Development of novel prostate cancer therapies. Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of CYP17A1 inhibitors and androgen receptor antagonists, with efforts on developing novel agents and characterizing the clinical pharmacology and/or treatment response of marketed agents. In collaboration with the University of Chicago, we recently participated in a food effect study of abiraterone for patients with CRPC and found that low-dose abiraterone acetate (with low-fat breakfast) is non-inferior to standard dosing with respect to PSA metrics. In collaboration with Dr. Ravi Madan (GMB, CCR, NCI), we recently completed a phase II trial of seviteronel in CRPC patients previously treated with enzalutamide; a manuscript is in progress to report the trial findings. 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. Upregulation of hypoxia inducible factor-1alpha (HIF-1a) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies by increasing angiogenesis and metastasis. Given that both AR and HIF-1a are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. We demonstrated in preclinical studies that 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. CRLX101 is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent and highly selective topoisomerase I inhibitor with anti-HIF-1a properties) conjugated to a linear, cyclodextrin-polyethylene glycol-based polymer. Preclinical and clinical studies have shown CRLX101 significantly downregulates HIF-1a, impacting tumor-driven angiogenesis. The treatment combination of CRLX101 and enzalutamide provides a reasonable approach to re-sensitizing prostate cancer cells to hormonal therapy via synergistic antitumor activity and inhibition of acquired resistance. Preliminary results from castrate-resistant prostate cancer xenograft models demonstrate synergistic effects from the treatment combination. In collaboration with Dr. Madan (NCI), we are currently enrolling patients on a single arm pilot study to evaluate the safety and activity of combining CRLX101 with enzalutamide in patients with progressive mCRPC following prior enzalutamide treatment. Enzalutamide is currently approved for the treatment of patients with mCRPC. The marketed (reference) formulation is a liquid-filled, soft gelatin capsule containing 40 mg enzalutamide dissolved in Labrasol; four such capsules are required to deliver a 160mg dose. The four-capsule regimen is inconvenient because of the number of capsules that must be taken per dose, particularly in light of the fact that cancer patients often have to take multiple drugs. In addition, some patients may have difficulty with swallowing. Therefore, alternate methods of oral administration are necessary. We initiated a single-dose randomized, open-label, 2-way crossover pilot bioequivalence study to compare two oral formulations of enzalutamide; the trial is currently open for accrual.
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