المؤلفون: Andrea Napolitano, Sharon Shacham, Michael Kauffman, Jatin J. Shah, Hua Chang, Bruno Bolognese, Jianjun Liu, Bruno Vincenzi, Christopher James Walker, Yosef Landesman

المصدر: Journal of Clinical Oncology. 39:11509-11509

مصطلحات موضوعية: Oncology, Cancer Research, medicine.medical_specialty, Poor prognosis, business.industry, Internal medicine, medicine, Treatment options, Liposarcoma, medicine.disease, business

الوصف: 11509 Background: Patients (pts) with recurrent inoperative DDLS have a poor prognosis and limited treatment options. Selinexor is an oral, selective inhibitor of nuclear export (SINE) compound approved for previously treated pts with myeloma and diffuse large B-cell lymphoma. SEAL was a Phase 2-3 randomized, double-blind, study of selinexor versus placebo in pts with progressive DDLS and 2-5 prior systemic therapies. SEAL showed significantly prolonged progression-free survival (PFS, HR = 0.70, p = 0.0228) with well managed toxicity. A biomarker predictive of clinical activity could be used to optimize selection of pts with DDLS for selinexor. Methods: Pts were randomized 2:1 for Phase 3: 188 received twice weekly selinexor (60mg) and 97 received placebo. Three exploratory biomarker analyses (RNA sequencing of biopsies) from selinexor-treated pts were performed: discovery set of sensitive (n = 8) or resistant (n = 9) tumors; a validation set of pts with favorable (n = 19) or poor (n = 14) tumor control based on PFS, and paired lesions from a pt who harbored both a responsive and resistant lesion. Tumor biopsies from 24 pts on placebo with short ( < 5 months, n = 18) and long ( > 6 months, n = 6) PFS were RNA sequenced. Gene expressions were compared using a negative binomial distribution with DeSeq2. Pathway analyses were performed using Gene Set Enrichment Analysis (GSEA) with MSigDB Cancer Gene Neighborhoods. Results: RNA sequencing analysis comparing 17 sensitive and resistant tumors identified 114 differentially expressed genes (adjusted p-values < 0.05). Expression of CALB1, which encodes the calcium-binding protein calbindin, was significantly lower in sensitive tumors (adjusted P [Padj] = 7.5x10-20), and expression of GRM1, which encodes a metabotropic glutamate receptor that activates phospholipase C, was higher in selinexor sensitive tumors (Padj= 0.003). These findings were confirmed in an independent validation set (Padj = 0.01 – 0.02). In the pt with paired sensitive and resistant lesions, CALB1 expression was 52-fold lower in the sensitive tumor. In a comparison of placebo-treated pts, neither CALB1 or GRM1 was differentially expressed between pts with short or long PFS, indicating they are markers of response to selinexor treatment, rather than general markers of disease aggressiveness. Gene set enrichment analyses revealed that selinexor sensitive tumors in the discovery and validation sets showed upregulation of cancer genes related to SNRK and the netrin 1 receptor tumor suppressor DCC. The resistant tumors showed upregulated EIF3S2 translation initiator-related genes. Conclusions: Selinexor sensitive DDLS tumors showed low expression of CALB1 and high GRM1. If validated, pts with DDLS whose tumors match this expression profile are especially likely to benefit from selinexor. Clinical trial information: NCT02606461.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::4bd0cfec00de52f5b7a7bb88946c616aTest
https://doi.org/10.1200/jco.2021.39.15_suppl.11509Test

المؤلفون: Christopher James Walker, Jatin J. Shah, Shirong Li, Yi Chai, Yosef Landesman, Sharon Shacham, Suzanne Lentzsch

المصدر: Journal of Clinical Oncology. 39:8027-8027

مصطلحات موضوعية: Neuroblastoma RAS viral oncogene homolog, Cancer Research, Bortezomib, business.industry, medicine.disease, medicine.disease_cause, Oncology, medicine, Cancer research, HRAS, KRAS, Previously treated, business, Bortezomib/dexamethasone, Multiple myeloma, Dexamethasone, medicine.drug

الوصف: 8027 Background: Activating mutations of the RAS genes NRAS, KRAS, and HRAS ( RASmut) occur in up to 50% of MM and portend poor survival and high recurrence rates. MM cells with RASmut are susceptible to inhibition of germinal center kinase (GCK), resulting in IKAROS degradation independent of cereblon (CRBN). Selinexor is a selective inhibitor of nuclear export (SINE) compound that can induce IKAROS degradation through CRBN-independent pathways to overcome immunomodulatory drug resistance. We explored the benefit of selinexor treatment for pts with RASmut MM. Methods: In the randomized BOSTON study, pts with MM after 1-3 therapies received weekly XVd or twice weekly Vd. In the single-arm STORM study pts with penta-treated, triple class refractory MM were treated with twice weekly Xd. Both treatment regimens are now FDA approved. Mutations were assessed post-hoc by exome sequencing of 119 and 52 pts from BOSTON and STORM, respectively. Pts were considered RASmut if their MM had NRAS, KRAS or HRAS mutations in codons 12, 13 or 61. Results: There were 54 pts (45%) with RASmut in BOSTON (XVd = 26, Vd = 28), and 17 (33%) in STORM. In BOSTON, pts with RASmut MM treated with XVd had significantly longer progression-free survival (PFS) than those treated with Vd (median [med] = 12.9 vs 6.7 months [mo], hazard ratio [HR] = 0.48 [95% CI 0.24-0.97], p = 0.039). For pts treated with Vd, those with RASmut had significantly shorter overall survival (OS) compared to RASwild-type (WT) (med = 16.8 mo vs not reached [NR], HR = 2.87 [95% CI 1.03-7.99], p = 0.035). PFS was not significantly different (med = 6.74 vs 9.82 mo, HR = 1.64 [95% CI 0.88-3.07], p = 0.122). Amongst pts on XVd, there was no difference in survival between RASmut and RASWT pts (PFS: med = 12.8 vs 12.9 mo, HR = 1.08 [95% CI 0.52-2.26], p = 0.83; OS: med = NR vs NR, HR = 0.94 [95% CI 0.36-2.45], p = 0.91). In STORM, pts with RASmut had shorter OS compared to RASwt pts (med = 6.1 vs NR, HR = 2.05 [95% CI 1.22-5.19], p = 0.010). Preliminary studies to explore the mechanisms of action related to RASmut MM sensitivity to XVd demonstrated that selinexor treatment in vitro leads to downregulation of GCK. Conclusions: Despite typically having the worst outcomes, pts with RASmut MM had a similar benefit from XVd as RASWT MM, showing that the XVd combination can overcome RASmut. Mechanistically, selinexor induced down regulation of GCK and enhanced killing of RASmut MM cells. With a manageable safety profile, the XVd regimen could provide a viable treatment option to improve survival of pts with MM with RAS mutations. Clinical trial information: NCT03110562. [Table: see text]

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::803ff0856715c3f7b14160879cd7ea93Test
https://doi.org/10.1200/jco.2021.39.15_suppl.8027Test

المؤلفون: Stacy Fechner, Leah Henegar, Thaddeus J. Unger, Patricia Cogswell, Yosef Landesman, Sharon Shacham, Trinayan Kashyap, Christopher James Walker, Michael M. Wick, Hua Chang, Joan Levy

المصدر: Journal of Clinical Oncology. 38:e23502-e23502

مصطلحات موضوعية: Cancer Research, business.industry, Cell biology, law.invention, XPO1, medicine.anatomical_structure, Oncology, Cytoplasm, law, Gene expression, medicine, Suppressor, Tumor growth inhibition, In patient, Nuclear export signal, business, Nucleus

الوصف: e23502 Background: Selinexor is a selective inhibitor of nuclear export that inhibits XPO1 from shuttling its cargo from the nucleus to the cytoplasm. This leads to accumulation of tumor suppressor proteins in the nucleus, activation of cell cycle checkpoints, cell cycle arrest and apoptosis in cancer cells. Chordomas are rare cancers emanating from the skull base and spine that originate from remnants of the notochord. Patients with chordomas have poor prognosis with limited treatment options. To investigate the in vivo efficacy and assess molecular effects of selinexor treatment in chordoma, two patient-derived xenograft (PDX) mouse models were tested. Methods: Murine chordoma PDX models of recurrent clival chordoma (SF8894) and metastatic sacral chordoma (CF466) were treated with selinexor (5mg/kg PO, 4x weekly). Tumor volume was monitored for 6 weeks of treatment, then excised tumors were used for immunohistochemistry (IHC) analysis and RNA sequencing. Results: Selinexor treatment significantly reduced the tumor volume of mice bearing CF466-derived tumors (5 mice/group; 57.6% reduction in volume compared to control; P = 0.031), and SF8894-derived tumors (4 mice/group; 76.2% reduction; P < 0.001). Differential gene expression between selinexor and vehicle treated samples showed significant differences in 428 genes and 156 genes in the CF466 and SF8894 tumors, respectively (adjusted P-value [Padj] < 0.01). In both models, XPO1 protein levels were markedly decreased and expression of the tumor suppressors TP53 (CF466: Padj = 1.4x10−17; SF8894: Padj = 0.002) and ARRDC3 (CF466: Padj = 2.2x10−72; SF8894: Padj = 2.9x10−12) were increased. In the CF466 chordoma model, selinexor reduced SOX9 (Padj = 1.6x10−18), SMAD4 (Padj = 0.019), and SHH (Padj = 0.028), which were confirmed to be reduced at the protein level by IHC. The SF8894 model showed reduction in EZH2 expression (Padj = 0.0012). Pathway analysis of both models showed activated TP53 signaling (CF466: z-score = 0.82; SF8894: z-score = 2.16) and apoptosis (CF466: P = 5.2x10−8; SF8894: P = 1.2x10−8). G2/M checkpoint regulators were upregulated in the CF466 model (z-score = 2.83). Conclusions: Selinexor treatment led to reduction in tumor growth in two PDX models of chordoma. Both models showed upregulation of TP53 signaling and apoptosis upon treatment, with downregulation of distinct oncogenic pathways. Further investigation of selinexor as a treatment option for chordoma is warranted.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::afa2515128d888b82615415bfd9e5f5bTest
https://doi.org/10.1200/jco.2020.38.15_suppl.e23502Test

المؤلفون: Yosef Landesman, Mariano J. Alvarez, Patrick Y. Wen, Yao Shen, Martin J. van den Bent, Andrew B. Lassman, Sharon Shacham, Scott R. Plotkin, Anna Maria Elisabeth Walenkamp, Hua Chang, Morten Mau-Sørensen, Adam L. Green, Leah Henegar, Christopher James Walker, Andrea Califano

المصدر: Journal of Clinical Oncology. 38:2565-2565

مصطلحات موضوعية: Cancer Research, XPO1, Oncology, business.industry, Exportin-1, Recurrent glioblastoma, Cancer research, Medicine, Nuclear export signal, business

الوصف: 2565 Background: The nuclear export protein exportin 1 (XPO1) is overexpressed in many cancers, including GBM. Selinexor is an inhibitor of XPO1 that crosses the blood-brain-barrier and targets cancer cells by sequestering tumor suppressor proteins and oncoprotein mRNAs in the cell nucleus, inducing cancer cell apoptosis. Selinexor is FDA approved for treatment of patients (pts) with refractory multiple myeloma and is under evaluation for GBM. Methods: We previously reported encouraging results from a phase II clinical trial of selinexor for molecularly unselected pts with recurrent GBM (ASCO 2019). On available pre-treatment archival tumor tissue from 57 cases, we performed DNA exome and RNA transcriptome sequencing to use both gene mutations and expressions for exploring molecular correlates of response in selinexor treated pts, in a hypothesis generating, post-hoc, exploratory analysis. Pts with inadequate drug exposure were excluded ( < 21 days or < 3 doses). We compared OS and PFS between mutated and wild-type patients for genes mutated in at least 5 cases. RNAseq data were used to infer differential protein activities between patients with selinexor sensitive disease (defined as best response of partial or complete response, n = 7) vs. resistant disease (defined as progressive disease as best response, n = 23). Results: Two mutated genes were associated with longer survival in selinexor treated pts: DOCK8 (n = 7; progression free survival [PFS], P = 0.013, hazard ratio [HR] = 3.75 [1.32-10.62]; overall survival, P = 0.009, HR = 15.39 [2.00-118.34]) and PDX1 (n = 5, PFS, P = 0.014, HR = 4.468 [1.361-14.670]). Other commonly mutated genes in glioma, including IDH1 (n = 9) were observed but not associated with survival. Protein activities inferred from RNA sequencing data were also correlated with response to selinexor. In a machine learning model, ZC3H12A (also called MCPIP-1), a negative regulator of inflammation; RAB43, a member of the RAS family that binds GTP and regulates vesicle trafficking, and SOCS3, a suppressor of cytokine signaling that can antagonize JAK/STAT signaling and repress innate immunity, predicted clinical benefit from selinexor (area under the ROC curve from leave one out cross validation = 0.89, permutation test P < 0.04). Conclusions: DOCK8 and PDX1 mutations were favorable prognostic factors in selinexor treated pts. Activity of three proteins (ZC3H12A, RAB43, and SOCS3) predicted clinical benefit from selinexor. Further studies with more pts are required to validate our findings. ClinicalTrials.gov: NCT01986348

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1e409e32defcaa57cdba500c4eda630cTest
https://doi.org/10.1200/jco.2020.38.15_suppl.2565Test

المؤلفون: Cheng Ean Chee, Wei Peng Yong, Sharon Friedlander, Raghav Sundar, Yee Liang Thian, Dilara McCauley, Priscillia Koe, Sharon Shacham, David Shao Peng Tan, Tami Rashal, Yosef Landesman, Boon Cher Goh, Ross A. Soo, Anil Gopinathan, Mei-Yan Pang, Soo-Chin Lee, Andrea Li Ann Wong, Jingshan Ho

المصدر: Journal of Clinical Oncology. 33:2542-2542

مصطلحات موضوعية: Cancer Research, business.industry, Pharmacology, Phase i study, law.invention, XPO1, Oncology, Tolerability, Exportin-1, law, Tumor cell death, Cancer research, Medicine, Suppressor, Multiple tumors, business

الوصف: 2542 Background: SXR is an orally administered potent XPO1 inhibitor that forces nuclear retention and activation of multiple tumor suppressor proteins resulting in tumor cell death. SXR was evalua...

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::d24655dc77cf984edfd0ba0ca7443abeTest
https://doi.org/10.1200/jco.2015.33.15_suppl.2542Test

المؤلفون: Sharon Shacham, Ana Aparicio, Jing-Fang Lu, Christopher J. Logothetis, Tami Rashal, Yosef Landesman, Dilara McCauley, Guanglin Wu, Keith A. Baggerly, Sankar N. Maity, John C. Araujo, Eleni Efstathiou, Robert W. Carlson, Bradley M. Broom, Anh Hoang

المصدر: Journal of Clinical Oncology. 33:277-277

مصطلحات موضوعية: Cancer Research, medicine.medical_specialty, medicine.drug_class, Biology, urologic and male genital diseases, medicine.disease, Androgen, law.invention, XPO1, Prostate cancer, Endocrinology, Oncology, Cell culture, Exportin-1, law, Internal medicine, medicine, Cancer research, Suppressor, Cell Cycle Protein, Nuclear export signal

الوصف: 277 Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs & cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign & primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 & inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth & reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::ece1a98b0fb508803463762b067492dcTest
https://doi.org/10.1200/jco.2015.33.7_suppl.277Test

المؤلفون: Morten Mau-Soerensen, Albiruni R. A. Razak, Anthony Frank Shields, Nashat Y. Gabrail, John F. Gerecitano, Sharon Shacham, Ulrik Niels Lassen, Tami Rashal, Jennifer Cooksey, Yosef Landesman, Gregory Pond, Amit M. Oza, Michael Kauffman, Lillian L. Siu, Philippe L. Bedard, Hemchandra Mahaseth, Mansoor Raza Mirza, Amit Mahipal

المصدر: Journal of Clinical Oncology. 32:2537-2537

مصطلحات موضوعية: Cancer Research, Oncology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::de97cbad672bec6db931775e920aea4dTest
https://doi.org/10.1200/jco.2014.32.15_suppl.2537Test

المؤلفون: Bin Bao, William Senapedis, Asfar S. Azmi, Yosef Landesman, Ramzi M. Mohammad, Erkan Baloglu, Sharon Shacham, Amro Aboukameel, Fazlul H. Sarkar, Michael Kauffman, Ori Kalid

المصدر: Journal of Clinical Oncology. 32:233-233

مصطلحات موضوعية: Cancer Research, Cell growth, Kinase, Effector, GTPase, Biology, medicine.disease, medicine.disease_cause, Oncology, RNA interference, Cell culture, Pancreatic cancer, Cancer research, medicine, KRAS

الوصف: 233 Background: Pancreatic cancer (PC) is a deadly disease in urgent need of novel molecularly targeted drugs. Gene copy number amplification studies in PC patient cohorts has shown amplification of the p21-activated kinase (PAK) family member PAK4. PAK4 acts as a key effector of the Rho family GTPases downstream of Ras signaling. Moreover, PAK4 protein is over-expressed in PC cell lines but not in normal human pancreatic ductal epithelial (HPDE) cells. Most importantly, RNA interference of PAK4 has been shown to suppress PC cell proliferation. These studies clearly make PAK4 an attractive therapeutic target especially because direct targeting of Kras has been a failure. Methods: We have identified a new class of PAK4 allosteric modulators that show anti-proliferative activity against several PC cell lines (IC50s 50s5 fold higher). Results: Cell growth inhibition is concurrent with apoptosis induction and suppression of colony formation in the PC cell lines (and not in HPDE cells). Our small molecule PAK4 allosteric modulator, KPT-7189, suppresses PAK4 protein expression and caused reversal of anti-apoptotic signaling. PAK4 RNA interference enhances KPT-7189 activity, and co-immunoprecipitation experiments showed disruption of PAK4 binding partners. KPT-7189 also inhibited spheroid forming ability of highly resistant PC cells carrying markers of cancer stem cells (CSCs;triple positive for CD33+CD44+EpCAM+) consistent with epithelial-to-mesenchymal (EMT) phenotype. Molecular analyses of KPT-7189 treated CD33+CD44+EpCAM+ spheroids showed suppression of EMT and CSC markers with re-expression of epithelial phenotype markers. Another potent PAK allosteric modulator in the same series, KPT-7651 showing good oral bioavailability (%F = 95%) was well tolerated by mice with a maximum tolerated dose of 60 mg/kg following oral administration. Pre-clinical animal efficacy trial in sub-cutaneous, orthotopic and LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre transgenic mice model is currently under investigation. Conclusions: This is the first proof of concept study demonstrating the development of a PAK4-targeted drug for the treatment of PC, and thus further pre-clinical and clinical investigations are warranted.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::e91812f34ae9735ef39b996e6108e340Test
https://doi.org/10.1200/jco.2014.32.3_suppl.233Test

المؤلفون: John F. Gerecitano, Anthony F. Shields, Jennifer Cooksey, Hemchandra Mahaseth, Sharon Shacham, Morten Mau-Soerensen, Albiruni Ryan Abdul Razak, Eran Shacham, Cindy Y. F. Yau, Lillian L. Siu, Gregory R. Pond, Mansoor Raza Mirza, Michael Kauffman, Tami Rashal, David Shao Peng Tan, Yosef Landesman, Ulrik Lassen, Dilara McCauley, Amit M. Oza, Amit Mahipal

المصدر: Journal of Clinical Oncology. 32:482-482

مصطلحات موضوعية: Antitumor activity, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, business.industry, Pharmacology, medicine.disease, Phase i study, XPO1, Pharmacokinetics, Internal medicine, Pharmacodynamics, Cohort, medicine, Nuclear export signal, business

الوصف: 482 Background: Tumor suppressor proteins (TSPs) are inactivated by their export from the nucleus by Exportin1 (XPO1/CRM1). The oral selective inhibitor of nuclear export selinexor (KPT-330)restores the nuclear localization and function of TSPs and shows a broad anti-tumor activity in animal models. Here we report on the treatment of a subset of patients (pts) with metastatic colorectal cancer (CRC) in a phase I trial of selinexor. Methods: Objectives were to determine the recommended phase 2 dose, evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and tumor response (RECIST 1.1) of selinexor administered in two different schedules with 8 or 10 doses in a 28-day cycle. An expansion cohort of 15 pts with CRC was planned. Results: Twenty-seven pts with CRC were treated across eight doses (3-40 mg/m2) including 15 pts in the expansion cohort (30-35 mg/m2). Median age was 61 yrs and median number of prior regimens was 4. MTD of the 10-dose schedule was 30 mg/m2. MTD for the 8-dose schedule has not been reached. Thirteen pts experienced drug related gr 3-4 adverse events (AEs) including fatigue (n = 6), hyponatremia (n = 5), thrombocytopenia (n = 3), anorexia (n = 3), dehydration (n = 2), anemia (n = 2), hyperglycemia (n = 1), pulmonary embolism (n = 1), and hypotension (n = 1). The most common gr 1-2 drug related AEs were nausea (74 %), anorexia (67 %), fatigue (67 %), vomiting (59 %), dysgeusia (52 %), and weight loss (48 %). Cmax increased with dose to ≈ 1.4 µM with T½ of 4.0 – 7.4 hrs. Significant increases (2-20x) in PD marker XPO1 mRNA in circulating leukocytes were observed at all doses. Analysis of tumor biopsies confirmed nuclear localization of TSPs and induction of apoptosis following selinexor. CEA decreased in 4 of 12 pts. One pt had a partial response at 23 mg/m2, 6 patients had stable disease ≥8 weeks, and 3 patients had stable disease ≥24 weeks in 25 evaluable pts Conclusions: Preliminary signals of antitumor activity in CRC pts were observed. Selinexor is generally well tolerated and prolonged drug exposure is feasible. Selinexor induces Exportin in leucocytes and apoptosis in tumor biopsies with restoration of the nuclear location of TSPs. Clinical trial information: NCT01607905.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::bf33984e4d025003326bb97c41f8b764Test
https://doi.org/10.1200/jco.2014.32.3_suppl.482Test

المؤلفون: Michael Kauffman, Sharon Shacham, Christopher P. Evans, Joy C. Yang, Yosef Landesman, Robert H. Weiss, Hiromi I. Wettersten

المصدر: Journal of Clinical Oncology. 31:411-411

مصطلحات موضوعية: chemistry.chemical_classification, Cancer Research, medicine.diagnostic_test, business.industry, Bioinformatics, medicine.disease, Immunofluorescence, First generation, Clinical trial, XPO1, Oncology, chemistry, Cell culture, Renal cell carcinoma, Cancer research, Medicine, business, Nuclear export signal, Karyopherin

الوصف: 411 Background: The currently available targeted therapies for RCC have had limited success, so it is imperative to discover new therapeutic approaches for metastatic RCC. In a search for new such targets, we have identified inhibitors of CRM1 (XPO1, exportin1), the major karyopherin that mediates the export of most tumor suppressor proteins from the nucleus. To expand our initial work on the first generation of CRM1 inhibitors, we now evaluate KPT-330, an orally available Selective Inhibitor of Nuclear Export (SINE), the best tolerated among a series of CRM1 inhibitors that is currently in phase I clinical trials. Methods: The RCC cell lines (Caki-1 and 786-O) and a primary normal human kidney (NHK) cell line were treated with KPT-330, and MTT assays were performed. The cells were subjected to immunofluorescence and immunoblotting for appropriate proteins. Caki-1 xenograft mice were treated with KPT-330 for 15 days, and tumor volume was assessed. Results: KPT-330 selectively attenuated CRM1 levels and caused dose-dependent toxicity (EC50 < 1 µM) through apoptosis in all RCC cells. In untreated RCC cells, p21 was localized in the nucleus, where it likely functions as a cell cycle arrest protein, and in the cytosol, where it functions as an anti-apoptotic protein. However, in NHK cells, p21 was confined to the nucleus. KPT-330 increased p53 and p21 and confined them to the nucleus in both NHK and RCC cells. KPT-330 given orally inhibited RCC growth in xenograft mice (85.3 % inhibition, p < 0.001). Moreover, KPT-330 showed synergism with a Bcl-2 inhibitor ABT-737 in vitro, indicating the potential for combination therapy with a CRM1 inhibitor and Bcl-2 inhibitor. In vivo studies to test the combination of KPT-330 with Bcl-2 inhibitors are ongoing. Conclusions: We introduce a new therapeutic approach for RCC treatment based on the inhibition of the nuclear export of key tumor suppressors. Inhibition of CRM1 causes forced nuclear retention, and thereby activation, of several key p53-pathway proteins, leading to apoptosis in RCC cell lines in vitro and tumor growth inhibition in vivo.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::c66a5a19e26ae4f7ce5f138a2af43446Test
https://doi.org/10.1200/jco.2013.31.6_suppl.411Test