109 results on '"Christopher R Cogle"'
Search Results
2. Finding incident cancer cases through outpatient oncology clinic claims data and integration into a state cancer registry
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David J. Lee, Megsys C. Herna, Tara Hylton, Steven Peace, Celeste Philip, Gary Levin, Clement K. Gwede, Jill MacKinnon, and Christopher R. Cogle
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Cancer Research ,medicine.medical_specialty ,education.field_of_study ,Bladder cancer ,business.industry ,Public health ,Population ,Cancer ,medicine.disease ,Cancer registry ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Breast cancer ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,Epidemiology ,medicine ,030212 general & internal medicine ,business ,education - Abstract
Cancer data from population-based cancer registries under-report cancer cases, especially for cancers primarily diagnosed and treated in outpatient clinical settings, away from hospital-based cancer registrars. Previously, we developed alternative methods of cancer case capture including a claims-based method, which identified a large proportion of cancer cases missed by traditional population-based cancer registries. In this study, we adapted a claims-based method for statewide implementation of cancer surveillance in Florida. Between 2010 and 2017 the claims-based method identified 143,083 cancer abstracts, of which 42% were new and 58% were previously registered. The claims-based method led to the creation of 53,419 new cancer cases in the state cancer registry, which made up 9.3% of all cancer cases registered between 2010 and 2017. The types of cancers identified by the claims-based method were typical of the kinds primarily diagnosed and treated in outpatient oncology clinic settings, such as hematological malignancies, prostate cancer, melanoma, breast cancer, and bladder cancer. These cases were added to the Florida cancer registry and may produce an artefactual increase in cancer incidence, which is believed to be closer to the actual burden of cancer in the state.
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- 2020
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3. Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA
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Justin Watts, Tara L. Lin, Alice Mims, Prapti Patel, Cynthia Lee, Anoush Shahidzadeh, Paul Shami, Elizabeth Cull, Christopher R. Cogle, Eunice Wang, and Fatih M. Uckun
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AML – acute myeloid leukaemia ,Cancer Research ,Oncology ,hemic and lymphatic diseases ,myelodysplastic and myeloproliferative syndromes ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,bispecific antibody (bsAb) ,CD123 expression ,RC254-282 ,venetoclax (BCL2 inhibitor) ,Original Research - Abstract
APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.
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- 2022
4. Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436
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Christopher R. Cogle, Alice S. Mims, Cynthia Lee, Paul J. Shami, Elizabeth Cull, Prapti A. Patel, Eunice S. Wang, Fatih M. Uckun, Tara L. Lin, and Justin M. Watts
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Cancer Research ,medicine.medical_specialty ,Gastroenterology ,Article ,chemistry.chemical_compound ,Immunophenotyping ,Tocilizumab ,AML ,Internal medicine ,otorhinolaryngologic diseases ,Medicine ,Dexamethasone ,RC254-282 ,business.industry ,T-cells ,leukemia ,Myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,clinical study ,medicine.disease ,APVO436 ,Leukemia ,Cytokine release syndrome ,bispecific antibody ,medicine.anatomical_structure ,Oncology ,chemistry ,CD123 ,Interleukin-3 receptor ,Bone marrow ,business ,medicine.drug - Abstract
Simple Summary Cytokine release syndrome is a potentially life-threatening complication of therapy with T-cell engaging bispecific antibodies. Here we evaluated the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome who received weekly intravenous infusions of the CD3xCD123 bispecific antibody APVO436. Cytokine release syndrome was encountered in 10 of 46 patients (21.7%) treated with APVO436 with a cumulative Grade 3/4 cytokine release syndrome incidence of 8.7%. Cytokine profiling in patients who developed cytokine release syndrome after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6. The findings from this research provide new insights regarding the biology and effective management of cytokine release syndrome in leukemia patients treated with T-cell redirecting bispecific antibodies. Abstract We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions.
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- 2021
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5. DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks
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Jonathan D. Licht, Daphné Dupéré-Richer, Huanzhou Xu, Kartika Venugopal, Yang Feng, Richard L. Bennett, Brian K. Law, Heidi L. Casellas Roman, Luisa M Posada, Alberto Riva, Rene Opavsky, Daniil Shabashvili, Kathryn I. Krajcik, Prabhjot Kaur, Chamara Gunaratne, Pawel Nowialis, Christopher R. Cogle, Zachary Zaroogian, Santhi Pondugula, Jianping Li, Jonathan E. Bird, Christina Taragjini, Philipp B. Staber, Olga A. Guryanova, Sumita Bhaduri-McIntosh, Stefan Kubicek, and Cassandra M. Berntsen
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DNA Replication ,Cancer Research ,DNA damage ,Myeloid leukemia ,Biology ,medicine.disease ,Prognosis ,Cell biology ,DNA Methyltransferase 3A ,Replication fork arrest ,Leukemia ,Leukemia, Myeloid, Acute ,Mice ,PARP1 ,Oncology ,Mutation ,medicine ,Cytarabine ,Animals ,Humans ,Epigenetics ,Mitosis ,medicine.drug ,DNA Damage - Abstract
Purpose: In acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations. Experimental Design: Leukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression. Results: We found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra–S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism. Conclusions: Together, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress. See related commentary by Viny, p. 573
- Published
- 2021
6. A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
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Paul J. Shami, Prapti Patel, Fatih M. Uckun, Anoush Shahidzadeh, Justin M. Watts, Alice S. Mims, Elizabeth Cull, Christopher R. Cogle, Tara L. Lin, and Cynthia Lee
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Oncology ,Cancer Research ,medicine.medical_specialty ,Bispecific antibody ,T cells ,Article ,AML ,Internal medicine ,hemic and lymphatic diseases ,medicine ,MDS ,In patient ,Adverse effect ,RC254-282 ,business.industry ,leukemia ,Myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,CD123 ,bispecific antibody ,clinical study ,APVO436 ,medicine.disease ,Leukemia ,Cytokine release syndrome ,Tolerability ,Interleukin-3 receptor ,business - Abstract
Simple Summary AML is a common form of blood cancer in adults. This study was undertaken to evaluate if AML patients who have failed the available standard treatment options could tolerate and potentially benefit from a new form of therapy. This new therapy activates patients’ own immune system against AML cells. The findings from this research may provide the foundation for a potentially more effective future form of standard therapy that is less likely to fail. Abstract APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1–8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.
- Published
- 2021
7. Sequential azacitidine and lenalidomide for patients with relapsed and refractory acute myeloid leukemia: Clinical results and predictive modeling using computational analysis
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Shireen Vali, Diana Abbott, Andrew Hammes, Derek Schatz, Gregory Hemenway, Neeraj Kumar Singh, Clayton A. Smith, Taher Abbasi, Brett M. Stevens, Jonathan A. Gutman, Daniel A. Pollyea, Craig T. Jordan, Christopher R. Cogle, Aaron Fullerton, Amanda Winters, Nicholas Miltgen, Qi Wei, and Leylah Drusbosky
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Azacitidine ,Phases of clinical research ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Predictive Value of Tests ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,Lenalidomide ,Aged ,Retrospective Studies ,Aged, 80 and over ,Salvage Therapy ,business.industry ,Mortality rate ,Computational Biology ,Myeloid leukemia ,Hematology ,Middle Aged ,Survival Rate ,Leukemia, Myeloid, Acute ,Regimen ,Drug Resistance, Neoplasm ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,030215 immunology ,medicine.drug - Abstract
Background Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Genomically-defined personalized therapies are only applicable for a minority of patients. Therapies without identifiable targets can be effective but patient selection is challenging. The sequential combination of azacitidine with high-dose lenalidomide has shown activity; we aimed to determine the efficacy of this genomically-agnostic regimen in patients with R/R AML, with the intention of applying sophisticated methods to predict responders. Methods Thirty-seven R/R AML/myelodysplastic syndrome patients were enrolled in a phase 2 study of azacitidine with lenalidomide. The primary endpoint was complete remission (CR) and CR with incomplete blood count recovery (CRi) rate. A computational biological modeling (CBM) approach was applied retrospectively to predict outcomes based on the understood mechanisms of azacitidine and lenalidomide in the setting of each patients’ disease. Findings Four of 37 patients (11%) had a CR/CRi; the study failed to meet the alternative hypothesis. Significant toxicity was observed in some cases, with three treatment-related deaths and a 30-day mortality rate of 14%. However, the CBM method predicted responses in 83% of evaluable patients, with a positive and negative predictive value of 80% and 89%, respectively. Interpretation Sequential azacitidine and high-dose lenalidomide is effective in a minority of R/R AML patients; it may be possible to predict responders at the time of diagnosis using a CBM approach. More efforts to predict responses in non-targeted therapies should be made, to spare toxicity in patients unlikely to respond and maximize treatments for those with limited options.
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- 2019
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8. Lenalidomide and Prednisone in Low and Intermediate-1 IPSS Risk, Non-Del(5q) Patients With Myelodysplastic Syndromes: Phase 2 Clinical Trial
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Rami S. Komrokji, Sara Tinsley, Alan F. Lis, Eric Padron, David A. Sallman, Christopher R. Cogle, Jeffrey E. Lancet, and Najla Al Ali
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Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Anemia ,Drug Resistance ,Administration, Oral ,Phases of clinical research ,Gastroenterology ,Drug Administration Schedule ,03 medical and health sciences ,0302 clinical medicine ,Prednisone ,Internal medicine ,Humans ,Medicine ,Lenalidomide ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Myelodysplastic syndromes ,Hematology ,medicine.disease ,Clinical trial ,Treatment Outcome ,030104 developmental biology ,Oncology ,Hypomethylating agent ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Hematinics ,Drug Therapy, Combination ,Female ,Erythrocyte Transfusion ,business ,medicine.drug - Abstract
Purpose To test the hypothesis that combination treatment with lenalidomide and prednisone will yield a higher erythroid response rate in patients with non-del(5q) lower-risk myelodysplastic syndromes compared to the historical clinical trial data with lenalidomide monotherapy, which reported a 26% transfusion independence rate. Patients and Methods The study enrolled 25 patients with lower-risk myelodysplastic syndromes by the International Prognostic Scoring System who were transfusion dependent or who had symptomatic anemia and prior erythroid stimulating agent failure or low chance of response. The planned dose of lenalidomide was 10 mg per day. Prednisone dose was 30 mg by mouth, daily cycle 1 tapered by 10 mg after each cycle to 5 mg by mouth every other day for those with response beyond cycle 6. The primary objective was best response (hematologic improvement–erythroid, HI-E) by International Working Group 2006 criteria within 24 weeks. Results The HI-E rate was 20% (5/25) and was 22% (5/23) for patients with evaluable data. All those with response became red blood cell–transfusion independent (5/23). The median time to response was 57 days. The median duration of response was 80 days (95% confidence interval, 69–91). Three of 5 of those with response did not have prior hypomethylating agent, while 14 of 20 those without response received a hypomethylating agent. Conclusion The combination was relatively well tolerated, with no additional observed toxicity to single-agent lenalidomide.
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- 2019
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9. Computational modeling of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) to identify personalized therapy using genomics
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Leylah Drusbosky, Shireen Vali, Shahabuddin Usmani, Shivgonda C. Birajdar, Ansu Kumar, Christopher R. Cogle, P. R. K. Bhargav, Anuj Tyagi, Aftab Alam, Taher Abbasi, Amy Meacham, Deepak Anil Lala, Anusha Pampana, Kunal Ghosh Roy, Sumanth Vasista, Girish Chinnaswamy, Madeleine Turcotte, Swaminathan Rajagopalan, Manju Sengar, Bijal D. Shah, and Kabya Basu
- Subjects
Drug ,Cancer Research ,NPM1 ,media_common.quotation_subject ,T cell ,Lymphoblastic Leukemia ,Genomics ,Computational biology ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Biomarkers, Tumor ,medicine ,Humans ,Computer Simulation ,Precision Medicine ,Personalized therapy ,media_common ,Computational Biology ,Myeloid leukemia ,Hematology ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Nucleophosmin ,030215 immunology - Abstract
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematological malignancy for which optimal therapeutic approaches are poorly characterized. Using computational biology modeling (CBM) in conjunction with genomic data from cell lines and individual patients, we generated disease-specific protein network maps that were used to identify unique characteristics associated with the mutational profiles of ETP-ALL compared to non-ETP-ALL (T-ALL) cases and simulated cellular responses to a digital library of FDA-approved and investigational agents. Genomics-based classification of ETP-ALL patients using CBM had a prediction sensitivity and specificity of 93% and 87%, respectively. This analysis identified key genomic and pathway characteristics that are distinct in ETP-ALL including deletion of nucleophosmin-1 (NPM1), mutations of which are used to direct therapeutic decisions in acute myeloid leukemia. Computational simulations based on mutational profiles of 62 ETP-ALL patient models identified 87 unique targeted combination therapies in 56 of the 62 patients despite actionable mutations being present in only 37% of ETP-ALL patients. Shortlisted two-drug combinations were predicted to be synergistic in 11 profiles and were validated by in vitro chemosensitivity assays. In conclusion, computational modeling was able to identify unique biomarkers and pathways for ETP-ALL, and identify new drug combinations for potential clinical testing.
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- 2019
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10. Integrative analysis of drug response and clinical outcome in acute myeloid leukemia
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Daniel Bottomly, Nicola Long, Anna Reister Schultz, Stephen E. Kurtz, Cristina E. Tognon, Kara Johnson, Melissa Abel, Anupriya Agarwal, Sammantha Avaylon, Erik Benton, Aurora Blucher, Uma Borate, Theodore P. Braun, Jordana Brown, Jade Bryant, Russell Burke, Amy Carlos, Bill H. Chang, Hyun Jun Cho, Stephen Christy, Cody Coblentz, Aaron M. Cohen, Amanda d’Almeida, Rachel Cook, Alexey Danilov, Kim-Hien T. Dao, Michie Degnin, James Dibb, Christopher A. Eide, Isabel English, Stuart Hagler, Heath Harrelson, Rachel Henson, Hibery Ho, Sunil K. Joshi, Brian Junio, Andy Kaempf, Yoko Kosaka, Ted Laderas, Matt Lawhead, Hyunjung Lee, Jessica T. Leonard, Chenwei Lin, Evan F. Lind, Selina Qiuying Liu, Pierrette Lo, Marc M. Loriaux, Samuel Luty, Julia E. Maxson, Tara Macey, Jacqueline Martinez, Jessica Minnier, Andrea Monteblanco, Motomi Mori, Quinlan Morrow, Dylan Nelson, Justin Ramsdill, Angela Rofelty, Alexandra Rogers, Kyle A. Romine, Peter Ryabinin, Jennifer N. Saultz, David A. Sampson, Samantha L. Savage, Robert Schuff, Robert Searles, Rebecca L. Smith, Stephen E. Spurgeon, Tyler Sweeney, Ronan T. Swords, Aashis Thapa, Karina Thiel-Klare, Elie Traer, Jake Wagner, Beth Wilmot, Joelle Wolf, Guanming Wu, Amy Yates, Haijiao Zhang, Christopher R. Cogle, Robert H. Collins, Michael W. Deininger, Christopher S. Hourigan, Craig T. Jordan, Tara L. Lin, Micaela E. Martinez, Rachel R. Pallapati, Daniel A. Pollyea, Anthony D. Pomicter, Justin M. Watts, Scott J. Weir, Brian J. Druker, Shannon K. McWeeney, and Jeffrey W. Tyner
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Cohort Studies ,Leukemia, Myeloid, Acute ,Cancer Research ,Oncology ,Humans ,Cell Differentiation ,Receptors, Cell Surface ,Transcriptome - Abstract
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.
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- 2022
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11. DNMT3A harboring leukemia-associated mutations directs sensitivity to DNA damage at replication forks
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Santhi Pondugula, Brian K. Law, C. Taragjini, Pawel Nowialis, Stefan Kubicek, Cassandra M. Berntsen, Jennifer W Li, Chamara Gunaratne, Philipp B. Staber, Kartika Venugopal, Daniil Shabashvili, Olga A. Guryanova, Luisa M Posada, Yang Feng, Richard L. Bennett, Kathryn I. Krajcik, Zachary Zaroogian, Jonathan E. Bird, H. L. Casellas-Roman, Christopher R. Cogle, Alberto Riva, Rene Opavsky, Daphné Dupéré-Richer, and Jonathan D. Licht
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Gene expression profiling ,Replication fork arrest ,DNA damage ,DNA replication ,Cytarabine ,medicine ,Cancer research ,Epigenetics ,Biology ,Gene ,Chromatin ,medicine.drug - Abstract
Mutations in the DNA methyltransferase 3A (DNMT3A) gene are recurrent in de novo acute myeloid leukemia (AML) and are associated with resistance to standard chemotherapy, disease relapse, and poor prognosis, especially in advanced-age patients. Previous gene expression studies in cells with DNMT3A mutations identified deregulation of cell cycle-related signatures implicated in DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here we tested whether pharmacologically-induced replication fork stalling creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations. We observed increased sensitivity to nucleoside analogs such as cytarabine in multiple cellular systems expressing mutant DNMT3A, ectopically or endogenously, in vitro and in vivo. Analysis of DNA damage signaling in response to cytarabine revealed persistent intra-S phase checkpoint activation, accompanied by accumulation of DNA damage in the DNMT3A(R882) overexpressing cells, which was only partially resolved after drug removal and carried through mitosis, resulting in micronucleation. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine wash-out demonstrated that cells with DNMT3A(mut) were able to restart replication but showed a higher rate of fork collapse. Gene expression profiling by RNA-seq identified deregulation of pathways associated with cell cycle progression and p53 activation, as well as metabolism and chromatin. Together, our studies show that cells with DNMT3A mutations have a defect in recovery from replication fork arrest and subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during DNA replication.
- Published
- 2021
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12. Novel CD33 antibodies unravel localization, biology and therapeutic implications of CD33 isoforms
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Mohammed Gbadamosi, Ioannis Papageorgiou, Soheil Meshinchi, Michael R. Loken, Tiffany A. Hylkema, Laura Pardo, Jatinder K. Lamba, Christopher R. Cogle, Vivek M. Shastri, and Andria L. Doty
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0301 basic medicine ,Gene isoform ,Male ,Cancer Research ,Adolescent ,Genotype ,medicine.medical_treatment ,Cell ,CD33 ,Sialic Acid Binding Ig-like Lectin 3 ,Bone Marrow Cells ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Isoforms ,Progenitor cell ,Child ,biology ,Myeloid leukemia ,Antibodies, Monoclonal ,Infant ,General Medicine ,Immunotherapy ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Child, Preschool ,biology.protein ,Cancer research ,Female ,Antibody ,Immunoglobulin Domains - Abstract
The aim of this study was to establish the therapeutic relevance of the CD33D2 isoform by developing novel antibodies targeting the IgC domain of CD33. Two novel IgC-targeting antibodies, HL2541 and 5C11-2, were developed, and CD33 isoforms were assessed using multiple assays in cells overexpressing either CD33FL or CD33D2 isoforms, unmodified acute myeloid leukemia (AML) cell lines and primary AML specimens representing different genotypes for the CD33 splicing single nucleotide polymorphism. CD33D2 was recognized on cells overexpressing CD33D2 and unmodified AML cell lines; however, minimal/no cell surface detection of CD33D2 was observed in primary AML specimens. Both isoforms were detected intracellularly using novel antibodies. Minimal cell surface expression of CD33D2 on primary AML/progenitor cells warrants further studies on anti-CD33D2 immunotherapeutics.
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- 2020
13. Functional Dependency Analysis Identifies Potential Druggable Targets in Acute Myeloid Leukemia
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Jatinder K. Lamba, Christopher R. Cogle, Chris D. Vulpe, Yujia Zhou, and Gregory P. Takacs
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0301 basic medicine ,Drug ,Cancer Research ,media_common.quotation_subject ,Druggability ,Biology ,acute myeloid leukemia ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,target identification ,hemic and lymphatic diseases ,Gene ,Gene knockout ,media_common ,Drug discovery ,screening ,Myeloid leukemia ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Haematopoiesis ,030104 developmental biology ,Oncology ,Drug development ,030220 oncology & carcinogenesis ,CRISPR ,Cancer research - Abstract
Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ). Ninety-four gene KOs met the criteria of (A) specifically essential to AML cell survival, (B) non-essential in non-AML cells, and (C) druggable according to three-dimensional (3D) modeling or ligand-based druggability scoring. Forty-four of 94 gene-KOs (47%) had an already-approved drug match and comprised a drug development list termed &ldquo, deKO.&rdquo, Fifty of 94 gene-KOs (53%) had no drug in development and comprised a drug discovery list termed &ldquo, disKO.&rdquo, STRING analysis and gene ontology categorization of the disKO targets preferentially cluster in the metabolic processes of UMP biosynthesis, IMP biosynthesis, dihydrofolate metabolism, pyrimidine nucleobase biosynthesis, vitellogenesis, and regulation of T cell differentiation and hematopoiesis. Results from this study serve as a testable compendium of AML drug targets that, after validation, may be translated into new therapeutics.
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- 2020
14. Clinical Application of Computational Methods in Precision Oncology: A Review
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Constantine Gatsonis, Hedvig Hricak, Robert A. Winn, Lori Hoffman Hogg, Martin J. Murphy, Mia A. Levy, Christopher R. Cogle, Orestis A. Panagiotou, Bakul Patel, Sharyl J. Nass, David Magnus, and Samir N. Khleif
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Cancer Research ,Data collection ,business.industry ,Best practice ,MEDLINE ,Computational Biology ,Precision medicine ,Medical Oncology ,Data science ,Health informatics ,Data Accuracy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Analytics ,030220 oncology & carcinogenesis ,Data quality ,Neoplasms ,Medicine ,Humans ,Relevance (information retrieval) ,030212 general & internal medicine ,Precision Medicine ,business - Abstract
Importance There is an enormous and growing amount of data available from individual cancer cases, which makes the work of clinical oncologists more demanding. This data challenge has attracted engineers to create software that aims to improve cancer diagnosis or treatment. However, the move to use computers in the oncology clinic for diagnosis or treatment has led to instances of premature or inappropriate use of computational predictive systems. Objective To evaluate best practices for developing and assessing the clinical utility of predictive computational methods in oncology. Evidence Review The National Cancer Policy Forum and the Board on Mathematical Sciences and Analytics at the National Academies of Sciences, Engineering, and Medicine hosted a workshop to examine the use of multidimensional data derived from patients with cancer and the computational methods used to analyze these data. The workshop convened diverse stakeholders and experts, including computer scientists, oncology clinicians, statisticians, patient advocates, industry leaders, ethicists, leaders of health systems (academic and community based), private and public health insurance carriers, federal agencies, and regulatory authorities. Key characteristics for successful computational oncology were considered in 3 thematic areas: (1) data quality, completeness, sharing, and privacy; (2) computational methods for analysis, interpretation, and use of oncology data; and (3) clinical infrastructure and expertise for best use of computational precision oncology. Findings Quality control was found to be essential across all stages, from data collection to data processing, management, and use. Collecting a standardized parsimonious data set at every cancer diagnosis and restaging could enhance reliability and completeness of clinical data for precision oncology. Data completeness refers to key data elements such as information about cancer diagnosis, treatment, and outcomes, while data quality depends on whether appropriate variables have been measured in valid and reliable ways. Collecting data from diverse populations can reduce the risk of creating invalid and biased algorithms. Computational systems that aid clinicians should be classified as software as a medical device and thus regulated according to the potential risk posed. To facilitate appropriate use of computational methods that interpret high-dimensional data in oncology, treating physicians need access to multidisciplinary teams with broad expertise and deep training among a subset of clinical oncology fellows in clinical informatics. Conclusions and Relevance Workshop discussions suggested best practices in demonstrating the clinical utility of predictive computational methods for diagnosing or treating cancer.
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- 2020
15. Infusion of Alloanergized Donor Lymphocytes after CD34-selected Haploidentical Myeloablative Hematopoietic Stem Cell Transplantation
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Eva C. Guinan, John R. Wingard, Christopher R. Cogle, Peter F. Thall, Laurence J.N. Cooper, Bimalangshu R. Dey, Lisa L. Brennan, Neena Kapoor, Ami J. Shah, Thomas R. Spitzer, Richard E. Champlin, Jeff K. Davies, Lee M. Nadler, and Marcos de Lima
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Adult ,CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Transplantation Conditioning ,Lymphocyte Transfusion ,T-Lymphocytes ,medicine.medical_treatment ,Graft vs Host Disease ,Antigens, CD34 ,Hematopoietic stem cell transplantation ,Article ,Donor lymphocyte infusion ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Lymphocytes ,Acute leukemia ,Leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Myeloablative Agonists ,Donor Lymphocytes ,Immunity, Innate ,Tissue Donors ,Transplantation ,surgical procedures, operative ,030104 developmental biology ,Myelodysplastic Syndromes ,Transplantation, Haploidentical ,Female ,business ,030215 immunology - Abstract
Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown. Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution. Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells. Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098–109. ©2018 AACR.
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- 2018
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16. Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study
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Ronan T. Swords, Diana Azzam, Hassan Al-Ali, Ines Lohse, Claude-Henry Volmar, Justin M. Watts, Aymee Perez, Ana Rodriguez, Fernando Vargas, Roy Elias, Francisco Vega, Arthur Zelent, Shaun P. Brothers, Taher Abbasi, Jonathan Trent, Shaukat Rangwala, Yehuda Deutsch, Eibhlin Conneally, Leylah Drusbosky, Christopher R. Cogle, and Claes Wahlestedt
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Adult ,Male ,0301 basic medicine ,Oncology ,Drug ,Cancer Research ,Treatment response ,medicine.medical_specialty ,media_common.quotation_subject ,Clinical Decision-Making ,Antineoplastic Agents ,Pilot Projects ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Clinical decision making ,Internal medicine ,medicine ,Humans ,Precision Medicine ,Cells, Cultured ,Aged ,media_common ,Aged, 80 and over ,business.industry ,Myeloid leukemia ,Hematology ,Middle Aged ,Precision medicine ,Response to treatment ,Surgery ,Leukemia, Myeloid, Acute ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Female ,Drug Screening Assays, Antitumor ,business ,Ex vivo - Abstract
A precision medicine approach is appealing for use in AML due to ease of access to tumor samples and the significant variability in the patients' response to treatment. Attempts to establish a precision medicine platform for AML, however, have been unsuccessful, at least in part due to the use of small compound panels and having relatively slow turn over rates, which restricts the scope of treatment and delays its onset. For this pilot study, we evaluated a cohort of 12 patients with refractory AML using an ex vivo drug sensitivity testing (DST) platform. Purified AML blasts were screened with a panel of 215 FDA-approved compounds and treatment response was evaluated after 72h of exposure. Drug sensitivity scoring was reported to the treating physician, and patients were then treated with either DST- or non-DST guided therapy. We observed survival benefit of DST-guided therapy as compared to the survival of patients treated according to physician recommendation. Three out of four DST-treated patients displayed treatment response, while all of the non-DST-guided patients progressed during treatment. DST rapidly and effectively provides personalized treatment recommendations for patients with refractory AML.
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- 2018
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17. Computational Modeling and Treatment Identification in the Myelodysplastic Syndromes
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Christopher R. Cogle and Leylah Drusbosky
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0301 basic medicine ,Cancer Research ,Standard of care ,Computational biology ,Bioinformatics ,Models, Biological ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Computer Simulation ,Data input ,Exome sequencing ,INVESTIGATIONAL AGENTS ,business.industry ,Myelodysplastic syndromes ,In silico ,Hematology ,medicine.disease ,Identification (information) ,030104 developmental biology ,Oncology ,Early results ,Analytics ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Myelodysplastic Syndromes (M Savona, Section Editor) ,business ,Biomarkers - Abstract
Purpose of Review This review discusses the need for computational modeling in myelodysplastic syndromes (MDS) and early test results. Recent Findings As our evolving understanding of MDS reveals a molecularly complicated disease, the need for sophisticated computer analytics is required to keep track of the number and complex interplay among the molecular abnormalities. Computational modeling and digital drug simulations using whole exome sequencing data input have produced early results showing high accuracy in predicting treatment response to standard of care drugs. Furthermore, the computational MDS models serve as clinically relevant MDS cell lines for pre-clinical assays of investigational agents. Summary MDS is an ideal disease for computational modeling and digital drug simulations. Current research is focused on establishing the prediction value of computational modeling. Future research will test the clinical advantage of computer-informed therapy in MDS.
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- 2017
18. The Incidence and Health Care Resource Burden of the Myelodysplastic Syndromes in Patients in Whom First-Line Hypomethylating Agents Fail
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Eunice Chang, Steven M. Fruchtman, Tanya G K Bentley, Michael E. Petrone, Sandra E. Kurtin, Michael S. Broder, Sudipto Mukherjee, Christopher R. Cogle, and Scott Megaffin
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Male ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,First line ,Unmet needs ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Health care ,medicine ,Humans ,In patient ,Treatment Failure ,Intensive care medicine ,health care economics and organizations ,Insurance, Health ,business.industry ,Incidence (epidemiology) ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,DNA Methylation ,medicine.disease ,Academia‐Pharma Intersect ,Patient management ,Oncology ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Cohort ,Health Resources ,Female ,business ,030215 immunology - Abstract
Background Although hypomethylating agents (HMAs) are effective and approved therapies for patients with myelodysplastic syndromes (MDS), many patients do not benefit from treatment, and nearly all ultimately stop responding to HMAs. The incidence and cost burden of HMA failure are unknown yet needed to appreciate the magnitude and significance of such failure. Methods We analyzed a de-identified dataset of over 5 million individuals with private health insurance in the U.S. to estimate MDS incidence, prevalence, and treatments. Based on MDS provider interviews, a conceptual model of MDS patient management was constructed to create a new, claims-relevant and drug development-relevant definition of HMA treatment failure. This algorithm was used to define resource encumbrance of MDS patients in whom HMA treatment failed. Results We estimated an MDS incidence rate of ~70 cases per 100,000 enrollees per year and a prevalence of 155 cases per 100,000 enrollees. The proportion of MDS patients receiving HMA treatment was low (~3%), and treatment was typically initiated within 1 year of the first MDS claim. Notably, HMA-treated individuals were older and had more comorbidities than the overall MDS cohort. Total health care costs of managing MDS patients after HMA failure were high (~$77,000 during the first 6 months) and were driven primarily by non-pharmacy costs. Conclusion This study quantifies for the first time the burden of significant unmet need in caring for MDS patients following HMA treatment failure.
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- 2017
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19. Ex Vivo Oncolytic Virotherapy with Myxoma Virus Arms Multiple Allogeneic Bone Marrow Transplant Leukocytes to Enhance Graft versus Tumor
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Jess-Karan S. Dhillon, Bjarne Bogen, Tom Hofland, Cameron L. Lilly, Grant McFadden, Winnie M. Chan, Haider M. Ali, Christopher R. Cogle, Masmudur M. Rahman, Nancy Y. Villa, Ana Lemos de Matos, CCA - Cancer biology and immunology, AII - Cancer immunology, and Graduate School
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0301 basic medicine ,Cancer Research ,allogenic transplant ,MOPC315.BM ,T cells ,Myxoma virus ,lcsh:RC254-282 ,03 medical and health sciences ,myxoma virus ,neutrophils ,medicine ,Pharmacology (medical) ,Virotherapy ,Multiple myeloma ,biology ,business.industry ,Cancer ,medicine.disease ,biology.organism_classification ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Oncolytic virus ,Transplantation ,multiple myeloma ,030104 developmental biology ,Oncology ,Immunology ,Molecular Medicine ,Original Article ,Stem cell ,business ,Ex vivo - Abstract
Allogeneic stem cell transplant-derived T cells have the potential to seek and eliminate sites of residual cancer that escaped primary therapy. Oncolytic myxoma virus (MYXV) exhibits potent anti-cancer efficacy against human cancers like multiple myeloma (MM) and can arm transplant-derived T cells to become more effective cancer killers in vitro and in an immunodeficient xenotransplant murine model. Here, we tested ex vivo MYXV virotherapy against residual murine MM in immunocompetent mice using an allogeneic mouse-mouse model. In contrast to all human MM cell lines previously tested, the murine MM cell line tested here was highly resistant to direct MYXV infection and oncolysis in vitro. Despite this in vitro resistance, we found that ex vivo MYXV-armed allogeneic bone marrow (BM) transplantation dramatically ablated pre-seeded residual MM in vivo. Unexpectedly, we show that both neutrophils and activated T cells from the donor function as virus-armed carrier cells, and MYXV-preloaded cells enhanced MM killing. Our results demonstrate a novel therapeutic paradigm for residual cancer, in which multiple classes of allotransplant leukocytes can be armed by MYXV ex vivo to enhance the graft-versus-tumor effects.
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- 2017
20. Computational drug treatment simulations on projections of dysregulated protein networks derived from the myelodysplastic mutanome match clinical response in patients
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Jatinder K. Lamba, Ansu Kumar, Mar Mallo, Myron Chang, Christopher R. Cogle, Rafael Bejar, Leylah Drusbosky, Francesc Solé, Kimberly E. Hawkins, Taher Abbasi, Shireen Vali, Regina T. Martuscello, Mikkael A. Sekeres, Cindy Medina, and Neeraj Kumar Singh
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0301 basic medicine ,Cancer Research ,Myelodysplastic syndromes ,Decitabine ,Drug resistance ,Bioinformatics ,Cohort Studies ,Computational biology ,03 medical and health sciences ,0302 clinical medicine ,Response prediction ,medicine ,Hma ,Humans ,Computer Simulation ,Protein Interaction Maps ,Adverse effect ,Lenalidomide ,Retrospective Studies ,Chromosome Aberrations ,business.industry ,Retrospective cohort study ,Hematology ,medicine.disease ,Thalidomide ,3. Good health ,Treatment Outcome ,030104 developmental biology ,Hypomethylating agent ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cohort ,Mutanome ,business ,medicine.drug - Abstract
Although the majority of MDS patients fail to achieve clinical improvement to approved therapies, some patients benefit from treatment. Predicting patient response prior to therapy would improve treatment effectiveness, avoid treatment-related adverse events and reduce healthcare costs. Three separate cohorts of MDS patients were used to simulate drug response to lenalidomide alone, hypomethylating agent (HMA) alone, or HMA plus lenalidomide. Utilizing a computational biology program, genomic abnormalities in each patient were used to create an intracellular pathway map that was then used to screen for drug response. In the lenalidomide treated cohort, computer modeling correctly matched clinical responses in 37/46 patients (80%). In the second cohort, 15 HMA patients were modeled and correctly matched to responses in 12 (80%). In the third cohort, computer modeling correctly matched responses in 10/10 patients (100%). This computational biology network approach identified GGH overexpression as a potential resistance factor to HMA treatment and paradoxical activation of beta-catenin (through Csnk1a1 inhibition) as a resistance factor to lenalidomide treatment. We demonstrate that a computational technology is able to map the complexity of the MDS mutanome to simulate and predict drug response. This tool can improve understanding of MDS biology and mechanisms of drug sensitivity and resistance. (C) 2016 The Authors. Published by Elsevier Ltd.
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- 2017
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21. Preliminary Results from a Phase 1 Study of APVO436, a Novel Anti-CD123 x Anti-CD3 Bispecific Molecule, in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome
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Ruth A. Chenault, Alice S. Mims, Christopher R. Cogle, Paul J. Shami, Bret Macpherson, Tara L. Lin, Catherine J. McMahan, Justin M. Watts, Scott Stromatt, Jane A. Gross, Eunice S. Wang, Roland B. Walter, Allison Given Chunyk, Elizabeth H. Cull, and Prapti A. Patel
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business.industry ,Phase (matter) ,Immunology ,Relapsed refractory ,Cancer research ,Myeloid leukemia ,Medicine ,Cell Biology ,Hematology ,Interleukin-3 receptor ,Anti cd3 ,business ,Biochemistry - Abstract
Introduction Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). CD123, the IL-3 receptor alpha-chain, represents an attractive target for antibody therapies because of its high expression on AML/MDS blasts and leukemic stem cells compared to normal hematopoietic stem and progenitor cells. APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, depleted CD123+ cells in AML patient samples ex vivo (Godwin et al. ASH 2017), reduced leukemia engraftment in a systemic AML xenograft model (Comeau et al. AACR 2018), and transiently reduced peripheral CD123+ cells in non-human primates with minimal cytokine release and in a dose-dependent fashion (Comeau et al. AACR 2019). These data provide a basis for the clinical application of APVO436 as a treatment in AML and MDS. Here, we report preliminary data from a first-in-human dose-escalation study of APVO436 in patients with R/R AML and high-risk MDS. Study Design/Methods This ongoing Phase 1/1b study (ClinicalTrials.gov: NCT03647800) was initiated to determine the safety, immunogenicity, pharmacokinetics, pharmacodynamics, and clinical activity of APVO436 as a single agent. Major inclusion criteria were: R/R AML with no other standard treatment option available, R/R MDS with > 5% marrow blasts or any peripheral blasts and failure of a hypomethylating agent, ECOG performance status ≤ 2, life expectancy > 2 months, white blood cells ≤ 25,000 cells/mm3, creatinine ≤ 2 x upper limit of normal (ULN), INR and PTT < 1.5 x ULN and alanine aminotransferase < 3 x ULN. Patients were not restricted from treatment due to cytogenetic or mutational status. Intravenous doses of APVO436 were administered weekly for up to six 28-day cycles (24 doses) with the option to continue dosing for up to 36 total cycles (144 doses). Flat and step dosing regimens were escalated using a safety-driven modified 3 + 3 design. Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). First doses and increasing step doses of APVO436 were infused over 20-24 hours followed by an observation period of 24 hours or more. Bone marrow biopsies were performed every other cycle with responses assessed by European Leukemia Net 2017 criteria for AML or International Working Group (IWG) 2006 criteria for MDS. Results The data cut-off for this interim analysis was July 9, 2020. Twenty-eight patients with primary R/R AML (n=19), therapy-related R/R AML (n=3), or high-risk MDS (n=6) have been enrolled and received a cumulative total of 186 doses. The number of doses received per patient ranged from 1 to 43 (mean of 6.4 doses). Most patients discontinued treatment due to progressive disease; however, blast reduction was achieved in 2 patients, with one patient with MDS maintaining a durable response for 11 cycles before progressing. APVO436 was tolerated across all dose regimens in all cohorts tested. The most common adverse events (AEs), regardless of causality, were edema (32%), diarrhea (29%), febrile neutropenia (29%), fever (25%), hypokalemia (25%), IRR (21%), CRS (18%), chills (18%), and fatigue (18%). AEs ≥ Grade 3 occurring in more than one patient were: febrile neutropenia (25%), anemia (18%), hyperglycemia (14%), decreased platelet count (11%), CRS (11%), IRR (7%), and hypertension (7%). After observing a single dose limiting toxicity (DLT) at a flat dose of 9 µg, step dosing was implemented and no DLTs have been observed thereafter. No treatment-related anti-drug antibodies (ADA) were observed. Transient serum cytokine elevations occurred after several reported IRR and CRS events, with IL-6 most consistently elevated. Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study. Disclosures Watts: BMS: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Lin:Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Celgene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding. Wang:Abbvie: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Agios: Consultancy; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cull:Aptevo Therapeutics: Research Funding. Patel:Agios: Consultancy; Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria. Shami:Aptevo Therapeutics: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Cogle:Aptevo Therapeutics: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Chenault:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Macpherson:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chunyk:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. McMahan:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gross:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stromatt:Aptevo Therapeutics: Current equity holder in publicly-traded company.
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- 2020
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22. A Phase 1B Clinical Study of Combretastatin A1 Diphosphate (OXi4503) and Cytarabine (ARA-C) in Combination (OXA) for Patients with Relapsed or Refractory Acute Myeloid Leukemia
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Vuong N. Trieu, Gary J. Schiller, Justin M. Watts, Christopher R. Cogle, Fatih M. Uckun, Sanjive Qazi, and Tara L. Lin
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Anemia ,lcsh:RC254-282 ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,AML ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Adverse effect ,business.industry ,leukemia ,Myeloid leukemia ,clinical study ,OXA ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Regimen ,Leukemia ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cytarabine ,business ,Febrile neutropenia ,combretastatin ,medicine.drug - Abstract
Combretastatin A1 (OXi4503) is a dual-function drug with vascular disrupting and cytotoxic properties that has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML) and in a prior Phase 1A clinical study for relapsed/refractory (R/R) AML. The purpose of the present multicenter Phase 1B study was to define the maximum tolerated dose (MTD) and safety profile of OXi4503 and cytarabine (ARA-C) administered in combination (OXA). At four centers, 29 patients with R/R AML or myelodysplastic syndrome (MDS) were treated with OXA. The most common grade 3/4 treatment-emergent adverse events (AEs) were febrile neutropenia (28%), hypertension (17%), thrombocytopenia (17%), and anemia (14%). There were no treatment-emergent grade 5 AEs. Drug-related serious adverse events (SAEs) developed in 4/29 patients (14%) and included febrile neutropenia (N = 2), pneumonia/acute respiratory failure (N = 1), and hypotension (N = 1). 9.76 mg/m2 was defined as the MTD of OXi4503 when administered in combination with 1 g/m2 ARA-C. In 26 evaluable AML patients, there were 2 complete remissions (CR), 2 complete remissions with incomplete count recovery (CRi) and one partial response (PR), for an overall response rate (ORR) of 19%. The median overall survival (OS) time for the four patients who achieved a CR/CRi was 528 days (95% CI: 434&ndash, NA), which was significantly longer than the median OS time of 113 days (95% CI: 77&ndash, 172) for the remaining 22 patients who did not achieve a CR/CRi (Log Rank Chi Square = 11.8, p-value = 0.0006). The safety and early evidence of efficacy of the OXA regimen in R/R AML patients warrant further investigation in a Phase 2 clinical study.
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- 2019
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23. Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia
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Christopher R. Cogle, Gerard J. Madlambayan, Samuel D. Lipten, Timothy J. Geddes, Gau Shoua Vue, Mida Bahareh Pezeshkian, Michael Maywood, Yuri A. Pompeu, David A. Ostrov, Vindhya Vijay, Alan D. Salgado, Ann Marie Blenc, Allison M. Ast, Yubin Ge, Leylah Drusbosky, and Regan Miller
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Models, Molecular ,Cancer Research ,Cell Survival ,medicine.medical_treatment ,Cell ,Antineoplastic Agents ,Article ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Humans ,Secretion ,Interleukin 8 ,Cell Proliferation ,Chemotherapy ,Chemistry ,Interleukin-8 ,Cytarabine ,Myeloid leukemia ,Endothelial Cells ,Hematology ,medicine.disease ,Endothelial stem cell ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
One of the greatest challenges in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. Previously, we demonstrated a novel mechanism whereby AML-induced endothelial cell (EC) activation leads to subsequent leukemia cell adherence, quiescence and chemoresistance, identifying activated ECs as potential mediators of relapse. We now show mechanistically that EC activation induces the secretion of interleukin-8 (IL-8) leading to significant expansion of non-adherent AML cells and resistance to cytarabine (Ara-C). Through crystallography and computational modeling, we identified a pocket within IL-8 responsible for receptor binding, screened for small molecules that fit within this pocket, and blocked IL-8 induced proliferation and chemo-protection of AML cells with a hit compound. Results from this study show a new therapeutic strategy for targeting the sanctuary of an activated leukemia microenvironment.
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- 2019
24. Improving Cancer Diagnosis and Care: Patient Access to Oncologic Imaging Expertise
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James A. Brink, Dana Siegal, Christopher R. Cogle, Erin Balogh, Sharyl J. Nass, Ada Muellner, Hedvig Hricak, Curtis P. Langlotz, and Richard L. Schilsky
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Diagnostic Imaging ,Cancer Research ,medicine.medical_specialty ,Decision support system ,Treatment outcome ,MEDLINE ,Medical Oncology ,Patient care ,Health Services Accessibility ,Text mining ,X ray computed ,Neoplasms ,Medicine ,Humans ,Diagnostic Errors ,Intensive care medicine ,Quality of Health Care ,business.industry ,Remote Consultation ,Neoplasms therapy ,Cancer ,medicine.disease ,Decision Support Systems, Clinical ,Telemedicine ,United States ,Comments and Controversies ,Treatment Outcome ,Oncology ,business ,Tomography, X-Ray Computed ,Delivery of Health Care - Published
- 2019
25. Circulating tumor DNA-based genomic profiling of small bowel adenocarcinoma
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Christopher R. Cogle, Pat Gulhati, Leylah Drusbosky, Sujith Kalmadi, Jason S. Starr, Karan Pandya, Hiba I. Dada, and Fadi Braiteh
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Cancer Research ,Genomic profiling ,business.industry ,Small bowel adenocarcinoma ,Malignancy ,medicine.disease ,Lower incidence ,Oncology ,Circulating tumor DNA ,medicine ,Overall survival ,Cancer research ,business ,Intestinal Cancer ,neoplasms ,Stage at diagnosis - Abstract
3523 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, with lower incidence, later stage at diagnosis, and worse overall survival compared to other intestinal cancers, such as colorectal cancer (CRC). Since the majority of small bowel tumors are not accessible to endoscopic biopsy, comprehensive genomic profiling using circulating tumor DNA (ctDNA) may enable non-invasive detection of targetable genomic alterations (GA) in SBA patients. In this study, we characterize the ctDNA GA landscape in SBA. Methods: Analysis of 299 ctDNA samples prospectively collected from 265 SBA patients between 2017 to 2020 was performed using a 73 gene next generation sequencing panel (Guardant360). A subset of patients underwent longitudinal analysis of changes in GA associated with systemic therapy. Results: Of the 265 patients, 160 (60.3%) were male; the median age was 66 (range: 21-93 years). The most common GA identified in SBA patients included TP53 [58%], KRAS [44%], and APC [40%]. MSI was detected in 3.4% of SBA patients. When stratified by primary tumor location, APC, KRAS, TP53, PIK3CA, and ARID1A were the most common GA identified in both duodenal and jejunal adenocarcinomas. ERBB2, BRCA2 and CDK6 alterations were enriched in duodenal adenocarcinoma, while NOTCH and BRAF alterations were enriched in jejunal adenocarcinoma. The most common currently-targetable GA identified were ATM [18%], PIK3CA [17%], EGFR [15%], CDK4/6 [11%], BRAF [10%], and ERBB2 [10%]. Unique differences in GA between SBA and CRC were identified: i) the majority of ERBB2 alterations are mutations (89%) in the extracellular domain and kinase domain, not amplifications (11%); ii) the majority of BRAF alterations are non V600E mutations (69%) and amplifications (28%); iii) there is a significantly lower rate of APC mutations (40%). Alterations in DNA damage response pathway proteins, including ATM and BRCA 1/2, were identified in 30% of SBA patients. ATM alterations were more common in patients ³65 years old. The most common mutations predicted to be related to clonal hematopoiesis of indeterminate potential were TP53, KRAS and GNAS. Longitudinal ctDNA analysis in 4 SBA patients revealed loss of mutations associated with therapeutic response (TP53 R342*, MAPK3 R189Q) and acquired mutations associated with therapeutic resistance (NF1 R1968*, MET S170N, RAF1 L613V). Conclusions: This study represents the first large-scale blood-based ctDNA genomic profiling of SBA. SBA represents a unique molecular entity with differences in frequency and types of GA compared to CRC. Variations in GA were noted based on anatomic origin within the small intestine. Longitudinal ctDNA monitoring revealed novel GA associated with therapeutic resistance. Identification of multiple targetable GA may facilitate clinical decision making and improve patient outcomes in SBA, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.
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- 2021
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26. Health-related quality of life (HRQoL) in patients (pts) with myelodysplastic syndromes (MDS) in the Connect Myeloid Disease Registry
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Michael R. Savona, Pavel Kiselev, Rami S. Komrokji, E. Dawn Flick, Bart L. Scott, Melissa Nifenecker, Dennis A. Revicki, David L. Grinblatt, Adeola Y. Makinde, Chrystal U. Louis, Christopher R. Cogle, Irene DeGutis, Mikkael A. Sekeres, and Guillermo Garcia-Manero
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Health related quality of life ,Cancer Research ,medicine.medical_specialty ,Disease status ,Myeloid ,business.industry ,Myelodysplastic syndromes ,medicine.disease ,medicine.anatomical_structure ,Disease registry ,Oncology ,Internal medicine ,medicine ,Disease risk ,In patient ,business - Abstract
7040 Background: At diagnosis, disease risk and transfusion burden (TB) can impact HRQoL in pts with MDS. The impact of disease status and higher transfusion requirements on HRQoL has not been well studied. We used data from the Connect Myeloid Disease Registry, an ongoing, prospective, observational cohort study that includes adult pts with lower-risk (LR) and higher-risk (HR) MDS, to investigate factors influencing baseline (BL) and subsequent HRQoL. Methods: BL and Month 6 (M6) data from pts enrolled from Dec 12, 2013 to Mar 6, 2020 (data cutoff) were analyzed. Pts were stratified by International Prognostic Scoring System (IPSS) risk (LR, HR), treatment (Tx) within 45 days post-enrollment (no Tx, best supportive care [BSC], active Tx), and TB 16 weeks post-BL (non-transfusion dependent [NTD], low TB [LTB]; 1−3 transfusions, high TB [HTB]: ≥4 transfusions). Pts completed EQ-5D, FACT-An trial outcome index (TOI), and FACT-Fatigue (FACT-F) questionnaires at BL and quarterly thereafter. Clinically meaningful change, based on minimally important differences, was defined as a change of ±0.07 for EQ-5D, ±6 for FACT-An TOI, and ±3 for FACT-F. Results: At data cutoff, 830 (489 LR, 341 HR) pts were enrolled. Median age was 74 years. 278 pts received no initial Tx, 161 BSC, and 378 active Tx. At BL, 470 were NTD, 197 LTB, and 163 HTB. Of 670 pts still on-study at M6, 462 completed the questionnaires at both BL and M6. At BL , clinically meaningful differences were observed in FACT-An TOI and FACT-F scores, but not EQ-5D, between LR- and HR-MDS and the Tx subgroups . From BL to M6, no clinically meaningful changes were observed in mean scores for each questionnaire. For the TB subgroups, meaningful differences were observed at BL in FACT-An TOI and FACT-F scores, but not EQ-5D (Table). From BL to M6, meaningful decreases in scores were reported by 26%, 30%, and 35% of NTD, LTB, and HTB pts in EQ-5D, 41%, 43%, and 48% for FACT-An TOI, and 40%, 42%, and 48% for FACT-F; increases were reported by 19%, 19%, and 20% pts for EQ-5D, 31%, 32%, and 39% for FACT-An TOI, and 30%, 39%, and 40% for FACT-F. Conclusions: This preliminary analysis suggests that pts with HR-MDS, and transfusion-dependent pts, generally had worse HRQoL at BL, providing further support to initiating active Tx in pts with TB. Possible limitations of the analysis are lower completion rates in pts with more severe disease, and EQ-5D may not capture changes in these subgroups at M6. A longer follow-up may help delineate the impact of Tx on HRQoL assessments in pts with MDS. Clinical trial information: NCT01688011. [Table: see text]
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- 2021
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27. Angiotensin II Regulation of Proliferation, Differentiation, and Engraftment of Hematopoietic Stem Cells
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Michael Zingler, Seungbum Kim, Defang Luo, Jeffrey K. Harrison, Mohan K. Raizada, Edward W. Scott, and Christopher R. Cogle
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Male ,0301 basic medicine ,medicine.medical_specialty ,Angiotensin receptor ,Cellular differentiation ,Video Recording ,Biology ,Article ,Mice ,03 medical and health sciences ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Progenitor cell ,Cell Proliferation ,Mice, Inbred BALB C ,Angiotensin II ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,hemic and immune systems ,Cell Differentiation ,Hematopoietic Stem Cells ,Disease Models, Animal ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Hypertension ,Cancer research ,Bone marrow ,Stem cell - Abstract
Emerging evidence indicates that differentiation and mobilization of hematopoietic cell are critical in the development and establishment of hypertension and hypertension-linked vascular pathophysiology. This, coupled with the intimate involvement of the hyperactive renin–angiotensin system in hypertension, led us to investigate the hypothesis that chronic angiotensin II (Ang II) infusion affects hematopoietic stem cell (HSC) regulation at the level of the bone marrow. Ang II infusion resulted in increases in hematopoietic stem/progenitor cells (83%) and long-term HSC (207%) in the bone marrow. Interestingly, increases of HSCs and long-term HSCs were more pronounced in the spleen (228% and 1117%, respectively). Furthermore, we observed higher expression of C–C chemokine receptor type 2 in these HSCs, indicating there was increased myeloid differentiation in Ang II–infused mice. This was associated with accumulation of C–C chemokine receptor type 2 + proinflammatory monocytes in the spleen. In contrast, decreased engraftment efficiency of GFP + HSC was observed after Ang II infusion. Time-lapse in vivo imaging and in vitro Ang II pretreatment demonstrated that Ang II induces untimely proliferation and differentiation of the donor HSC resulting in diminished HSC engraftment and bone marrow reconstitution. We conclude that (1) chronic Ang II infusion regulates HSC proliferation, mediated by angiotensin receptor type 1a, (2) Ang II accelerates HSC to myeloid differentiation resulting in accumulation of C–C chemokine receptor type 2 + HSCs and inflammatory monocytes in the spleen, and (3) Ang II impairs homing and reconstitution potentials of the donor HSCs. These observations highlight the important regulatory roles of Ang II on HSC proliferation, differentiation, and engraftment.
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- 2016
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28. CC-486 (Oral Azacitidine) Induces Responses in Patients with Hematological Malignancies Who had Failed Prior Treatment with Injectable Hypomethylating Agents (HMAS)
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P. Conkling, Steven D. Gore, Thomas E. Boyd, G. Garcia-Manero, Christopher R. Cogle, Michael R. Savona, Qian Dong, Barry Skikne, Stacey M. Ukrainskyj, Keshava Kumar, Bart L. Scott, and Joel Hetzer
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Prior treatment ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,In patient ,Hematology ,business ,Oral Azacitidine - Published
- 2017
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29. Patient and physician perceptions about blood transfusions in the myelodysplastic syndromes
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Alice Houk, David J. King, Rodney A. Schmidt, Matthew Lesser, Ellen Salkeld, and Christopher R. Cogle
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Blood transfusion ,medicine.medical_treatment ,Disease ,Lower risk ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Informed consent ,Physicians ,hemic and lymphatic diseases ,medicine ,Humans ,Blood Transfusion ,Patient Comfort ,Aged ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Health services research ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Cross-Sectional Studies ,Oncology ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Cohort ,Emergency medicine ,Female ,Perception ,Patient Safety ,business ,Follow-Up Studies ,030215 immunology - Abstract
Background Little is known about the shared decision-making between patients with transfusion-dependent (TD) myelodysplastic syndromes (MDS) and their physicians about the benefits, risks, and alternatives to reduce the need for blood transfusions. Methods and Materials We conducted interviews and two cross-sectional surveys of MDS patients and MDS physicians in the US about the use of blood transfusions and disease-modifying therapies (DMTs). Responses from 157 MDS patients and 109 MDS physicians were analyzed. Results The TD-MDS patient cohort had a median age of 69 years and a greater proportion of lower IPSS risk. The MDS physicians primarily practiced in large centers, evenly distributed between academic and community hospitals. There was a high level of independence and generally positive quality of life among patients, who were mostly concerned about effectiveness of blood transfusions and iron overload. MDS patients with shorter duration of disease (less than 5 years) were primarily concerned with transfusion reaction, while MDS patients with longer duration of disease were primarily concerned with iron overload. Approximately half of TD-MDS patients stated they had not discussed alternatives to reduce the need for blood transfusions with their physician. Patients with longer duration of disease were more likely to have a discussion with their physician about alternatives to blood transfusions. Physicians stated that they administered blood transfusions as primary therapy for MDS when it was patient preference, advanced age of patient, frailty, lower risk MDS, significant comorbidities, or failed prior treatments. Conclusions While quality of life seemed generally positive in TD-MDS patients, there were differing perceptions about blood transfusions between patients and physicians. In the future, appraisal and optimization of the informed consent process between MDS patients and physicians are needed.
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- 2020
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30. MDS-120: Molecular and Diagnostic Testing Patterns in Elderly Patients with Myelodysplastic Syndromes (MDS) in the Connect® MDS/AML Disease Registry
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Tracy I. George, David L. Grinblatt, Guillermo Garcia-Manero, Michael R. Savona, Rami S. Komrokji, Chrystal U. Louis, Arlene S. Swern, Christopher R. Cogle, Bart L. Scott, David P. Steensma, Melissa Nifenecker, Jaroslaw P. Maciejewski, Pavel Kiselev, Sandra E. Kurtin, Kathryn Foucar, Mikkael A. Sekeres, and E. Dawn Flick
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Cancer Research ,Pediatrics ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Molecular genetic testing ,Diagnostic test ,Context (language use) ,Hematology ,Newly diagnosed ,medicine.disease ,Disease registry ,Oncology ,hemic and lymphatic diseases ,Baseline characteristics ,medicine ,business ,Cohort study - Abstract
Context: Molecular genetic testing is an important diagnostic tool for MDS. WHO MDS classification criteria were updated in 2016; how they are implemented in practice is unclear. Our knowledge of molecular testing in elderly patients is limited. Objective: To compare testing patterns in elderly (≥80 years) and younger ( Design: Baseline characteristics and laboratory data were collected from patients enrolled from Dec 12, 2013 to data cutoff Dec 13, 2019 in the Connect® MDS/AML Disease Registry ( NCT01688011 ), an ongoing, US, multicenter, prospective observational cohort study of patients with newly diagnosed MDS (aged ≥18 years) or AML (aged ≥55 years). Testing patterns were compared between elderly and younger MDS patients. Results: 234/800 (29.3%) MDS patients were aged ≥80 years and 566/800 (70.7%) Conclusions: Although molecular testing rates have increased since 2017, testing rates for elderly MDS patients remained lower than for younger patients. Education focused on increasing testing rates in elderly patients is needed to ensure appropriate care. The study was supported by Bristol-Myers Squibb.
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- 2020
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31. RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia
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Yinhuai Chen, Huiying Chen, Chun-Wei Chen, Chuan He, Yueh-Chiang Hu, Xi Jiang, Lei Dong, Emily Prince, Zhijian Qian, Huilin Huang, Hengyou Weng, Christopher R. Cogle, Allen C. Zhu, Zhe Yin, Miao Sun, Rui Su, Wei Li, Xiaolan Deng, Yue Sheng, Bin Zhang, Chao Shen, Jianjun Chen, Guido Marcucci, and Sean Robinson
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0303 health sciences ,Messenger RNA ,biology ,Oncogene ,Myeloid leukemia ,Cell Biology ,medicine.disease ,medicine.disease_cause ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,Breast cancer ,Cancer stem cell ,hemic and lymphatic diseases ,Genetics ,biology.protein ,Cancer research ,medicine ,Molecular Medicine ,Demethylase ,Carcinogenesis ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
N6-methyladenosine (m6A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m6A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, we show that ALKBH5 deletion is rare in human AML; instead, ALKBH5 is aberrantly overexpressed in AML. Moreover, its increased expression correlates with poor prognosis in AML patients. We demonstrate that ALKBH5 is required for the development and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs) but not essential for normal hematopoiesis. Mechanistically, ALKBH5 exerts tumor-promoting effects in AML by post-transcriptional regulation of its critical targets such as TACC3, a prognosis-associated oncogene in various cancers. Collectively, our findings reveal crucial functions of ALKBH5 in leukemogenesis and LSC/LIC self-renewal/maintenance and highlight the therapeutic potential of targeting the ALKBH5/m6A axis.
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- 2020
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32. Molecular diagnostic testing patterns in patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) in the Connect MDS/AML Registry
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David L. Grinblatt, Guillermo Garcia-Manero, Jay Patel, Bart L. Scott, Gail J. Roboz, David P. Steensma, Pavel Kiselev, Kathryn Foucar, Michael R. Savona, Rami S. Komrokji, Mehrdad Abedi, Melissa Nifenecker, Harry P. Erba, Jaroslaw P. Maciejewski, Chrystal U. Louis, Christopher R. Cogle, Michael A. Thompson, Daniel A. Pollyea, Mikkael A. Sekeres, and Tracy I. George
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Oncology ,Cancer Research ,medicine.medical_specialty ,Molecular Diagnostic Testing ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,macromolecular substances ,Integrated approach ,medicine.disease ,carbohydrates (lipids) ,stomatognathic diseases ,hemic and lymphatic diseases ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,In patient ,business ,Who classification - Abstract
7553 Background: MDS and AML diagnosis requires an integrated approach including morphologic, cytogenetic and molecular testing. The WHO classification criteria for MDS and AML diagnosis were updated in 2016; however, the impact on clinical practice is unclear. We investigated molecular testing patterns for pts with MDS or AML treated in academic (AC) or community/government (CO/GOV)-based centers in the Connect MDS/AML Registry. Methods: The Connect MDS/AML Disease Registry (NCT01688011) is a large ongoing, US, multicenter, prospective observational cohort study of pts with MDS (aged ≥ 18 yrs) or AML (aged ≥ 55 yrs). Patient data were collected for this analysis upon enrollment from 12 Dec 2013 to 13 Dec 2019, the analysis cut-off. Differences in molecular testing between MDS and AML pts were evaluated and logistic regression used to assess factors associated with increased molecular testing. Results: As of 13 Dec 2019, 800 MDS pts and 626 AML pts were enrolled; median age was 74 vs 71 yrs, 66.3% vs 61.5% were male, and 73.5% vs 60.2% were insured by Medicare/Medicaid. A greater proportion of AML pts (77.5%) had molecular testing vs MDS pts (29.1%). Of 380 MDS pts enrolled before 2017 (< 2017), 16.8% had molecular testing, increasing to 40.2% in 420 MDS pts enrolled from 2017 onward (≥ 2017). Of 289 AML pts enrolled < 2017, 68.9% had molecular testing, increasing to 84.9% in 337 AML pts enrolled ≥ 2017. Mean number of mutations tested increased between < 2017 and ≥ 2017 from 6.9 to 12.7 in MDS pts and from 6.1 to 10.4 in AML pts. Of the 11 mutations most frequently tested ≥ 2017 in MDS and AML pts, 0% and 36%, respectively, have FDA-approved targeted therapies. Gene mutations tested differed between MDS and AML pts; ASXL1 was most frequently tested in MDS pts (68.2%) and FLT3-ITD in AML pts (89.7%). Testing rates increased between < 2017 and ≥ 2017 for ASXL1 from 48.4% to 75.7% in MDS pts and for FLT3-ITD from 84.4% to 93.4% in AML pts. Factors associated with increased testing were age < 75 (vs ≥ 75) yrs, ELN score ≥ 2 (vs 1) and enrollment at AC site (vs CO/GOV) (all P < 0.01) in AML pts and age < 80 (vs ≥ 80 yrs; P < 0.01), AC site (vs CO/GOV; P < 0.01), and geographic region outside the Midwest ( P = 0.015) in MDS pts. Conclusions: While molecular testing rates have increased since the publication of the WHO 2016 criteria, molecular testing rates for MDS pts remain lower than those for AML pts in real-world clinical practice. Elderly pts and pts enrolled in CO/GOV sites were found to have lower rates of molecular testing in both MDS and AML patient cohorts.
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- 2020
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33. Exploring the structure activity relationship and mechanism of a chromene scaffold (CXL series) for its selective anti-proliferative activity towards multidrug resistant cancer cells
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Santanu Hati, Kavitha Chandagirikoppal Vijendra, Tengfei Bian, Haifeng Sun, Christopher R. Cogle, Amy Meacham, Yi Wang, and Chengguo Xing
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0301 basic medicine ,HL60 ,Cell Survival ,Antineoplastic Agents ,Endoplasmic Reticulum ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Cytosol ,In vivo ,Cell Line, Tumor ,Drug Discovery ,medicine ,Structure–activity relationship ,Humans ,Benzopyrans ,Cell Proliferation ,medicine.disease ,In vitro ,Drug Resistance, Multiple ,Multiple drug resistance ,Leukemia ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Molecular Medicine ,Calcium - Abstract
Multidrug resistance (MDR) is one major barrier in cancer management, which urges for new drugs to help treat MDR malignancies and elucidate MDR mechanisms. A series of chromene compounds (the CXL series) demonstrate increased antiproliferative activity toward MDR acute-myeloid-leukemia (AML) cells. The structure-activity relationship (SAR) of the antiproliferative potency has been partly characterized, whereas the structural determinants contributing to selectivity have not been investigated. In this study, three series of CXL compounds were synthesized and evaluated in HL60 and HL60/MX2 leukemia cells. The results not only confirmed previous SAR studies but also, for the first time, provided structural insights into the selectivity for MDR HL60/MX2 cells. Using the lead compounds as probes, we demonstrated that their modulation of intracellular-calcium homeostasis results in their antiproliferative potency and selectivity. Three candidates also demonstrate excellent in vitro safety profiles between cancer cells and normal cells, which will be evaluated in vivo in future studies.
- Published
- 2018
34. CC-486 (oral azacitidine) in patients with myelodysplastic syndromes with pretreatment thrombocytopenia
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Barry S. Skikne, C.L. Beach, Bart L. Scott, Qian Dong, Guillermo Garcia-Manero, Stacey M. Ukrainskyj, Christopher R. Cogle, Keshava Kumar, Joel Hetzer, Thomas E. Boyd, and Suman Kambhampati
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Administration, Oral ,Hemorrhage ,Gastroenterology ,Oral Azacitidine ,03 medical and health sciences ,0302 clinical medicine ,Risk groups ,Internal medicine ,medicine ,Humans ,Platelet ,In patient ,Aged ,Aged, 80 and over ,business.industry ,Platelet Count ,Myelodysplastic syndromes ,Hematology ,Middle Aged ,medicine.disease ,Low platelets ,Thrombocytopenia ,Oncology ,Hypomethylating agent ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Azacitidine ,Female ,business ,030215 immunology - Abstract
Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS) across all prognostic risk groups. The safety and efficacy of CC-486 (oral azacitidine) was investigated in early-phase studies; we assessed clinical outcomes among subgroups of MDS patients from these studies, defined by presence or lack of pretreatment thrombocytopenia (≤75 × 109/L platelet count). Patients received CC-486 300 mg once-daily for 14 or 21 days of repeated 28-day cycles. Overall, 81 patients with MDS, median age 72 years, comprised the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 109/L and 198 × 109/L, respectively. Grade 3–4 bleeding events occurred in 2 patients in the Low Platelets and 1 patient in the High Platelets groups; events resolved without sequelae. Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values
- Published
- 2018
35. Predicting response to BET inhibitors using computational modeling: A BEAT AML project study
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Anjanasree V. Lakshminarayana, Brian J. Druker, Shannon K. McWeeney, Christopher R. Cogle, Leylah Drusbosky, Stephen E. Kurtz, Shireen Vali, Vijayashree P Shyamasundar, Ashish Kumar Agrawal, Saji Gera, Taher Abbasi, Robinson Vidva, Cristina E. Tognon, Anay Talawdekar, and Jeffrey W. Tyner
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Models, Molecular ,Cancer Research ,Databases, Factual ,In silico ,JQ1 ,Drug response ,Genomics ,Antineoplastic Agents ,Disease ,Computational biology ,Biology ,BET inhibitor ,Article ,03 medical and health sciences ,0302 clinical medicine ,AML ,Genetics ,Humans ,Molecular Targeted Therapy ,Chromosome Aberrations ,Computational Biology ,Computational modeling ,Hematology ,3. Good health ,Bromodomain ,Gene Expression Regulation, Neoplastic ,Leukemia, Myeloid, Acute ,Oncology ,030220 oncology & carcinogenesis ,Genomic Profile ,Chemosensitivity assay ,Ex vivo ,030215 immunology ,Transcription Factors - Abstract
Despite advances in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), overall survival rates remain low. The ability to predict treatment response based on individual cancer genomics using computational modeling will aid in the development of novel therapeutics and personalize care. Here, we used a combination of genomics, computational biology modeling (CBM), ex vivo chemosensitivity assay, and clinical data from 100 randomly selected patients in the Beat AML project to characterize AML sensitivity to a bromodomain (BRD) and extra-terminal (BET) inhibitor. Computational biology modeling was used to generate patient-specific protein network maps of activated and inactivated protein pathways translated from each genomic profile. Digital drug simulations of a BET inhibitor (JQ1) were conducted by quantitatively measuring drug effect using a composite AML disease inhibition score. 93% of predicted disease inhibition scores matched the associated ex vivo IC50 value. Sensitivity and specificity of CBM predictions were 97.67%, and 64.29%, respectively. Genomic predictors of response were identified. Patient samples harbouring chromosomal aberrations del(7q) or -7, +8, or del(5q) and somatic mutations causing ERK pathway dysregulation, responded to JQ1 in both in silico and ex vivo assays. This study shows how a combination of genomics, computational modeling and chemosensitivity testing can identify network signatures associating with treatment response and can inform priority populations for future clinical trials of BET inhibitors.
- Published
- 2018
36. Diagnostic Testing Patterns for Ring Sideroblasts (RS) in Patients with Newly Diagnosed Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the Connect® MDS/AML Disease Registry
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Chrystal U. Louis, Dawn Flick, Jay Patel, Christopher R. Cogle, Michael R. Savona, Rami S. Komrokji, Pavel Kiselev, Arlene S. Swern, David L. Grinblatt, Tracy I. George, Bart L. Scott, David P. Steensma, Kathryn Foucar, Mikkael A. Sekeres, and Melissa Nifenecker
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Diagnostic test ,Hematology ,Ring sideroblasts ,Newly diagnosed ,medicine.disease ,Lower risk ,Disease registry ,Oncology ,Internal medicine ,Medicine ,In patient ,business - Published
- 2019
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37. Clinical significance ofin vivocytarabine-induced gene expression signature in AML
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James R. Downing, Raul C. Ribeiro, Stanley Pounds, Jatinder K. Lamba, Xueyuan Cao, Jeffrey E. Rubnitz, Sharyn D. Baker, Susana C. Raimondi, Kristine R. Crews, Neha Bhise, and Christopher R. Cogle
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Male ,0301 basic medicine ,Antimetabolites, Antineoplastic ,Cancer Research ,Adolescent ,medicine.medical_treatment ,Cell ,Bioinformatics ,Article ,Transcriptome ,03 medical and health sciences ,RNA interference ,medicine ,Humans ,Gene Regulatory Networks ,Clinical significance ,RNA, Small Interfering ,Child ,Chemotherapy ,Gene Expression Regulation, Leukemic ,business.industry ,Gene Expression Profiling ,Cytarabine ,Reproducibility of Results ,Hematology ,medicine.disease ,Gene expression profiling ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Child, Preschool ,Gene Knockdown Techniques ,Cancer research ,Female ,RNA Interference ,business ,medicine.drug - Abstract
Despite initial remission, approximately 60-70% of adult and 30% of pediatric patients experience relapse or refractory AML. Studies so far have identified base line gene expression profiles of pathogenic and prognostic significance in AML, however extent of change in gene expression post-initiation of treatment has not been investigated. Exposure of leukemic cells to chemotherapeutic agents such as cytarabine, a mainstay of AML chemotherapy can trigger adaptive response by influencing leukemic cell transcriptome and hence development of resistance or refractory disease. It is however challenging to perform such a study due to lack of availability of specimens post-drug treatment. In this study our primary objective was to identify in vivo cytarabine induced changes in leukemia cell transcriptome and to evaluate their impact on clinical outcome. Our results highlight genes relevant to cytarabine resistance and support the concept of targeting cytarabine-induced genes as a means of improving response.
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- 2015
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38. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes
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Kyle J. MacBeth, Barry S. Skikne, Tao Shi, William Jeffery Edenfield, G. Garcia-Manero, Eric Laille, A Tefferi, Keshava Kumar, Bart L. Scott, Joel Hetzer, Steven D. Gore, Suman Kambhampati, and Christopher R. Cogle
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Adult ,Male ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Azacitidine ,Administration, Oral ,Pharmacology ,Lower risk ,Gastroenterology ,Drug Administration Schedule ,Oral Azacitidine ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Tissue Distribution ,Dosing ,Aged ,Neoplasm Staging ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Therapeutic effect ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Platelet transfusion ,Oncology ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Original Article ,Female ,Safety ,business ,Follow-Up Studies ,030215 immunology ,medicine.drug - Abstract
CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.
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- 2015
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39. Endothelial cell derived angiocrine support of acute myeloid leukemia targeted by receptor tyrosine kinase inhibition
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Christopher R. Cogle, Amy Meacham, Christie McGee, Elizabeth Wise, Leylah Drusbosky, Eric Gars, Edward W. Scott, and Angelica Trujillo
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Vascular Endothelial Growth Factor A ,Cancer Research ,Myeloid ,medicine.medical_treatment ,Mice, SCID ,Mice ,hemic and lymphatic diseases ,Medicine ,Receptors, Platelet-Derived Growth Factor ,Platelet-Derived Growth Factor ,Sulfonamides ,Neovascularization, Pathologic ,Gene Expression Regulation, Leukemic ,Cytarabine ,Myeloid leukemia ,Hematology ,Tumor Burden ,Endothelial stem cell ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,Leukemia ,medicine.anatomical_structure ,Oncology ,Signal Transduction ,medicine.drug ,Antimetabolites, Antineoplastic ,Indazoles ,Bone Marrow Cells ,Pazopanib ,Cell Line, Tumor ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Protein Kinase Inhibitors ,neoplasms ,Cell Proliferation ,Chemotherapy ,business.industry ,Endothelial Cells ,medicine.disease ,Coculture Techniques ,Pyrimidines ,Receptors, Vascular Endothelial Growth Factor ,Drug Resistance, Neoplasm ,Cell culture ,Immunology ,Cancer research ,business ,Neoplasm Transplantation - Abstract
In acute myeloid leukemia (AML), refractory disease is a major challenge and the leukemia microenvironment may harbor refractory disease. Human AML cell lines KG-1 and HL-60 expressed receptors also found on endothelial cells (ECs) such as VEGFRs, PDGFRs, and cKit. When human AML cells were co-cultured with human umbilical vein endothelial cells (HUVECs) and primary bone marrow endothelial cell (BMECs), the AML cells were more resistant to cytarabine chemotherapy, even in transwell co-culture suggesting angiocrine regulation. Primary BMECs secreted significantly increased levels of VEGF-A and PDGF-AB after exposure to cytarabine. Pazopanib, a receptor tyrosine kinase inhibitor (RTKI) of VEGFRs, PDGFRs, and cKit, removed EC protection of AML cells and enhanced AML cell sensitivity to cytarabine. Xenograft modeling showed significant regression of AML cells and abrogation of BM hypervascularity in RTKI treated cohorts. Together, these results show direct cytotoxicity of RTKIs on AML cells and reversal of EC protection. Combining RTKIs with chemotherapy may serve as promising therapeutic strategy for patients with AML.
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- 2015
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40. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease
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Masmudur M. Rahman, Manbok Kim, Grant McFadden, and Christopher R. Cogle
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Herpesvirus 4, Human ,Lymphoma, B-Cell ,Xenotransplantation ,medicine.medical_treatment ,Biophysics ,Myxoma virus ,Biochemistry ,Virus ,Mice ,hemic and lymphatic diseases ,medicine ,Animals ,Molecular Biology ,Oncolytic Virotherapy ,Transplantation ,biology ,business.industry ,Cell Biology ,medicine.disease ,biology.organism_classification ,Lymphoproliferative Disorders ,Oncolytic virus ,Lymphoma ,Disease Models, Animal ,Leukemia ,medicine.anatomical_structure ,Immunology ,Cancer research ,Heterografts ,Bone marrow ,business - Abstract
Epstein-Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts.
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- 2015
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41. Refractory macrocytic anemias in patients with clonal hematopoietic disorders and isolated mutations of the spliceosome gene ZRSR2
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Roger A. Fleischman, Shannon Stockton, and Christopher R. Cogle
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0301 basic medicine ,Male ,Cancer Research ,Myeloid ,Biology ,medicine.disease_cause ,03 medical and health sciences ,hemic and lymphatic diseases ,medicine ,Humans ,Anemia, Macrocytic ,Gene ,Allele frequency ,Aged ,Aged, 80 and over ,Mutation ,Acute leukemia ,Myelodysplastic syndromes ,High-Throughput Nucleotide Sequencing ,Nuclear Proteins ,Hematology ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Ribonucleoproteins ,RNA splicing ,Immunology ,Cancer research ,Spliceosomes ,Macrocytic anemia - Abstract
Although mutations in RNA splicing genes occur frequently in patients with clonal cytopenias of unknown significance (CCUS) and myelodysplastic syndromes (MDS), very often additional common myeloid gene driver mutations are present at diagnosis. Thus, the clinical significance of isolated mutations in the most commonly mutated RNA splicing genes remains unknown. Here we report five unusual patients with an isolated mutation causing a loss of function of ZRSR2, a protein required for recognition of a functional 3' splice site. Two of the patients had a diagnosis of CCUS and three patients had an MDS disorder characterized by low risk features and absence of complex cytogenetic abnor-malities. Notably, all five cases were characterized predominantly by macrocytic anemia. In addition, one CCUS patient followed for more than 15 years with a transfusion dependent macrocytic anemia was found to have an inactivating ZRSR2 mutation with an allele frequency of >60%. We conclude that the common clinical features of patients with an isolated mutation of ZRSR2 are a macrocytic anemia without leukopenia, thrombocytopenia or an increase in marrow blast percentage. At least in some cases, the presence of an isolated ZRSR2 mutation can accompany a dominant hematopoietic clone with a low risk for transformation to frank dysplasia or acute leukemia.
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- 2017
42. The role and clinical implications of the endosteal niche and osteoblasts in regulating leukemia
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Najmaldin Saki, Elahe Khodadi, Shirin Azizidoost, Christopher R. Cogle, and Vindhya Vijay
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0301 basic medicine ,Cancer Research ,Chemokine ,Niche ,Metastasis ,03 medical and health sciences ,Bone Marrow ,medicine ,Animals ,Humans ,Stem Cell Niche ,Leukemia ,Osteoblasts ,biology ,Hematopoietic stem cell ,Osteoblast ,General Medicine ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Oncology ,Immunology ,biology.protein ,Cancer research ,Bone marrow ,Signal transduction - Abstract
Osteoblasts are one among the critical components of the endosteal bone marrow (BM) niche. In addition to hematopoietic stem cell fate, their role in leukemogenesis as well as metastasis of a variety of cancers has been demonstrated in various studies. In this regard, endosteal niche can have a dual role as an initiator and protective role against leukemia. Knowledge of growth factors, chemokines and cytokines secreted by osteoblasts as well as their interaction with signaling pathways inform our understanding of the development, prognosis, recurrence and treatment of malignant BM diseases. Clinical progress in targeting the endosteal niche is also discussed.
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- 2017
43. High rate of uncaptured myelodysplastic syndrome cases and an improved method of case ascertainment
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Christopher R. Cogle, Michelle R. Iannacone, Lulu Yan, Alan F. List, Dana E. Rollison, Daohai Yu, Iman Imanirad, Jill MacKinnon, and Ashley L. Cole
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Male ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,Pathology ,Improved method ,hemic and lymphatic diseases ,Epidemiology ,Humans ,Medicine ,Outpatient clinic ,Registries ,Aged ,High rate ,business.industry ,Incidence ,Incidence (epidemiology) ,Myelodysplastic syndromes ,Reproducibility of Results ,Hematology ,Middle Aged ,medicine.disease ,United States ,Cancer registry ,Case ascertainment ,Oncology ,Myelodysplastic Syndromes ,Population Surveillance ,Female ,business ,Algorithms ,SEER Program - Abstract
The myelodysplastic syndromes (MDS) are often diagnosed in outpatient clinics and may be under-reported to state cancer registries, which predominantly rely on hospital records and laboratory reports. We used a new method of cancer case capture to determine the rate of missed cases and estimate a more accurate incidence of MDS. Using a unique keyword algorithm, we queried all electronic pathology (E-path) reports sent to the state of Florida cancer registry in 2006 to identify potential MDS cases. A stratified, random sample of E-path reports was then reviewed to confirm diagnosis and assign MDS subtype. Characteristics were compared between captured and uncaptured MDS cases. 7111 E-path reports with MDS keyword hits were identified, of which only 18% linked to a registered MDS case, 47% linked to a different cancer, and 34% did not link with any record. Case review of a stratified, random sampling of 285 individuals led to the discovery that uncaptured cases made up 37.7% of the total true MDS cases in 2006. It is estimated that the true incidence of MDS is 5.3 individuals out of 100,000, compared to previous reports of 3.3 out of 100,000. Uncaptured MDS cases were younger and more likely to have information in the pathology report facilitating MDS subtype assignment. Only two-thirds of true MDS cases are captured in Florida using current case-finding mechanisms. Application of a keyword search strategy to identify cases among E-path reports is a feasible technique to improve MDS case ascertainment.
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- 2014
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44. Disparities in First-line Treatment Initiation Among US Medicare Beneficiaries with Myelodysplastic Syndromes (MDS)
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Sheila R. Reddy, Eunice Chang, Sohum Gokhale, Michael McGuire, Christopher R. Cogle, and Michael S. Broder
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First line treatment ,Cancer Research ,medicine.medical_specialty ,Oncology ,business.industry ,Internal medicine ,Myelodysplastic syndromes ,medicine ,Medicare beneficiary ,Hematology ,business ,medicine.disease - Published
- 2018
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45. HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice
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Feng Chun Yang, Fei Wang, Bing Xu, Bernd B. Zeisig, Suming Huang, Ganqian Zhu, Chi Wai Eric So, Ya Cui, Bowen Yan, Yi Qiu, Qian Lai, Huacheng Luo, Tsz Kan Fung, Ying Guo, Christopher R. Cogle, Jie Zha, Wei Li, Mingjiang Xu, and Jianfeng Xu
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0301 basic medicine ,Cancer Research ,HOX and hematopoietic gene regulation ,Biology ,WNT signaling targets ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,enhancer/promoter accessibility ,medicine ,Animals ,Cell Self Renewal ,Hox gene ,Cell Proliferation ,Homeodomain Proteins ,Gene Expression Regulation, Leukemic ,leukemia ,HOTTIP transgenic mice ,Myeloid leukemia ,Hematopoietic stem cell ,Cell Biology ,Hematopoietic Stem Cells ,Chromatin ,HSC self-renewal ,Cell biology ,Leukemia, Myeloid, Acute ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,HOTTIP lncRNA ,Oncology ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,CTCF boundary ,RNA, Long Noncoding ,chromatin domain ,Homeotic gene ,Reprogramming - Abstract
SUMMARY Long non-coding RNAs (lncRNAs) are critical for regulating HOX genes, aberration of which is a dominant mechanism for leukemic transformation. How HOX gene-associated lncRNAs regulate hematopoietic stem cell (HSC) function and contribute to leukemogenesis remains elusive. We found that HOTTIP is aberrantly activated in acute myeloid leukemia (AML) to alter HOXA-driven topologically associated domain (TAD) and gene expression. HOTTIP loss attenuates leukemogenesis of transplanted mice, while reactivation of HOTTIP restores leukemic TADs, transcription, and leukemogenesis in the CTCF-boundary-attenuated AML cells. Hottip aberration in mice abnormally promotes HSC self-renewal leading to AML-like disease by altering the homeotic/hematopoietic gene-associated chromatin signature and transcription program. Hottip aberration acts as an oncogenic event to perturb HSC function by reprogramming leukemic-associated chromatin and gene transcription., In Brief Luo et al. find that the lncRNA HOTTIP is overexpressed in acute myeloid leukemia (AML). They show that HOTTIP coordinates topologically associated domain organization in the AML genome, including the posterior HOXA genes and various key hematopoietic regulator loci, and is important for AML growth., Graphical Abstract
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- 2019
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46. Abstract 3042: Splicing repressor HNRNPC is an indispensable and 'druggable' target in acute myeloid leukemia
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Aaron Winer, Jon Boatwright, Christopher R. Cogle, Jodi L. Bubenik, Brian J. Druker, Lauren Katzell, Jesse Terrell, Vindhya Vijay, Amy Meacham, Cristina E. Tognon, Alberto Riva, Jeffrey W. Tyner, and Vincent Archibald
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Cancer Research ,Haematopoiesis ,Heterogeneous nuclear ribonucleoprotein ,HNRNPC ,Oncology ,hemic and lymphatic diseases ,RNA splicing ,Alternative splicing ,Cancer research ,CD34 ,Myeloid leukemia ,Biology ,Gene mutation - Abstract
Refractory and relapsed disease is the greatest challenge in acute myeloid leukemia (AML), and we have shown that blood vessels serve as sanctuary sites for AML. Using a high throughput screening assay mimicking AML in the vascular niche, we screened 31 million compounds and identified a hit compound 2470-51 that selectively killed AML cells and CD34+CD38-CD123+ AML stem cells, while sparing bone marrow-derived endothelial cells, normal hematopoietic stem and progenitor cells (HSPC) as well as CD4+ T lymphocytes from healthy volunteers. In vivo AML patient-derived xenograft modeling further validated the efficacy of 2470-51 as a selective anti-leukemic agent compared to cytarabine (conventional control). We performed quantitative proteomics combining ITRAQ differential protein expression analysis, label-free shotgun analysis and SPR imaging to identify heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) as the target of 2470-51. HNRNPC depletion in AML cell lines THP1, K562, MV411 and HL-60 significantly decreased cell proliferation, viability and clonogenic capacity of the AML cells. In contrast, normal mesenchymal/fibroblastic cells, endothelial cells and normal HSPCs from human umbilical cord blood specimens were unaffected by HNRNPC depletion, indicating the selective dependence of AML cells on hnRNPC. Furthermore, clinical studies using TCGA AML datasets showed significant survival advantage associated with lower HNRNPC expression. RNA-seq analyses revealed a distinct gene expression pattern suggesting widespread inhibition of Myc transcriptional targets. Using differential alternative splicing and differential transcript expression analyses, we discovered significant alternative splicing of MAX after HNRNPC depletion, resulting in MAX transcript isoforms that lacked Myc-interacting domains (“inactive” MAX). These Myc-interacting domains are necessary for the obligate heterodimerization of Myc and Max and are critical for Myc transcriptional activation. We further analyzed splicing landscapes of 578 AML patients and 33 healthy controls and identified substantial mis-splicing of mRNA in AML patients, despite the absence of somatic gene mutations of splicing factors, when compared to the healthy controls. Moreover, we found significant overexpression of “inactive” MAX isoforms in the healthy controls, while AML patients overexpressed fully functional MAX isoforms, suggesting that MAX splicing may have an important functional role in AML. Collectively, our studies show significant RNA splicing changes in AML and an essential role of HNRNPC in AML in contrast to normal hematopoietic and stromal cells where HNRNPC is dispensable. We present a pharmacologic agent for targeting HNRNPC and Myc-Max as a molecular mechanism of action. Our data indicate that hnRNPC is a critical factor in AML and inhibiting this splicing repressor may represent a new therapeutic strategy. Citation Format: Vindhya Vijay, Amy Meacham, Lauren Katzell, Aaron Winer, Jesse Terrell, Vincent Archibald, Jodi Bubenik, Alberto Riva, Jon Boatwright, Cristina Tognon, Jeffrey Tyner, Brian Druker, Christopher Cogle. Splicing repressor HNRNPC is an indispensable and 'druggable' target in 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 3042.
- Published
- 2019
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47. PARP1 is required for chromosomal translocations
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Sudha B. Singh, Rupak Pathak, Daohong Zhou, Lijian Shao, Yuehan Wu, David M. Weinstock, Elizabeth A. Williamson, Jac A. Nickoloff, Martin Hauer-Jensen, Suk Hee Lee, Virginia M. Klimek, Christopher R. Cogle, Yu Zhang, Robert Hromas, and Justin Wray
- Subjects
Indoles ,Poly ADP ribose polymerase ,Immunology ,Poly (ADP-Ribose) Polymerase-1 ,Chromosomal translocation ,Poly(ADP-ribose) Polymerase Inhibitors ,Biochemistry ,Poly (ADP-Ribose) Polymerase Inhibitor ,Piperazines ,Translocation, Genetic ,Classical complement pathway ,PARP1 ,Humans ,DNA Breaks, Double-Stranded ,RNA, Small Interfering ,Psychological repression ,Cells, Cultured ,Polymerase ,Myeloid Neoplasia ,Leukemia ,biology ,fungi ,food and beverages ,Cell Biology ,Hematology ,Fibroblasts ,Acute Disease ,Alternative complement pathway ,biology.protein ,Cancer research ,Phthalazines ,Poly(ADP-ribose) Polymerases - Abstract
Chromosomal translocations are common contributors to malignancy, yet little is known about the precise molecular mechanisms by which they are generated. Sequencing translocation junctions in acute leukemias revealed that the translocations were likely mediated by a DNA double-strand break repair pathway termed nonhomologous end-joining (NHEJ). There are major 2 types of NHEJ: (1) the classical pathway initiated by the Ku complex, and (2) the alternative pathway initiated by poly ADP-ribose polymerase 1 (PARP1). Recent reports suggest that classical NHEJ repair components repress translocations, whereas alternative NHEJ components were required for translocations. The rate-limiting step for initiation of alternative NHEJ is the displacement of the Ku complex by PARP1. Therefore, we asked whether PARP1 inhibition could prevent chromosomal translocations in 3 translocation reporter systems. We found that 2 PARP1 inhibitors or repression of PARP1 protein expression strongly repressed chromosomal translocations, implying that PARP1 is essential for this process. Finally, PARP1 inhibition also reduced both ionizing radiation-generated and VP16-generated translocations in 2 cell lines. These data define PARP1 as a critical mediator of chromosomal translocations and raise the possibility that oncogenic translocations occurring after high-dose chemotherapy or radiation could be prevented by treatment with a clinically available PARP1 inhibitor.
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- 2013
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48. Acute myeloid leukemia targeting by myxoma virus in vivo depends on cell binding but not permissiveness to infection in vitro
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Masmudur M. Rahman, Amy Meacham, Christopher R. Cogle, Edward W. Scott, Grant McFadden, Eric Bartee, Manbok Kim, and Gerard J. Madlambayan
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Cancer Research ,Myxoma virus ,Biology ,Article ,Virus ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Sarcoma, Myeloid ,Oncolytic Virotherapy ,Hematopoietic stem cell ,Myeloid leukemia ,Hematology ,medicine.disease ,biology.organism_classification ,Virology ,Oncolytic virus ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Oncology ,Bone marrow ,Ex vivo - Abstract
Some oncolytic viruses, such as myxoma virus (MYXV), can selectively target malignant hematopoietic cells, while sparing normal hematopoietic cells. This capacity for discrimination creates an opportunity to use oncolytic viruses as ex vivo purging agents of autologous hematopoietic cell grafts in patients with hematologic malignancies. However, the mechanisms by which oncolytic viruses select malignant hematopoietic cells are poorly understood. In this study, we investigated how MYXV specifically targets human AML cells. MYXV prevented chloroma formation and bone marrow engraftment of two human AML cell lines, KG-1 and THP-1. The reduction in human leukemia engraftment after ex vivo MYXV treatment was dose-dependent and required a minimum MOI of 3. Both AML cell lines demonstrated MYXV binding to leukemia cell membranes following co-incubation: however, evidence of productive MYXV infection was observed only in THP-1 cells. This observation, that KG-1 can be targeted in vivo even in the absence of in vitro permissive viral infection, contrasts with the current understanding of oncolytic virotherapy, which assumes that virus infection and productive replication is a requirement. Preventing MYXV binding to AML cells with heparin abrogated the purging capacity of MYXV, indicating that binding of infectious virus particles is a necessary step for effective viral oncolysis. Our results challenge the current dogma of oncolytic virotherapy and show that in vitro permissiveness to an oncolytic virus is not necessarily an accurate predictor of oncolytic potency in vivo.
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- 2012
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49. Early Treatment Initiation in Myelodysplastic Syndromes (MDS) Produces Higher Rate of and Earlier Transfusion Independence (TI)
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Sheila R. Reddy, Eunice Chang, Elya Papoyan, Christopher R. Cogle, Michael McGuire, and Michael S. Broder
- Subjects
Cancer Research ,Pediatrics ,medicine.medical_specialty ,Oncology ,business.industry ,Myelodysplastic syndromes ,medicine ,Transfusion independence ,Hematology ,medicine.disease ,business - Published
- 2017
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50. Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia
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Barry S. Skikne, Kyle J. MacBeth, Elias J. Jabbour, Renee Ward, Tao Shi, Heidi Giordano, Steven D. Gore, Guillermo Garcia-Manero, Sarah Sakoian, Hagop M. Kantarjian, Eric Laille, and Christopher R. Cogle
- Subjects
Adult ,Male ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Maximum Tolerated Dose ,Antimetabolites ,Gastrointestinal Diseases ,Azacitidine ,Administration, Oral ,Biological Availability ,Chronic myelomonocytic leukemia ,Pharmacology ,Gastroenterology ,Oral Azacitidine ,Myelogenous ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,Original Reports ,medicine ,Humans ,Adverse effect ,Fatigue ,Aged ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,Leukemia, Myelomonocytic, Chronic ,DNA Methylation ,Middle Aged ,medicine.disease ,Leukemia ,Oncology ,Myelodysplastic Syndromes ,Female ,business ,medicine.drug - Abstract
Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.
- Published
- 2011
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