Novel drug combination targeting the HOXB13:AR axis show efficacy in castration resistant prostate cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-322
Sarath Chandran Dhananjayan*
Duke University, Durham, NC
Dysregulated AR signaling is causally associated with prostate cancer (PCa) tumorigenesis. Thus, androgen depletion alone or in combination with antiandrogens is frontline therapies for PCa. However, invariably PCa adapts to low circulating levels of androgens or escapes the inhibitory actions of antagonists and progresses to Castrate Resistant Prostate Cancer (CRPC). Whereas monotherapies are the mainstay for endocrine therapy in prostate cancer, there is increasing evidence that a poly-pharmacy approach may be necessary for durable responses in prostate cancer. The AR coregulator, HOXB13, functions as a positive regulator of genes involved in proliferative responses and as an inhibitor of genes associated with differentiation. Recently, a germline mutation in HOXB13 has been identified that is associated with a significantly increased risk of early onset prostate cancer.  Given the central role of HOXB13 in AR signaling and in prostate biology, pharmacological inhibitors of the HOXB13:AR axis may have therapeutic potential.  To date, transcription factors have been considered to be intractable drug targets. Through a rigorous search of publically available datasets, we identified that the cardioglycoside, digoxin, inhibited both prostate cancer cell proliferation and the expression of HOXB13.  Cardiac glycosides (CG) are routinely used to treat congestive heart failure and arrhythmia. A recent study indicated that patients taking CG for heart arrhythmias are at a 25% reduced risk for prostate cancer. Our recent data shows that at concentrations readily achievable in vivo, digoxin and other CGs inhibit the expression of HOXB13.  In addition, we observed a dramatic inhibition of AR expression using CGs in several cellular models of PCa. However, RNAi-mediated silencing of HOXB13, but not AR, resulted in a significant decrease in the IC50 of CGs. We show that CGs can inhibit androgen-induced proliferation and attenuate the partial-agonistic activity of the commonly utilized anti-androgens like casodex and flutamide in multiple PCa cell models. Moreover, Co-treatment of CGs with first- and second-generation antiandrogens (MDV3100) has proven to be more effective than either monotherapy alone, suggesting an additive effect in androgen-dependent PCa cells. Importantly, CGs show efficacy in antiandrogen-resistant CRPC model (22Rv1), which expresses high levels of truncated AR variants (ARVs) in in vivoxenograft assays. Cumulatively, our data suggest that CGs have the potential to provide near-term clinical benefit using a class of drugs that disrupts AR signaling by two distinct mechanisms.

This work was funded by CA139818 (DPM)

1. Chen, C.D., et al., Molecular determinants of resistance to antiandrogen therapy. Nat Med, 2004. 10(1): p. 33-9. 2. 2. Norris, J.D., et al., The homeodomain protein HOXB13 regulates the cellular response to androgens. Mol Cell, 2009. 36(3): p. 405-16.3. Ewing, C.M., et al., Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med, 2012. 366(2): p. 141-9. 4.             4. Platz, E.A., et al., A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment. Cancer Discov, 2011. 1(1): p. 68-77.

Nothing to Disclose: SCD

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Sources of Research Support: This work was funded by CA139818 (DPM)