Abstract A150: Anti-BIRC6 antisense oligonucleotide inhibits enzalutamide-resistant castration-resistant prostate cancer growth in patient-derived xenograft model by suppressing multiple signaling pathways
Authors: Luk Iris Sze Ue , Shrestha Raunak , Xue Hui , Wang Yuwei , Gout Peter , Collins Colin , Gleave Martin , Wang Yuzhuo 
Published: May 2016

Background: Enzalutamide (ENZ) is the latest androgen receptor antagonist approved for treating castration-resistant prostate cancer (CRPC) and improves patient survival. However, increasing reports showing the development of ENZ-resistant tumor in patients and no known therapies were shown to be effective to-date. Our group has identified that BIRC6, an Inhibitor of Apoptosis (IAP) member, was elevated in CRPC. We developed antisense oligonucleotides (ASOs) that specifically target BIRC6 and demonstrated a significant inhibitory effect towards various CRPC models in vitro and in vivo. Most recently, we observed that BIRC6 expression was also elevated in an ENZ-resistant CRPC patient-derived xenograft (PDX) model. Thus, we hypothesize that anti-BIRC6 ASO may inhibit Enz-resistant CRPC.

Materials and Methods: PDX model LTL313BR was a castration relapsed tumor line developed after androgen ablation in animal bearing LTL313B, a patient derived prostate cancer tumor line (androgen sensitive, AR+). LTL313BR was a typical CRPC (adenocarcinoma, AR+) and was resistant to Bicalutamide and Enzalutamide. The model was used to study the effect of anti-BIRC6 ASO on the growth of ENZ-resistant CRPC. Mice bearing LTL313BR tumors were randomized into scrambled control (Scrb) ASO or anti-BIRC6 ASO groups for 21-day treatment (n = 30 per group). Tumors were harvested 1 week after the end of treatment. Tumor volume and serum PSA was measured and the effect on tumor apoptosis was examined. Gene expression profiling was performed to investigate the mechanism of action of anti-BIRC6 ASO.

Results: We demonstrated that anti-BIRC6 ASO significantly impeded the growth of Enz- resistant CRPC LTL313BR. Anti-BIRC6 ASO treated group showed median tumor volume of 385mm3 comparing to 521 mm3 in control ASO group, i.e. a 37% reduction. The marked tumor suppression was also coupled with significant reduction in serum PSA and induction of tumor apoptosis. Pathway enrichment analysis of gene expression profile indicates that anti-BIRC6 ASO altered gene expressions that inhibit pathways in mitogenic signalling, proliferation, cell migration, neutrophils chemotaxis and increased T-cell recruitment.

Conclusion: Current study provides proof-of-principle data that anti-BIRC6 ASO may represent as novel therapeutic agent against ENZ-resistant CRPC.

Citation Format: Iris Sze Ue Luk, Raunak Shrestha, Hui Xue, Yuwei Wang, Peter Gout, Colin Collins, Martin Gleave, Yuzhuo Wang. Anti-BIRC6 antisense oligonucleotide inhibits enzalutamide-resistant castration-resistant prostate cancer growth in patient-derived xenograft model by suppressing multiple signaling pathways. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A150.