Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia
ABSTRACT Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (e.g., p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500 nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD-positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.
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- "Previous studies showed that LMB induced p53 activation, suggesting this was the key to inducing growth arrest associated with apoptosis in prostate cancers (Lecane et al, 2003), neuroblastomas (Smart et al, 1999), and melanoma (Pathria et al, 2012). Recently, a study showed that p53 was a critical mediator of KPT-induced differentiation and apoptosis of acute myeloid leukaemia cells (Ranganathan et al, 2012). Interestingly, we observed that KPT-330 induced apoptosis in both p53-wt and -mut NSCLC cells. "
ABSTRACT: Background:We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo.Methods:The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed.Results:KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation.Conclusions:Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.British Journal of Cancer advance online publication, 19 June 2014; doi:10.1038/bjc.2014.260 www.bjcancer.com.British Journal of Cancer 06/2014; DOI:10.1038/bjc.2014.260 · 4.82 Impact Factor
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ABSTRACT: The study of the detailed molecular history of cancer development is one of the most promising techniques to understand and fight this diverse and prevalent disease. Unfortunately, this history is as diverse as cancer itself. Therefore, even with next-generation sequencing techniques, it is not easy to distinguish significant (driver) from random (passenger) events. The International Cancer Genome Consortium (ICGC) was formed to solve this fundamental issue by coordinating the sequencing of samples from 50 different cancer types and/or sub-types that are of clinical and societal importance. The contribution of Spain in this consortium has been focused on chronic lymphocytic leukemia (CLL). This approach has unveiled new and unexpected events in the development of CLL. In this review, we introduce the approaches utilized by the consortium for the study of the CLL genome and discuss the recent results and future perspectives of this work.Clinical and Translational Oncology 08/2012; 15(1). DOI:10.1007/s12094-012-0922-z · 2.08 Impact Factor
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ABSTRACT: In this issue of Blood, Ranganathan et al seek a holy grail: evidence that a drug with a novel mechanism of action may be effective for acute myeloid leukemia patients.(1)Blood 08/2012; 120(9):1759-60. DOI:10.1182/blood-2012-07-439166 · 10.43 Impact Factor