LAUSR

Metastatic castration resistant prostate cancer (mCRPC) is an advanced form of prostate cancer (PC) associated with poor prognosis. Approximately 20 - 40% of mCRPCs are androgen-independent and do not respond to treatment with abiraterone or enzalutamide, drugs that suppress androgen synthesis or directly target androgen ligand binding domains (LBD) respectively. Patients initially responding to these drugs eventually relapse, highlighting the need for alternative therapies. Resistance is attributed to the emergence of constitutively active AR splice variants lacking C-terminal LBDs such as AR variant 7. Although ARv7 activity cannot be mitigated by current therapeutic approaches, it is known that AR mRNA is exported from the nucleus by eIF4E and exportin-1 (XPO1). Selinexor and KPT-8602 are orally bioavailable SINE (Selective Inhibitor of Nuclear Export) compounds that specifically target XPO1. The purpose of this study is to provide mechanistic evidence for using SINE compounds as novel therapies for androgen-independent mCRPC. Methods: In vitro, selinexor or KPT-8602 were tested on androgen-independent PC cell line 22Rv1. RNA and protein were analyzed by qPCR and immunoblot. Cell viability was examined using the Celltiter-Glo assay. In vivo, immune deficient SCID mice were injected subcutaneously with 22Rv1 cells. Tumors were grown to ~150 mm3 before treatment with selinexor (10 mg/kg qodx3) or KPT-8602 (15 mg/kg reduce to 10 mg/kg qdx5). Tumor growth and animal weights were monitored to determine tumor growth inhibition (TGI) and tolerability to treatment. Tumors were analyzed using immunohistochemistry (IHC). Results: We found that expression of AR, ARv7 and prostate specific antigen (PSA; transcriptionally regulated by AR) proteins are reduced following 24-hour treatment with SINE compounds. Nuclear vs. cytoplasmic fractionation of RNA revealed that ARv7 and PSA mRNA localization was increased in the nucleus (4-fold and 3-fold, respectively) and reduced in the cytoplasm (5-fold and 3-fold, respectively). Moreover, KPT-8602 potently inhibited cell viability (IC50: 100 nM), while enzalutamide and abiraterone had no effect. Finally, mice bearing 22Rv1 xenografts, treated with selinexor or KPT-8602 exhibited a complete reduction in tumor volume (95% and 94% TGI, respectively), which coincided with prolonged overall survival. IHC analysis showed a reduction of proliferation markers and a concomitant increase in cell death makers in selinexor and KPT-8602 treated tumors. Conclusion: SINE compounds show strong anti-tumor activity in androgen-independent prostate cancer models in vitro and in vivo by reducing AR, ARv7, and PSA expression. These findings highlight the promise of SINE compounds as treatment options for androgen-independent mCRPCs resistant to first line therapies. Citation Format: Christian Argueta, Boris Klebanov, Trinayan Kashyap, Hua Chang, Sharon Friedlander, Erkan Baloglu, Margaret Lee, Humphrey Gardner, Sharon Shacham, William Senapedis. Disruption of nuclear export with selinexor or KPT-8602 reduces androgen receptor expression and leads to potent anti-tumor activity in preclinical models of androgen-independent prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1587. doi:10.1158/1538-7445.AM2017-1587