76 results on '"Senapedis W"'
Search Results
2. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells
- Author
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Etchin, J, Berezovskaya, A, Conway, A S, Galinsky, I A, Stone, R M, Baloglu, E, Senapedis, W, Landesman, Y, Kauffman, M, Shacham, S, Wang, J CY, and Look, A T
- Published
- 2017
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3. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications
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Tai, Y-T, Landesman, Y, Acharya, C, Calle, Y, Zhong, M Y, Cea, M, Tannenbaum, D, Cagnetta, A, Reagan, M, Munshi, A A, Senapedis, W, Saint-Martin, J-R, Kashyap, T, Shacham, S, Kauffman, M, Gu, Y, Wu, L, Ghobrial, I, Zhan, F, Kung, A L, Schey, S A, Richardson, P, Munshi, N C, and Anderson, K C
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- 2014
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4. Expression of wild type and mutant TSC2, but not TSC1, causes an increase in the G1 fraction of the cell cycle in HEK293 cells
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Khare, L, Astrinidis, A, Senapedis, W, Adams, P D, and Henske, E Petri
- Published
- 2002
5. Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic colorectal cancer (mCRC)
- Author
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Hays, J., primary, Zhang, J., additional, Berlin, J.D., additional, O'Hara, M., additional, Shah, M.A., additional, Reichmann, W., additional, Senapedis, W., additional, Achour, H., additional, Baloglu, E., additional, Shacham, S., additional, and Kauffman, M., additional
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- 2018
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6. Co-crystal structure of NAMPT dimer with KPT-9274
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Neggers, J.E., primary, Kwanten, B., additional, Dierckx, T., additional, Noguchi, H., additional, Voet, A., additional, Vercruysse, T., additional, Baloglu, E., additional, Senapedis, W., additional, Jacquemyn, M., additional, and Daelemans, D., additional
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- 2018
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7. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia
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Takao, S, primary, Chien, W, additional, Madan, V, additional, Lin, D-C, additional, Ding, L-W, additional, Sun, Q-Y, additional, Mayakonda, A, additional, Sudo, M, additional, Xu, L, additional, Chen, Y, additional, Jiang, Y-Y, additional, Gery, S, additional, Lill, M, additional, Park, E, additional, Senapedis, W, additional, Baloglu, E, additional, Müschen, M, additional, and Koeffler, H P, additional
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- 2017
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8. A first in human phase 1 study of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL
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Naing, A., primary, Leong, S., additional, Pishvaian, M.J., additional, Razak, A.R.A., additional, Mahipal, A., additional, Berlin, J., additional, Cho, D., additional, Senapedis, W., additional, Shacham, S., additional, Kauffman, M., additional, Ellis, J., additional, Meade, J., additional, and Baloglu, E., additional
- Published
- 2017
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9. LBA23 - Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic colorectal cancer (mCRC)
- Author
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Hays, J., Zhang, J., Berlin, J.D., O'Hara, M., Shah, M.A., Reichmann, W., Senapedis, W., Achour, H., Baloglu, E., Shacham, S., and Kauffman, M.
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- 2018
- Full Text
- View/download PDF
10. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells
- Author
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Etchin, J, primary, Berezovskaya, A, additional, Conway, A S, additional, Galinsky, I A, additional, Stone, R M, additional, Baloglu, E, additional, Senapedis, W, additional, Landesman, Y, additional, Kauffman, M, additional, Shacham, S, additional, Wang, J C Y, additional, and Look, A T, additional
- Published
- 2016
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11. 492 Quantification of exportin-1 (XPO1) occupancy by selective inhibitors of nuclear export (SINE)
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Crochiere, M., primary, Klebanov, B., additional, Baloglu, E., additional, Kalid, O., additional, Kashyap, T., additional, Senapedis, W., additional, del Alamo, D., additional, Tamir, S., additional, McCauley, D., additional, Carlson, R., additional, Kauffman, M., additional, Shacham, S., additional, and Landesman, Y., additional
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- 2014
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12. 480 Identification of novel small molecules as selective PAK4 allosteric modulators (PAMs) by stable isotope labeling of amino acids in cells (SILAC)
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Senapedis, W., primary, Landesman, Y., additional, Schenone, M., additional, Karger, B., additional, Wu, S., additional, Shacham, S., additional, and Baloglu, E., additional
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- 2014
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13. 247 Selective inhibitors of nuclear export (SINE) block the expression of DNA damage repair proteins and sensitize cancer cells to DNA damage therapeutic agents
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Kashyap, T., primary, Crochiere, M., additional, Friedlander, S., additional, Klebanov, B., additional, Senapedis, W., additional, Baloglu, E., additional, del Alamo, D., additional, Tamir, S., additional, Rashal, T., additional, McCauley, D., additional, Carlson, R., additional, Kauffman, M., additional, Shacham, S., additional, and Landesman, Y., additional
- Published
- 2014
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14. 374PD - A first in human phase 1 study of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL
- Author
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Naing, A., Leong, S., Pishvaian, M.J., Razak, A.R.A., Mahipal, A., Berlin, J., Cho, D., Senapedis, W., Shacham, S., Kauffman, M., Ellis, J., Meade, J., and Baloglu, E.
- Published
- 2017
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15. Preclinical Evaluation of Novel Pak4 Allosteric Modulators Against Triple Negative Breast Cancer
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Senapedis, W., primary, McCauley, D., additional, Landesman, Y., additional, Kalid, O., additional, Ellis, J., additional, Carlson, R., additional, Shacham, S., additional, and Baloglu, E., additional
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- 2014
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- View/download PDF
16. Targeting the vulnerability to NAD+depletion in B-cell acute lymphoblastic leukemia
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Takao, S, Chien, W, Madan, V, Lin, D-C, Ding, L-W, Sun, Q-Y, Mayakonda, A, Sudo, M, Xu, L, Chen, Y, Jiang, Y-Y, Gery, S, Lill, M, Park, E, Senapedis, W, Baloglu, E, Müschen, M, and Koeffler, H P
- Abstract
Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD+depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD+reserve. NAD+depletion may be a promising alternative approach to treating patients with B-ALL.
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- 2018
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17. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications
- Author
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Tai, Y-T, primary, Landesman, Y, additional, Acharya, C, additional, Calle, Y, additional, Zhong, M Y, additional, Cea, M, additional, Tannenbaum, D, additional, Cagnetta, A, additional, Reagan, M, additional, Munshi, A A, additional, Senapedis, W, additional, Saint-Martin, J-R, additional, Kashyap, T, additional, Shacham, S, additional, Kauffman, M, additional, Gu, Y, additional, Wu, L, additional, Ghobrial, I, additional, Zhan, F, additional, Kung, A L, additional, Schey, S A, additional, Richardson, P, additional, Munshi, N C, additional, and Anderson, K C, additional
- Published
- 2013
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18. 386P - Preclinical Evaluation of Novel Pak4 Allosteric Modulators Against Triple Negative Breast Cancer
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Senapedis, W., McCauley, D., Landesman, Y., Kalid, O., Ellis, J., Carlson, R., Shacham, S., and Baloglu, E.
- Published
- 2014
- Full Text
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19. TACC3-TSC2 maintains nuclear envelope structure and controls cell division
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Gómez-Baldó L, Schmidt S, Ca, Maxwell, Bonifaci N, Gabaldón T, Po, Vidalain, Senapedis W, Kletke A, Rosing M, Barnekow A, Rottapel R, Capellá G, Vidal M, Aristotelis Astrinidis, Rp, Piekorz, and Ma, Pujana
20. The second-generation exportin-1 inhibitor KPT-8602 demonstrates potent activity against acute lymphoblastic leukemia
- Author
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Vercruysse T, De Bie J, Neggers J, Jacquemyn M, Vanstreels E, Jl, Schmid-Burgk, Hornung V, Baloglu E, Landesman Y, Senapedis W, Shacham S, Dagklis A, Jan Cools, and Daelemans D
21. Targeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models.
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Senapedis W, Gallagher KM, Figueroa E, Farelli JD, Lyng R, Hodgson JG, O'Donnell CW, Newman JV, Pacaro M, Siecinski SK, Chen J, and McCauley TG
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Epigenesis, Genetic, Xenograft Model Antitumor Assays, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Transcription, Genetic, RNA, Messenger genetics, RNA, Messenger metabolism, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Liver Neoplasms genetics, Liver Neoplasms metabolism, Liver Neoplasms pathology, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Gene Expression Regulation, Neoplastic, DNA Methylation, Down-Regulation genetics, Epigenomics methods
- Abstract
Dysregulation of master regulator c-MYC (MYC) plays a central role in hepatocellular carcinoma (HCC) and other cancers but remains an elusive target for therapeutic intervention. MYC expression is epigenetically modulated within naturally occurring DNA loop structures, Insulated Genomic Domains (IGDs). We present a therapeutic approach using an epigenomic controller (EC), a programmable epigenomic mRNA medicine, to precisely modify MYC IGD sub-elements, leading to methylation of MYC regulatory elements and durable downregulation of MYC mRNA transcription. Significant antitumor activity is observed in preclinical models of HCC treated with the MYC-targeted EC, as monotherapy or in combination with tyrosine kinase or immune checkpoint inhibitors. These findings pave the way for clinical development of MYC-targeting epigenomic controllers in HCC patients and provide a framework for programmable epigenomic mRNA therapeutics for cancer and other diseases., (© 2024. The Author(s).)
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- 2024
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22. Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers.
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Khan HY, Nagasaka M, Aboukameel A, Alkhalili O, Uddin MH, Bannoura SF, Mzannar Y, Azar I, Beal EW, Tobon ME, Kim SH, Beydoun R, Baloglu E, Senapedis W, El-Rayes BF, Philip PA, Mohammad RM, Shields AF, Al Hallak MN, and Azmi AS
- Subjects
- Humans, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, p21-Activated Kinases genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal drug therapy
- Abstract
KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line-derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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23. A phase 1 clinical trial of oral eltanexor in patients with relapsed or refractory multiple myeloma.
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Cornell RF, Baz R, Richter JR, Rossi A, Vogl DT, Chen C, Shustik C, Alvarez MJ, Shen Y, Unger TJ, Ben-Shahar O, Wang H, Baloglu E, Senapedis W, Ma X, Landesman Y, Bai X, Bader J, Xu H, Marshall T, Chang H, Walker CJ, Shah J, Shacham S, Kauffman MG, and Hofmeister CC
- Subjects
- Aged, Female, Humans, Male, Administration, Oral, Treatment Outcome, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local drug therapy
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- 2022
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24. PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma.
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Khan HY, Uddin MH, Balasubramanian SK, Sulaiman N, Iqbal M, Chaker M, Aboukameel A, Li Y, Senapedis W, Baloglu E, Mohammad RM, Zonder J, and Azmi AS
- Abstract
Diffuse large B-cell lymphoma (DLBCL), grade 3b follicular lymphoma (FL), and mantle cell lymphoma (MCL) are aggressive non-Hodgkin's lymphomas (NHL). Cure rates are suboptimal and novel treatment strategies are needed to improve outcomes. Here, we show that p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) is critical for lymphoma subsistence. Dual targeting of PAK4-NAMPT by the Phase I small molecule KPT-9274 suppressed cell proliferation in DLBCL, FL, and MCL. Growth inhibition was concurrent with apoptosis induction alongside activation of pro-apoptotic proteins and reduced pro-survival markers. We observed NAD suppression, ATP reduction, and consequent cellular metabolic collapse in lymphoma cells due to KPT-9274 treatment. KPT-9274 in combination with standard-of-care chemotherapeutics led to superior inhibition of cell proliferation. In vivo, KPT-9274 could markedly suppress the growth of WSU-DLCL2 (DLBCL), Z-138, and JeKo-1 (MCL) sub-cutaneous xenografts, and a remarkable increase in host life span was shown, with a 50% cure of a systemic WSU-FSCCL (FL) model. Residual tumor analysis confirmed a reduction in total and phosphorylated PAK4 and activation of the pro-apoptotic cascade. This study, using various preclinical experimental models, demonstrates the therapeutic potential of targeting PAK4-NAMPT in DLBCL, FL, and MCL. The orally bioavailable, safe, and efficacious PAK4-NAMPT dual inhibitor KPT-9274 warrants further clinical investigation.
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- 2021
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25. Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer.
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Trott JF, Aboud OA, McLaughlin B, Anderson KL, Modiano JF, Kim K, Jen KY, Senapedis W, Chang H, Landesman Y, Baloglu E, Pili R, and Weiss RH
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- Animals, Apoptosis Regulatory Proteins pharmacology, Cell Proliferation, Male, Mice, Nicotinamide Phosphoribosyltransferase, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy
- Abstract
Background: Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer., Methods: In this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti-programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies., Results: We demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) Naprt expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors., Conclusions: This study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.
- Published
- 2020
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26. Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies.
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Fischer MA, Friedlander SY, Arrate MP, Chang H, Gorska AE, Fuller LD, Ramsey HE, Kashyap T, Argueta C, Debler S, Byrne M, Villaume MT, Shaver AC, Senapedis W, Landesman Y, Baloglu E, Shacham S, and Savona MR
- Subjects
- Active Transport, Cell Nucleus, Cell Line, Tumor, Humans, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Hematologic Neoplasms drug therapy
- Abstract
The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial., (© 2020 by The American Society of Hematology.)
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- 2020
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27. Publisher Correction: PAK4 inhibition improves PD-1 blockade immunotherapy.
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Abril-Rodriguez G, Torrejon DY, Liu W, Zaretsky JM, Nowicki TS, Tsoi J, Puig-Saus C, Baselga-Carretero I, Medina E, Quist MJ, Garcia AJ, Senapedis W, Baloglu E, Kalbasi A, Cheung-Lau G, Berent-Maoz B, Comin-Anduix B, Hu-Lieskovan S, Wang CY, Grasso CS, and Ribas A
- Published
- 2020
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28. PAK4 inhibition improves PD-1 blockade immunotherapy.
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Abril-Rodriguez G, Torrejon DY, Liu W, Zaretsky JM, Nowicki TS, Tsoi J, Puig-Saus C, Baselga-Carretero I, Medina E, Quist MJ, Garcia AJ, Senapedis W, Baloglu E, Kalbasi A, Cheung-Lau G, Berent-Maoz B, Comin-Anduix B, Hu-Lieskovan S, Wang CY, Grasso CS, and Ribas A
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Mice, Immune Checkpoint Inhibitors, Immunotherapy, Neoplasms drug therapy, Programmed Cell Death 1 Receptor, p21-Activated Kinases genetics
- Abstract
Lack of tumor infiltration by immune cells is the main mechanism of primary resistance to programmed cell death protein 1 (PD-1) blockade therapies for cancer. It has been postulated that cancer cell-intrinsic mechanisms may actively exclude T cells from tumors, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. Here, we show that p21-activated kinase 4 (PAK4) is enriched in non-responding tumor biopsies with low T cell and dendritic cell infiltration. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD-1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of anti-PD-1 with the PAK4 inhibitor KPT-9274 improved anti-tumor response compared with anti-PD-1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and a lack of response to PD-1 blockade, which could be reversed with PAK4 inhibition., Competing Interests: Competing interests G.A.-R. has received honoraria for consulting with Arcus Biosciences. W.S. and E.B. were employees of Karyopharm Therapeutics when this study was conducted. A.R. has received honoraria for consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis, Roche and Sanofi, is or has been a member of the scientific advisory board, and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX Bio, ImaginAb, IsoPlexis, Gilead Kite, Lutris Pharma, Merus, PACT Pharma, Rgenix and Tango Therapeutics. G.A.-R., D.Y.T., C.S.G. and A.R. are inventors in a patent application covering the use of PAK4 inhibitors for cancer immunotherapy.
- Published
- 2020
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29. PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors.
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Mpilla G, Aboukameel A, Muqbil I, Kim S, Beydoun R, Philip PA, Mohammad RM, Kamgar M, Shidham V, Senapedis W, Baloglu E, Li J, Dyson G, Xue Y, El-Rayes B, and Azmi AS
- Abstract
Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation.
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- 2019
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30. Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer.
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Sexton R, Mahdi Z, Chaudhury R, Beydoun R, Aboukameel A, Khan HY, Baloglu E, Senapedis W, Landesman Y, Tesfaye A, Kim S, Philip PA, and Azmi AS
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Nucleus metabolism, Cell Survival, Humans, Paclitaxel chemistry, Paclitaxel pharmacology, Exportin 1 Protein, Active Transport, Cell Nucleus drug effects, Karyopherins metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Stomach Neoplasms metabolism
- Abstract
Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.
- Published
- 2019
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31. Targeting Rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-Bad-microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation.
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Mohammad RM, Li Y, Muqbil I, Aboukameel A, Senapedis W, Baloglu E, Landesman Y, Philip PA, and Azmi AS
- Subjects
- Acrylamides pharmacology, Aminopyridines pharmacology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Cell Line, Tumor, Cytokines antagonists & inhibitors, Cytokines genetics, Cytokines metabolism, Enzyme Activation drug effects, Enzyme Activation genetics, Humans, MicroRNAs genetics, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors, Nicotinamide Phosphoribosyltransferase genetics, Nicotinamide Phosphoribosyltransferase metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, RNA, Neoplasm genetics, bcl-Associated Death Protein genetics, p21-Activated Kinases genetics, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal metabolism, Cell Proliferation, Drug Resistance, Neoplasm, MicroRNAs metabolism, Pancreatic Neoplasms metabolism, RNA, Neoplasm metabolism, bcl-Associated Death Protein metabolism, p21-Activated Kinases metabolism
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and therapy resistant malignancy. Mutant K-Ras, found in >90% of refractory PDAC, acts as a molecular switch activating Rho GTPase signaling that in turn promotes a plethora of pro-survival molecules and oncogenic microRNAs. We investigated the impact of Rho GTPase effector protein p21 activated kinase 4 (PAK4) inhibition on pro-survival p-Bad and oncogenic miRNA signaling. We demonstrate that the dual NAMPT and PAK4 modulators (KPT-9274 and KPT-9307) inhibit PDAC cell proliferation through downregulation of Bad phosphorylation and upregulation of tumor suppressive miRNAs (miR-145, let-7c, let-7d, miR-34c, miR320 and miR-100). These results suggest that targeting PAK4 could become a promising approach to restore pro-apoptotic function of Bad and simultaneously activate tumor suppressive miRNAs in therapy resistant PDAC.
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- 2019
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32. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia.
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Mitchell SR, Larkin K, Grieselhuber NR, Lai TH, Cannon M, Orwick S, Sharma P, Asemelash Y, Zhang P, Goettl VM, Beaver L, Mims A, Puduvalli VK, Blachly JS, Lehman A, Harrington B, Henderson S, Breitbach JT, Williams KE, Dong S, Baloglu E, Senapedis W, Kirschner K, Sampath D, Lapalombella R, and Byrd JC
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Enzyme Inhibitors pharmacology, HL-60 Cells, Humans, K562 Cells, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute pathology, Mice, Mice, Inbred NOD, Mice, SCID, Xenograft Model Antitumor Assays, Acrylamides pharmacology, Aminopyridines pharmacology, Cytokines antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
- Abstract
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD
+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+ , whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML., (© 2019 by The American Society of Hematology.)- Published
- 2019
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33. Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenström Macroglobulinemia.
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Li N, Lopez MA, Linares M, Kumar S, Oliva S, Martinez-Lopez J, Xu L, Xu Y, Perini T, Senapedis W, Baloglu E, Shammas MA, Hunter Z, Anderson KC, Treon SP, Munshi NC, and Fulciniti M
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cytokines antagonists & inhibitors, DNA Breaks, Double-Stranded drug effects, DNA Damage drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors, Rad51 Recombinase genetics, Waldenstrom Macroglobulinemia genetics, Waldenstrom Macroglobulinemia pathology, p21-Activated Kinases antagonists & inhibitors, Acrylamides pharmacology, Aminopyridines pharmacology, Cytokines genetics, Nicotinamide Phosphoribosyltransferase genetics, Waldenstrom Macroglobulinemia drug therapy, p21-Activated Kinases genetics
- Abstract
Purpose: p21-activated kinase 4 (PAK4) plays a significant biological and functional role in a number of malignancies, including multiple myeloma (MM). On the basis of our promising findings in MM, we here characterize PAK4 expression and role in WM cells, as well effect of dual PAK4-NAMPT inhibitor (KPT-9274) against WM cell growth and viability., Experimental Design: We have analyzed mRNA and protein expression levels of PAK4 in WM cells, and used loss-of-function approach to investigate its contribution to WM cell viability. We have further tested the in vitro and in vivo effect of KPT-9274 against WM cell growth and viability., Results: We report here high-level expression and functional role of PAK4 in WM, as demonstrated by shRNA-mediated knockdown; and significant impact of KPT-9274 on WM cell growth and viability. The growth inhibitory effect of KPT-9274 was associated with decreased PAK4 expression and NAMPT activity, as well as induction of apoptosis. Interestingly, in WM cell lines treated with KPT-9274, we detected a significant impact on DNA damage and repair genes. Moreover, we observed that apart from inducing DNA damage, KPT-9274 specifically decreased RAD51 and the double-strand break repair by the homologous recombination pathway. As a result, when combined with a DNA alkylating agents bendamustine and melphalan, KPT-9274 provided a synergistic inhibition of cell viability in WM cell lines and primary patient WM cells in vitro and in vivo ., Conclusions: These results support the clinical investigation of KPT-9274 in combination with DNA-damaging agent for treatment of WM., (©2018 American Association for Cancer Research.)
- Published
- 2019
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34. Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression.
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Aboukameel A, Muqbil I, Baloglu E, Senapedis W, Landesman Y, Argueta C, Kauffman M, Chang H, Kashyap T, Shacham S, Neggers JE, Daelemans D, Heath EI, and Azmi AS
- Abstract
Emerging studies have shown that the expression of AR splice variants (ARv) lacking ligand-binding domain is associated with castrate-resistant prostate cancer (CRPC) and higher risk of tumor metastasis and recurrence. Nuclear export protein XPO1 regulates the nuclear localization of many proteins including tumor suppressor proteins. Increased XPO1 in prostate cancer is associated with a high Gleason score and bone metastasis. In this study, we found that high expression of AR splice variant 7 (AR-v7) was correlated with increased XPO1 expression. Silencing of XPO1 by RNAi or treatment with Selective Inhibitor of Nuclear Export (SINE) compounds selinexor and eltanexor (KPT-8602) down-regulated the expression of AR, AR-v7 and ARv567es at mRNA and protein levels. XPO1 silencing also inhibited the expression of AR and ARv regulators including FOXA1, Src, Vav3, MED1 and Sam68, leading to the suppression of ARv and AR target genes, UBE2C and PSA. By targeting XPO1/ARv signaling, SINE suppressed prostate cancer (PCa) growth in vitro and in vivo and potentiated the anti-cancer activity of anti-AR agents, enzalutamide and abiraterone. Therefore, XPO1 inhibition could be a novel promising agent used in combination with conventional chemotherapeutics and AR-targeted therapy for the better treatment of PCa, especially CRPC., Competing Interests: CONFLICTS OF INTEREST William Senapedis, Erkan Baloglu, Yosef Landesman, Michael Kauffman, Christian Argueta, Trinayan Kashyap, Hua Chang and Sharon Shacham are employees of Karyopharm Therapeutics and hold patents, equity and stocks and have received both major and minor remunerations from Karyopharm. All other authors have no potential conflict of interests.
- Published
- 2018
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35. Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents.
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Kashyap T, Argueta C, Unger T, Klebanov B, Debler S, Senapedis W, Crochiere ML, Lee MS, Kauffman M, Shacham S, and Landesman Y
- Abstract
Introduction: The goal of this study was to examine the effects of selinexor, an inhibitor of exportin-1 mediated nuclear export, on DNA damage repair and to evaluate the cytotoxic effects of selinexor in combination with DNA damaging agents (DDAs) in cancer cells., Results: Selinexor reduced the expression of DNA damage repair (DDR) proteins. This did not induce significant DNA damage in tested cell lines. Inhibition of DDR protein expression resulted in enhanced cancer cell death when cells were pretreated with DDAs. In contrast, enhanced cell death was not detected in cells that were pretreated with selinexor then with DDAs. In vivo , single-agent selinexor, docetaxel, or cisplatin treatment resulted in 66.7%, 51.5%, and 26.6% tumor growth inhibition (TGI), respectively, in an MDA-MB-231 xenograft model. Consequently, combination treatment with docetaxel or cisplatin followed by selinexor in vivo resulted in 93.9% and 103.4% TGI, respectively. Immunohistochemical staining and immunoblot analysis of tumor sections confirmed reduced expression of DDR proteins., Conclusion: Selinexor treatment inhibited DDR mechanisms in cancer cell lines and therefore potentiated DNA damage-based therapy. The sequential combination of DDAs followed by selinexor increased cancer cell death. This combination is superior to each individual therapy and has a mechanistic rationale as a novel anticancer strategy., Methods: Cancer cells treated with selinexor ± DDAs were analyzed using reverse phase protein arrays, immunoblots, quantitative PCR and immunofluorescence. Mice bearing MDA-MB-231 tumors were treated with subtherapeutic doses of selinexor, cisplatin, docetaxel and selinexor in combination with either cisplatin or docetaxel. Tumor growth was evaluated for 25 days., Competing Interests: CONFLICTS OF INTEREST The authors from Karyopharm Therapeutics are all full time Karyopharm employees and have no conflicts of interest to disclose. All authors have read and approved the manuscript for publication in “Oncotarget”.
- Published
- 2018
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36. Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death.
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Argueta C, Kashyap T, Klebanov B, Unger TJ, Guo C, Harrington S, Baloglu E, Lee M, Senapedis W, Shacham S, and Landesman Y
- Abstract
Multiple myeloma (MM) is a plasma cell neoplasm that results in over 11,000 deaths in the United States annually. The backbone therapy for the treatment of MM patients almost always includes combinations with corticosteroids such as dexamethasone (DEX). We found that DEX in combination with selinexor, an inhibitor of exportin-1 (XPO1) activity, synergistically inhibits the mTOR pathway and subsequently promotes cell death in MM cells. Specifically, we show that selinexor induces the expression of the glucocorticoid receptor (GR) and when combined with dexamethasone increases GR transcriptional activity. Moreover, we found that key downstream targets of the mTOR pathway are deregulated by the combination and identified a mechanism in which GR enhances the expression of REDD1 in GR positive cells while suppressing mTOR activity and cell viability. While the single agent activity of selinexor in MM cells appears to be GR-independent, synergy with DEX depends on GR expression. These data suggest that patients with tumor cells that are GR positive will benefit substantially from the combination. The current findings are consistent with the beneficial therapeutic outcome in patients with MM when treated with the combination of selinexor and DEX. In addition, they provide a rationale for testing GR and REDD1 as predictive and prognostic markers of response, respectively, for patients treated with this beneficial combination., Competing Interests: CONFLICTS OF INTEREST CA, TK, BK, TJU, CG, SH, EB, ML, WS, SS and YL are stockholders in Karyopharm; SS is Officer of Karyopharm. The study was sponsored by Karyopharm Therapeutics. All authors reviewed the manuscript and vouch for the accuracy of the data.
- Published
- 2018
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37. Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma.
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Gandhi UH, Senapedis W, Baloglu E, Unger TJ, Chari A, Vogl D, and Cornell RF
- Subjects
- Active Transport, Cell Nucleus drug effects, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Humans, Hydrazines adverse effects, Hydrazines pharmacology, Karyopherins antagonists & inhibitors, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local metabolism, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Signal Transduction drug effects, Treatment Outcome, Triazoles adverse effects, Triazoles pharmacology, Exportin 1 Protein, Antineoplastic Agents therapeutic use, Hydrazines therapeutic use, Karyopherins metabolism, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Triazoles therapeutic use
- Abstract
Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1. Selinexor (KPT-330) is the first-in-human SINE compound. Early phase clinical trials have established the safety profile of this agent and have shown promising efficacy in combination with low-dose dexamethasone and other anti-MM agents. The combination of selinexor and dexamethasone has demonstrated activity in "penta-refractory" MM, (ie, MM refractory to the 5 most active anti-MM agents currently used in treatment). We have reviewed the available data on the molecular implications of XPO1 inhibition in MM. We also reviewed the pertinent early phase clinical data with SINE compounds and discuss management strategies for common toxicities encountered with use of selinexor., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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38. Targeting the vulnerability to NAD + depletion in B-cell acute lymphoblastic leukemia.
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Takao S, Chien W, Madan V, Lin DC, Ding LW, Sun QY, Mayakonda A, Sudo M, Xu L, Chen Y, Jiang YY, Gery S, Lill M, Park E, Senapedis W, Baloglu E, Müschen M, and Koeffler HP
- Subjects
- Acrylamides chemistry, Acrylamides pharmacology, Aminopyridines chemistry, Aminopyridines pharmacology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cytokines antagonists & inhibitors, Disease Models, Animal, Female, Humans, Male, Mice, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Signal Transduction drug effects, Xenograft Model Antitumor Assays, p21-Activated Kinases antagonists & inhibitors, NAD metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism
- Abstract
Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD
+ depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD+ reserve. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL.- Published
- 2018
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39. Target identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes.
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Neggers JE, Kwanten B, Dierckx T, Noguchi H, Voet A, Bral L, Minner K, Massant B, Kint N, Delforge M, Vercruysse T, Baloglu E, Senapedis W, Jacquemyn M, and Daelemans D
- Subjects
- Acrylamides pharmacology, Aminopyridines pharmacology, Antineoplastic Agents pharmacology, Cell Line, Cell Survival drug effects, Cell Survival genetics, Drug Resistance genetics, HCT116 Cells, HL-60 Cells, Humans, K562 Cells, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors, Nicotinamide Phosphoribosyltransferase genetics, CRISPR-Cas Systems, Genes, Essential genetics, Molecular Targeted Therapy methods, Mutagenesis, Site-Directed methods, Small Molecule Libraries pharmacology
- Abstract
Unraveling the mechanism of action and molecular target of small molecules remains a major challenge in drug discovery. While many cancer drugs target genetic vulnerabilities, loss-of-function screens fail to identify essential genes in drug mechanism of action. Here, we report CRISPRres, a CRISPR-Cas-based genetic screening approach to rapidly derive and identify drug resistance mutations in essential genes. It exploits the local genetic variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair to generate a wide variety of functional in-frame mutations. Using large sgRNA tiling libraries and known drug-target pairs, we validate it as a target identification approach. We apply CRISPRres to the anticancer agent KPT-9274 and identify nicotinamide phosphoribosyltransferase (NAMPT) as its main target. These results present a powerful and simple genetic approach to create many protein variants that, in combination with positive selection, can be applied to reveal the cellular target of small-molecule inhibitors.
- Published
- 2018
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40. Decrypting the PAK4 transcriptome profile in mammary tumor forming cells using Next Generation Sequencing.
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Rane CK, Patel M, Cai L, Senapedis W, Baloglu E, and Minden A
- Abstract
The p-21 Activated Kinase 4 (PAK4) protein kinase is implicated in many cancers, including breast cancer. Overexpression of PAK4 is sufficient to cause mouse mammary epithelial cells (iMMECs) to become tumorigenic. To gain insight into the long-term gene expression changes that occur downstream to PAK4, we performed Next Generation Sequencing of RNA collected from PAK4 overexpressing iMMECs and wild-type iMMECs. We identified a list of genes whose expression levels were altered in response to PAK4 overexpression in iMMECs. Some of these genes, including FoxC2 and ParvB, are consistent with a role for PAK4 in cancer. In addition, PAK4 regulates many genes that are frequently associated with the inflammatory response, raising the possibility that there is a connection between PAK4, inflammation, and the tumor microenvironment. This study delineates the PAK4 transcriptome profile in transformed mammary cells and can provide translational utility in other types of cancers as well., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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41. Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease.
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Hwang VJ, Zhou X, Chen X, Trott J, Abu Aboud O, Shim K, Dionne LK, Chmiel KJ, Senapedis W, Baloglu E, Mahjoub MR, Li X, and Weiss RH
- Subjects
- Acrylamides therapeutic use, Aminopyridines therapeutic use, Animals, Apoptosis drug effects, Cell Proliferation drug effects, Disease Models, Animal, Drug Evaluation, Preclinical, Epithelial Cells, Female, Humans, Kidney cytology, Male, Mice, Mice, Transgenic, Organ Culture Techniques, Phosphorylation, Polycystic Kidney, Autosomal Dominant pathology, Receptors, Cell Surface genetics, Signal Transduction drug effects, TRPP Cation Channels genetics, beta Catenin metabolism, Acrylamides pharmacology, Aminopyridines pharmacology, Cytokines metabolism, NAD metabolism, Nicotinamide Phosphoribosyltransferase metabolism, Polycystic Kidney, Autosomal Dominant drug therapy, p21-Activated Kinases metabolism
- Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD. Treatment of PKD-derived cells with this compound not only reduces PAK4 steady-state protein levels and regulates β-catenin signaling, but also inhibits nicotinamide phosphoribosyl transferase, the rate-limiting enzyme in a key NAD salvage pathway. KPT-9274 can attenuate cellular proliferation and induce apoptosis associated with a decrease in active (phosphorylated) PAK4 and β-catenin in several Pkd1-null murine cell lines, with a less pronounced effect on the corresponding phenotypically normal cells. Additionally, KPT-9274 shows inhibition of cystogenesis in an ex vivo model of cyclic AMP-induced cystogenesis as well as in the early stage Pkd1
flox/flox :Pkhd1-Cre mouse model, the latter showing confirmation of specific anti-proliferative, apoptotic, and on-target effects. NAD biosynthetic attenuation by KPT-9274, while critical for highly proliferative cancer cells, does not appear to be important in the slower growing cystic epithelial cells during cystogenesis. KPT-9274 was not toxic in our ADPKD animal model or in other cancer models. Thus, this small molecule inhibitor could be evaluated in a clinical trial as a viable therapy of ADPKD., (Published by Elsevier Inc.)- Published
- 2017
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42. Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma.
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Jiang YY, Lin DC, Mayakonda A, Hazawa M, Ding LW, Chien WW, Xu L, Chen Y, Xiao JF, Senapedis W, Baloglu E, Kanojia D, Shang L, Xu X, Yang H, Tyner JW, Wang MR, and Koeffler HP
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Carcinoma, Squamous Cell drug therapy, Cell Line, Tumor, Cell Proliferation drug effects, Core Binding Factor Alpha 2 Subunit genetics, Cyclin-Dependent Kinases antagonists & inhibitors, Drug Screening Assays, Antitumor, Esophageal Neoplasms drug therapy, Female, Gene Expression Profiling, HSP40 Heat-Shock Proteins genetics, High-Throughput Screening Assays, Humans, Mice, Neoplasm Transplantation, Oncogenes genetics, Phosphoproteins genetics, Sequence Analysis, RNA, Sterol Regulatory Element Binding Protein 2 genetics, Transcription Factors, Transcriptome, YAP-Signaling Proteins, p21-Activated Kinases genetics, Cyclin-Dependent Kinase-Activating Kinase, Acrylamides pharmacology, Aminopyridines pharmacology, Antineoplastic Agents pharmacology, Carcinoma, Squamous Cell genetics, Esophageal Neoplasms genetics, Gene Expression drug effects, Phenylenediamines pharmacology, Pyrimidines pharmacology
- Abstract
Objectives: Oesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of OSCC, few targetable genomic lesions have been identified, and no molecular therapy is available. This study aims to identify druggable candidates in this tumour., Design: High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to decipher the mechanisms of action of CDK7 inhibition in OSCC. A variety of in vitro and in vivo cellular assays were performed to determine the effects of candidate genes on OSCC malignant phenotypes., Results: The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti-OSCC compound, THZ1, a specific CDK7 inhibitor. RNA-Seq revealed that low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts. Notably, further characterisation of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with super-enhancer (SE). Moreover, SE analysis alone uncovered many OSCC lineage-specific master regulators. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel OSCC oncogenes, including PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase., Conclusions: Our integrative approaches led to a catalogue of SE-associated master regulators and oncogenic transcripts, which may significantly promote both the understanding of OSCC biology and the development of more innovative therapies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
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- 2017
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43. Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration.
- Author
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Azmi AS, Li Y, Muqbil I, Aboukameel A, Senapedis W, Baloglu E, Landesman Y, Shacham S, Kauffman MG, Philip PA, and Mohammad RM
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT-330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities. A similar result was obtained with forced expression of miR-145 in PDAC cells. To this end, SINE compound treatment mediated the down-regulation of known miR-145 targets genes including EGFR, MMP1, MT-MMP, c-Myc, Pak4 and Sox-2. In addition, selinexor induced the expression of two important tumor suppressive miRNAs miR-34c and let-7d leading to the up-regulation of p21
WAF1 . These results are the first to report that targeted inhibition of the nuclear export machinery could restore tumor suppressive miRNAs in PDAC that warrants further clinical investigations., Competing Interests: CONFLICTS OF INTEREST William Senapedis, Erkan Baloglu, Yosef Landesman, Michael Kauffman and Sharon Shacham are employees of Karyopharm Therapeutics Inc. These authors hold patent, equity and stocks and has received both major and minor renumerations from Karyopharm. All other authors have no potential conflicts of interests.- Published
- 2017
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44. The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia.
- Author
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Vercruysse T, De Bie J, Neggers JE, Jacquemyn M, Vanstreels E, Schmid-Burgk JL, Hornung V, Baloglu E, Landesman Y, Senapedis W, Shacham S, Dagklis A, Cools J, and Daelemans D
- Subjects
- Active Transport, Cell Nucleus drug effects, Animals, Antineoplastic Agents chemistry, Apoptosis drug effects, CRISPR-Cas Systems, Cell Line, Tumor, Gene Editing, Humans, Karyopherins genetics, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Receptors, Cytoplasmic and Nuclear genetics, Xenograft Model Antitumor Assays, Exportin 1 Protein, Antineoplastic Agents administration & dosage, Karyopherins antagonists & inhibitors, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Thiazoles administration & dosage
- Abstract
Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug-target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL). Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602's drug-target interaction. In vivo , anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models. Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo , KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis. Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528-41. ©2016 AACR ., (©2016 American Association for Cancer Research.)
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- 2017
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45. Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma.
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Fulciniti M, Martinez-Lopez J, Senapedis W, Oliva S, Lakshmi Bandi R, Amodio N, Xu Y, Szalat R, Gulla A, Samur MK, Roccaro A, Linares M, Cea M, Baloglu E, Argueta C, Landesman Y, Shacham S, Liu S, Schenone M, Wu SL, Karger B, Prabhala R, Anderson KC, and Munshi NC
- Subjects
- Allosteric Regulation, Animals, Apoptosis drug effects, Bone Marrow Cells drug effects, Bone Marrow Cells enzymology, Bone Marrow Cells pathology, Caspases genetics, Caspases metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 4, Humans, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear enzymology, Leukocytes, Mononuclear pathology, Mice, Mice, Nude, Molecular Targeted Therapy, Multiple Myeloma enzymology, Multiple Myeloma pathology, Primary Cell Culture, Protein Binding, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Receptor, Fibroblast Growth Factor, Type 3 metabolism, Signal Transduction, Translocation, Genetic, Xenograft Model Antitumor Assays, p21-Activated Kinases antagonists & inhibitors, p21-Activated Kinases metabolism, Gene Expression Regulation, Neoplastic, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Protein Kinase Inhibitors pharmacology, Receptor, Fibroblast Growth Factor, Type 3 genetics, p21-Activated Kinases genetics
- Abstract
Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. This set of data supports PAK4 as an oncogene in myeloma and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.
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- 2017
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46. A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth.
- Author
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Rane C, Senapedis W, Baloglu E, Landesman Y, Crochiere M, Das-Gupta S, and Minden A
- Subjects
- Acrylamides administration & dosage, Acrylamides chemistry, Aminopyridines administration & dosage, Aminopyridines chemistry, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cell Transformation, Neoplastic, Disease Models, Animal, Female, Humans, Mice, Phosphorylation, Triple Negative Breast Neoplasms drug therapy, Xenograft Model Antitumor Assays, p21-Activated Kinases antagonists & inhibitors, Acrylamides pharmacology, Aminopyridines pharmacology, Antineoplastic Agents pharmacology, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, p21-Activated Kinases metabolism
- Abstract
Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative. PAK4 is also overexpressed in other types of cancer, making it a promising drug target. However, its inhibition is complicated by the fact that PAK4 has both kinase-dependent and -independent functions. Here we investigate a new clinical compound KPT-9274, which has been shown to inhibit PAK4 and NAMPT. We find that KPT-9274 (and its analog, KPT-8752) can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. These compounds also block the growth of the breast cancer cells in vitro, and stimulate apoptosis. Most importantly, oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. Our results indicate that KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy.
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- 2017
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47. Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma.
- Author
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Aboukameel A, Muqbil I, Senapedis W, Baloglu E, Landesman Y, Shacham S, Kauffman M, Philip PA, Mohammad RM, and Azmi AS
- Subjects
- Allosteric Regulation drug effects, Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation drug effects, Cell Self Renewal drug effects, Cell Survival drug effects, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Synergism, Female, Humans, Mice, Organoplatinum Compounds pharmacology, Oxaliplatin, Signal Transduction drug effects, Tumor Burden drug effects, Xenograft Model Antitumor Assays, p21-Activated Kinases antagonists & inhibitors, p21-Activated Kinases chemistry, Gemcitabine, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal metabolism, Drug Resistance, Neoplasm, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Pancreatic Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, p21-Activated Kinases metabolism
- Abstract
The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells but not in normal human pancreatic ductal epithelia (HPDE). Gene copy number amplification studies in PDAC patient cohorts confirmed PAK4 amplification making it an attractive therapeutic target in PDAC. We investigated the antitumor activity of novel PAK4 allosteric modulators (PAM) on a panel of PDAC cell lines and chemotherapy-resistant flow-sorted PDAC cancer stem cells (CSC). The toxicity and efficacy of PAMs were evaluated in multiple subcutaneous mouse models of PDAC. PAMs (KPT-7523, KPT-7189, KPT-8752, KPT-9307, and KPT-9274) show antiproliferative activity in vitro against different PDAC cell lines while sparing normal HPDE. Cell growth inhibition was concurrent with apoptosis induction and suppression of colony formation in PDAC. PAMs inhibited proliferation and antiapoptotic signals downstream of PAK4. Co-immunoprecipitation experiments showed disruption of PAK4 complexes containing vimentin. PAMs disrupted CSC spheroid formation through suppression of PAK4. Moreover, PAMs synergize with gemcitabine and oxaliplatin in vitro KPT-9274, currently in a phase I clinical trial (clinicaltrials.gov; NCT02702492), possesses desirable pharmacokinetic properties and is well tolerated in mice with the absence of any signs of toxicity when 200 mg/kg daily is administered either intravenously or orally. KPT-9274 as a single agent showed remarkable antitumor activity in subcutaneous xenograft models of PDAC cell lines and CSCs. These proof-of-concept studies demonstrated the antiproliferative effects of novel PAMs in PDAC and warrant further clinical investigations. Mol Cancer Ther; 16(1); 76-87. ©2016 AACR., Competing Interests: William Senapedis, Erkan Baloglu, Yosef Landesman, Michael Kauffman and Sharon Shacham are employees of Karyopharm Therapeutics Inc. William Senapedis holds patent, equity and stocks and has received both major and minor renumerations from Karyopharm. All other authors have no potential conflict of interests., (©2016 American Association for Cancer Research.)
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- 2017
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48. Anti-tumor activity of selective inhibitor of nuclear export (SINE) compounds, is enhanced in non-Hodgkin lymphoma through combination with mTOR inhibitor and dexamethasone.
- Author
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Muqbil I, Aboukameel A, Elloul S, Carlson R, Senapedis W, Baloglu E, Kauffman M, Shacham S, Bhutani D, Zonder J, Azmi AS, and Mohammad RM
- Subjects
- Acrylamides pharmacology, Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Survival drug effects, Cyclophosphamide pharmacology, Dose-Response Relationship, Drug, Doxorubicin pharmacology, Drug Synergism, Humans, Karyopherins metabolism, Lymphoma, Non-Hodgkin enzymology, Lymphoma, Non-Hodgkin pathology, Mice, Inbred ICR, Mice, SCID, Oxadiazoles pharmacology, Prednisone pharmacology, Receptors, Cytoplasmic and Nuclear metabolism, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Thiazoles pharmacology, Time Factors, Transcription Factor RelA antagonists & inhibitors, Transcription Factor RelA metabolism, Tumor Burden drug effects, Vincristine pharmacology, Xenograft Model Antitumor Assays, Exportin 1 Protein, Active Transport, Cell Nucleus drug effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Dexamethasone pharmacology, Everolimus pharmacology, Hydrazines pharmacology, Karyopherins antagonists & inhibitors, Lymphoma, Non-Hodgkin drug therapy, Protein Kinase Inhibitors pharmacology, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, TOR Serine-Threonine Kinases antagonists & inhibitors, Triazoles pharmacology
- Abstract
In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL. Combination of selinexor with DEX or EVER resulted in enhanced cytotoxicity in WSU-DLCL2 and WSU-FSCCL cells which was consistent with enhanced apoptosis. Molecular analysis showed enhancement in the activation of apoptotic signaling and down-regulation of XPO1. This enhancement is consistent with the mechanism of action of these drugs in that both selinexor and DEX antagonize NF-κB (p65) and mTOR (EVER target) is an XPO1 cargo protein. SINE compounds, KPT-251 and KPT-276, showed activities similar to CHOP (cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone) regimen in subcutaneous and disseminated NHL xenograft models in vivo. In both animal models the anti-lymphoma activity of selinexor is enhanced through combination with DEX or EVER. The in vivo activity of selinexor and related SINE compounds relative to 'standard of care' treatment is consistent with the objective responses observed in Phase I NHL patients treated with selinexor. Our pre-clinical data provide a rational basis for testing these combinations in Phase II NHL trials., (Copyright © 2016. Published by Elsevier Ireland Ltd.)
- Published
- 2016
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49. XPO1 Inhibition Preferentially Disrupts the 3D Nuclear Organization of Telomeres in Tumor Cells.
- Author
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Taylor-Kashton C, Lichtensztejn D, Baloglu E, Senapedis W, Shacham S, Kauffman MG, Kotb R, and Mai S
- Subjects
- Aged, Cell Line, Tumor, Female, Fibroblasts metabolism, Humans, Male, Middle Aged, Multiple Myeloma pathology, Exportin 1 Protein, Cell Nucleus metabolism, Imaging, Three-Dimensional, Karyopherins metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Telomere metabolism
- Abstract
Previous work has shown that the three-dimensional (3D) nuclear organization of telomeres is altered in cancer cells and the degree of alterations coincides with aggressiveness of disease. Nuclear pores are essential for spatial genome organization and gene regulation and XPO1 (exportin 1/CRM1) is the key nuclear export protein. The Selective Inhibitor of Nuclear Export (SINE) compounds developed by Karyopharm Therapeutics (KPT-185, KPT-330/selinexor, and KPT-8602) inhibit XPO1 nuclear export function. In this study, we investigated whether XPO1 inhibition has downstream effects on the 3D nuclear organization of the genome. This was assessed by measuring the 3D telomeric architecture of normal and tumor cells in vitro and ex vivo. Our data demonstrate for the first time a rapid and preferential disruption of the 3D nuclear organization of telomeres in tumor cell lines and in primary cells ex vivo derived from treatment-naïve newly diagnosed multiple myeloma patients. Normal primary cells in culture as well as healthy lymphocyte control cells from the same patients were minimally affected. Using both lymphoid and non-lymphoid tumor cell lines, we found that the downstream effects on the 3D nuclear telomere structure are independent of tumor type. We conclude that the 3D nuclear organization of telomeres is a sensitive indicator of cellular response when treated with XPO1 inhibitors. J. Cell. Physiol. 231: 2711-2719, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
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- 2016
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50. Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death.
- Author
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Kashyap T, Argueta C, Aboukameel A, Unger TJ, Klebanov B, Mohammad RM, Muqbil I, Azmi AS, Drolen C, Senapedis W, Lee M, Kauffman M, Shacham S, and Landesman Y
- Subjects
- Active Transport, Cell Nucleus drug effects, Animals, Bone Neoplasms drug therapy, Bone Neoplasms enzymology, Bone Neoplasms pathology, Cell Death drug effects, Cell Line, Tumor, Cell Nucleus drug effects, Cell Nucleus metabolism, Cell Nucleus pathology, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Drug Synergism, Female, Fibrosarcoma enzymology, Fibrosarcoma genetics, Fibrosarcoma pathology, Humans, Karyopherins metabolism, Mice, Inbred ICR, Mice, SCID, NF-KappaB Inhibitor alpha genetics, NF-KappaB Inhibitor alpha metabolism, NF-kappa B genetics, Osteosarcoma drug therapy, Osteosarcoma enzymology, Osteosarcoma pathology, Phosphorylation, Proteolysis, RNA Interference, Receptors, Cytoplasmic and Nuclear metabolism, Signal Transduction drug effects, Time Factors, Transcription Factor RelA genetics, Transcription Factor RelA metabolism, Transfection, Exportin 1 Protein, Antineoplastic Combined Chemotherapy Protocols pharmacology, Bortezomib pharmacology, Fibrosarcoma drug therapy, Hydrazines pharmacology, Karyopherins antagonists & inhibitors, NF-kappa B metabolism, Proteasome Endopeptidase Complex metabolism, Proteasome Inhibitors pharmacology, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Triazoles pharmacology
- Abstract
The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells. Here, we demonstrated that NF-κB transcriptional activity is up-regulated in cells that are naturally resistant or have acquired resistance to SINE compounds. Resistance to SINE compounds was created by knockdown of the cellular NF-κB inhibitor, IκB-α. Combination treatment of selinexor with proteasome inhibitors decreased NF-κB activity, sensitized SINE compound resistant cells and showed synergistic cytotoxicity in vitro and in vivo. Furthermore, we showed that selinexor inhibited NF-κB activity by blocking phosphorylation of the IκB-α and the NF-κB p65 subunits, protecting IκB-α from proteasome degradation and trapping IκB-α in the nucleus to suppress NF-κB activity. Therefore, combination treatment of selinexor with a proteasome inhibitor may be beneficial to patients with resistance to either single-agent.
- Published
- 2016
- Full Text
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