RISC-dependent manner, we mutated the miR-328 in the seed sequence (miR-328-Mut) while retaining its C-rich character. As expected, miR-328-Mut interacted with hnRNP-E2 and rescued C/EBPα-mediated differentiation, but did not silence PIM1 expression. Thus, the discovery of dual activities for miR-328 which affect myeloid differentiation and survival not only adds a layer to the complexity of mechanisms regulating CML-BC but also highlights the ability of miRNAs to alter mRNA metabolism by acting as molecular decoys for RNA binding proteins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1950.
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- 2010
50. BCR-ABL1INS35 Is Not Uncommon in CML Patients and Is Related to Resistance and Sensitivity to Inhibitors in CML Treatment - Response
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Hagop M. Kantarjian, Jorge E. Cortes, Xi Zhang, Maher Albitar, Tai-Sung Lee, Francis J. Giles, and Wanlong Ma
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Cancer Research ,Treatment response ,ABL ,business.industry ,Alternative splicing ,breakpoint cluster region ,Imatinib ,Bioinformatics ,Oncology ,Fusion transcript ,hemic and lymphatic diseases ,Cancer research ,Medicine ,Primer (molecular biology) ,business ,Nested polymerase chain reaction ,medicine.drug - Abstract
Santamaria et al. report the detection of the BCR-ABL1INS35 in 27% of 18 patients with CML being treated with imatinib. This is consistent with our finding of 2 of 21 (10%) at 3 months, 1 of 20 (5%) at 6 months, 4 of 25 (16%) at 9 months, and 6 of 23 (26%) at 12 months of imatinib therapy (1). However, it is important to point out that the relative level of expression of the BCR-ABL1 INS35 as compared with the wild-type fusion BCR-ABL1 transcript is very low in these patients (
- Published
- 2010
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