Abstract 1616: Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): a report from the Pediatric Preclinical Testing Program

Autor: Malcolm A. Smith, Richard B. Lock, Raushan T. Kurmasheva, Sharon Shacham, Jianrong Wu, John M. Maris, Peter J. Houghton, Dmitry Lyalin, Hernan Carol, Stephen T. Keir, E. Anders Kolb, Yosef Landesman, Richard Gorlick
Rok vydání: 2015
Předmět:
Zdroj: Cancer Research. 75:1616-1616
ISSN: 1538-7445
0008-5472
Popis: Background: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1 or CRM1) that has demonstrated activity in preclinical models of several solid and hematological cancers. Procedures: Selinexor was tested against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg (3 times per week) for 4 weeks. For collection of specimens for pharmacodynamic testing, KT-10 tumors that regressed rapidly after treatment with selinexor were harvested 24 hours after a single dose of drug (10 mg/kg). Other, less responsive tumors, were harvested 2 hours after dose 6 (MWF dosing) at 10 mg/kg/dose. Immunoblots were probed for p53, p21, PARP and cleaved PARP and XPO1/CRM1. IHC analysis was performed for a comparable set of proteins to assess nuclear localization. For exome sequencing, all mutations were verified and assessed as somatic using a virtual normal subtraction algorithm. Results: Objective responses (CRs) to selinexor were observed for 3 of 38 solid tumor xenografts including Wilms tumor (KT-10), medulloblastoma (BT-50) and ependymoma (BT-41) xenografts. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR or MCR (ALL-8 and ALL-19). The mutation profiles for models with objective responses for which exome sequencing data were available (KT-10, BT-50, ALL-8 and ALL-19) were examined. The only recurring mutation was for FBXW7, with known oncogenic mutations identified for both BT-50 (R465H) and ALL-8 (R465C). One additional tested xenograft (ALL-31) had an FBXW7 mutation, but it was in the N-terminal region in the nuclear localization signal domain (c.45_46insCCT; p.15_16TR>TLR). KT-10 has a PALB2 mutation that leads to defective homologous recombination and to sensitivity to PARP inhibition. Selinexor induced a robust increase in p53 in KT-10 xenografts with PUMA induction and cleavage of PARP that was apparent after the first dose of drug, consistent with the rapid response of this tumor to treatment. Models that showed growth delay rather than regression showed a lesser induction of p53 and showed increased nuclear localization of a number of proteins (e.g., FOXO1, NFκB, and p53). Conclusions: Selinexor induced regression against several solid tumor and ALL xenografts, and slowed tumor growth for a larger number of models. Pharmacodynamic effects expected for XPO1 inhibition were noted in models without regard to tumor regression, although p53 induction was most robust in a highly sensitive Wilms tumor model. Exome sequencing identified potential genomic alterations (FBXW7 mutation and mutation in a homologous recombination gene) associated with sensitivity that require validation in a larger, independent set of tumors. Citation Format: Malcolm A. Smith, Richard Lock, Hernan Carol, John M. Maris, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, Jianrong Wu, Yosef Landesman, Sharon Shacham, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J. Houghton. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): a report from the Pediatric Preclinical Testing Program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2015-1616
Databáze: OpenAIRE
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