Following the publication of two landmark randomized trials, docetaxel chemotherapy became the standard of care for men with metastatic castrate-resistant prostate cancer (mCRPC). Prior to 2010, docetaxel/prednisone was the only treatment which had demonstrated a survival benefit in patients with mCRPC. Recent advances in the treatment of mCRPC have revolutionized treatment algorithms. Despite their impact on overall survival (OS), sipuleucel-t and alpharadin have unknown impact in symptomatic patients or those with visceral metastasis, respectively. Abiraterone and enzalutamide have favorable toxicity profiles, however they share mechanisms of resistance that likely diminish the benefits of sequential use. Thus, the benefit of these treatment for mCRPC remains limited. We investigated the selectivity and efficacy of new docetaxel-based combinations and novel molecular agents for CRPC in both the preclinical and clinical setting. Dual targeting of the androgen and angiogenic axis represents a novel approach as a potential targeted therapy for patients with mCRPC. In collaboration with Dr. Bill Dahut (GMB, CCR, NCI), we initiated a randomized, phase II (with a run-in phase of the combination) trial of abiraterone/prednisone with or without trebananib, a novel peptide-Fc fusion protein that sequesters angiopoeitin 1/2, in patients with mCRPC. Trebananib in combination with abiraterone is well tolerated, displayed an acceptable safety profile in the run-in phase of the trial, and established 30 mg/kg as the phase II dose in combination with abiraterone. We are also conducting the angiogenesis biomarker and PG analyses in this trial. Analyses of the trial data is ongoing. In collaboration with Dr. Dahut, we conducted a phase I/II study to determine the safety profile of cabozantinib, a small molecule inhibitor of multiple tyrosine kinases including MET, VEGFRs and RET, in combination with docetaxel and prednisone, and to determine the MTD as the recommended phase II dose in combination with docetaxel in mCRPC patients. The phase I accrued 19 patients and established the MTD of cabozantinib at 40mg daily with docetaxel. Preliminary PK data showed no significant differences in any PK parameter alone or with cabozantinib. We are currently analyzing clinical outcome data from this trial versus genotypes obtained via the DMET array and several angiogenesis pathway polymorphisms. Our understanding of the biology of mCRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. Recognition of the anti-androgen withdrawal response resulted in the development of therapy targeting androgen production (anti-androgens) or AR-mediated signaling (AR antagonists). Seviteronel (VT-464) is a novel, non-steroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. We are involved in the preclinical and clinical development of this compound. In collaboration with Dr. Donald McDonnell (Duke University), we recently demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor-bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC. In collaboration with Dr. Ravi Madan (GMB, CCR, NCI), two phase II trials of seviteronel have been initiated at the NCI in CRPC patients previously treated with enzalutamide (BID dosing) or progressing on enzalutamide or abiraterone (QD dosing). Both trials are currently open to accrual and we are performing the PK and PG analyses for these trials. We are also interested in understanding the mechanisms of resistance of prostate cancer regimens. Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in CRPC. Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1alpha (HIF-1a) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Treatment of CRPC cells with enzalutamide or HIF-1a inhibition attenuated AR-regulated and HIF-1a-mediated gene transcription. The combination treatment was more effective than either treatment alone. Similarly, the combination also reduced VEGF protein levels. HIF-1a siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1a inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth, suggesting a possible mechanism for overcoming enzalutamide resistance and potentiating anti-AR therapy. Enzalutamide's effect on HIF-1a-regulated gene expression is specifically targeted to VEGF, thus making VEGF a potential biomarker for assessing enzalutamide response; studies are underway to evaluate this effect in clinical treatment samples. We are also developing several specific small-molecule HIF-1a inhibitors, and ongoing preclinical studies are evaluating the combination of these HIF-1a inhibitors with enzalutamide in prostate cancer xenografts. The goal is to identify a potential HIF-1a inhibitor candidate to move forward in a phase I trial in combination with enzalutamide for patients with mCRPC. We recently conducted a study to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the OATP1B3 transporter. Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (Km = 23.2 umol/L; Vmax = 321.6 pmol/mg/min), and cells expressing a doxycycline-inducible SLCO1B3 construct had greater uptake of clinically relevant concentrations of 3H-testosterone (50 nmol/L; 1.6-fold, P = 0.0027). When compared with Slco1b2 knockout mice, hSLCO1B3 knockins had greater hepatic uptake (15% greater AUC, P = 0.0040) and lower plasma exposure to 3H-testosterone. Results from the taqman low density array showed that of 82 transporters genes, SLCO1B3 is the second-most differentially expressed transporter in CRPC cell lines (116-fold vs. androgen-sensitive cells), with a differentially spliced cancer-type (ct)-SLCO1B3 making up the majority of SLCO1B3 expression. Overexpression of SLCO1B3 in androgen-responsive cells results in 1.5- to 2-fold greater testosterone uptake, whereas siRNA knockdown of SLCO1B3 in CRPC cells did not change intracellular testosterone concentration. Primary human prostate tumors express the liver type (lt)-SLCO1B3 to a greater extent than ct-SLCO1B3, suggesting that androgen uptake in these tumor cells also is greater.Taken together, these results suggest that OATP1B3 is a major physiologic contributor to androgen disposition in man. OATP1B3 is clinically expressed and its de novo expression, particularly that of lt-SLCO1B3, contributes to the mechanism by which prostate tumors subvert physiologic androgen regulation. OATP1B3 should be considered a viable biological target for therapeutic intervention in prostate cancer. A high throughput screen is currently underway to identify inhibitors of OATP1B3 by screening a library of compounds.
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