Abstract 3808: Preclinical efficacy of the novel, oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) on castration resistant prostate cancer

Abstract

Exportin 1/ Chromosomal Maintenance Protein 1 (XPO1/CRM1) is a key nuclear export protein whose inhibition leads to the nuclear accumulation of tumor suppressor proteins such as p53, FOXO, PTEN, pRB and I-κB. Selinexor is an orally bioavailable XPO1 inhibitor that represents a novel class of small molecule compounds with potent activity against a wide variety of cancers. Here we report the activity of Selinexor against Castration resistant prostate cancer (CRPC).

CRPC progression is mediated by activation of various adaptive Androgen Receptor (AR) signaling pathways. These pathways are currently being targeted by novel anti-androgen therapies such as abiraterone acetate and enzalutamide with favorable outcomes. However, resistance to anti-androgen therapy can be developed through deregulation of tumor suppressor pathways. XPO-1 is highly expressed in prostate cancer cells and therefore we tested the effects of Selinexor on CRPC cells and tumors models. Treatment of the C4-2B prostate cancer cell line with Selinexor in vitro significantly inhibited cell proliferation and resulted in nuclear accumulation of p53 and p21. In addition, Selinexor inhibited expression of the tumor-promoting gene Ubiquitin-Conjugating Enzyme E2C (UBE2C), which is activated by AR in these cells. Selinexor was also tested in tumor graft models of two patient tumors in castrated male mice. The MDA-PCa-133 tumor is an adenocarcinoma derived from a clinical CRPC bone metastasis. Subcutaneous MDA-PCa-133 tumors in castrated male mice express full-length AR and Prostate-Specific Antigen (PSA) but lack expression of p53. The MDA-PCa-144-13 tumor is a small cell carcinoma derived from a lethal variant of prostate cancer with anaplastic clinical phenotype and does not express AR or PSA but expresses a gain-of-function p53 mutant. Vehicle or Selinexor treatment (10 mg/kg p.o. QoDX3 M/W/F) of MDA-PCa-133 tumors for 34 days resulted in almost complete inhibition of tumor growth with a 30-fold reduction of PSA (p<0.001). Treatment of MDA-PCa-144-13 tumors for 22 days also resulted in significant reduction of tumor volume (>8 fold compared to vehicle only; p<0.0047). Immunohistochemical analysis of MDA-PCa-133 tumors showed that Selinexor induced nuclear accumulation of XPO1 cargos FOXO3a and p27 with concomitant reduction in the proliferation marker KI67.

In conclusion, Selinexor demonstrated robust inhibition of CRPC tumor growth and activated multiple tumor suppressors in prostate cancer cells. Selinexor is now being evaluated in Phase 1 clinical studies in patients with advanced hematological and solid tumor cancers, and preliminary results show adequate tolerability with evidence of anti cancer activity. Future clinical studies in patients with CRPC are planned and will provide more information on the use of Selinexor as monotherapy and in combination with anti-androgen therapy of CRPC.

Citation Format: Sankar Narayan Maity, Guanglin Wu, Jing-Fang Lu, Anh Hoang, Yosef Landesman, Dilara McCauley, Sharon Shacham, Michael G. Kauffman, Ana M. Aparicio, Eleni Efstathiou, John C. Araujo, Christopher J. Logothetis. Preclinical efficacy of the novel, oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) on castration resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3808. doi:10.1158/1538-7445.AM2014-3808