Following the publication of two landmark randomized trials, docetaxel chemotherapy is now the standard of care for men with metastatic castrate-resistant prostate cancer (mCRPC). However, the benefit of this treatment is limited. Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biological agents. Several new docetaxel-based combinations are under evaluation and promising results have been found for the combination of docetaxel with angiogenesis inhibitors. Following previous experiments demonstrating increased efficacy of microtubule-active drugs when combined with ketoconazole in vitro, when tested in multiple prostate cancer cell lines, we initiated a Phase I trial of high dose ketoconazole plus weekly docetaxel for mCRPC. The objective of the study was to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of co-administered docetaxel and ketoconazole. The study enrolled 42 patients at 9 different dose levels. Decreases in prostate specific antigen of 50% or greater were seen in 62% of patients. Of 25 patients with soft tissue disease 7 (28%) had a partial response. Median overall survival was 22.8 months and was significantly greater in docetaxel nave patients than in patients pretreated with docetaxel (36.8 vs 10.3 months, p = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure. Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1,200 mg daily, 1.6-fold with 800 mg daily and approximately 1.3 to 1.5-fold with 600 mg daily. Combination regimens using 600 mg ketoconazole daily were fairly well tolerated and the maximum tolerated dose of docetaxel was 32 mg/m(2). Results suggest that the combination has significant antitumor activity in CRPC. The long survival in the docetaxel naive cohort warrants additional, larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone. HIF-1 and Androgen Receptor (AR): AR, a member of the nuclear receptor superfamily, functions as a ligand-inducible transcriptional factor that controls the development and progression of prostate cancer. Our laboratory showed that in response to castration and anti-androgen therapy in mice, there was a strong transcriptional relationship between HIF-1a and AR, as measured by quantitative RT-PCR. We hypothesize that HIF-1alpha (HIF-1a) and AR co-regulate the transcription of genes that confer resistance to androgen withdrawal, thereby indicating that both proteins should be simultaneously targeted in CRPC. We demonstrate the cooperative regulation of HIF-1a- and AR-mediated signaling in cells by characterizing the bi-directional crosstalk between HIF-1a and AR using novel HIF-1a and AR inhibitors. We will elucidate the molecular mechanism underlying the co-regulation of HIF-1a- and AR-mediated gene transcription. Our results showed that expression of HIF-1a was increased in the presence of DHT and CoCl2 compared to CoCl2 treatment alone. In addition, compared to treatment with DHT alone, AR expression was increased in the presence of both treatments as well. We performed co-immunoprecipitation experiments, and found that HIF-1a and AR co-immunoprecipitated from cells treated with DHT and CoCl2. Binding assays using purified HIF-1a and AR proteins are currently underway to determine the nature of the interaction. Further elucidation of the cooperative effects of HIF-1a and AR will be examined after both proteins are individually knocked down. Finally, we will introduce novel HIF-1a inhibitors into our experiments to monitor both their cellular effects, and their effects on angiogenesis. These inhibitors may allow us to elucidate the mechanism of action by which HIF-1a is having its effect in prostate cancer, as preliminary data has shown that they function by disrupting the HIF-1a/p300 complex in vitro. Eovist (Gadoxetate) Enhanced MRI for the Detection of Prostate Cancer: The organic anion transporter polypeptide 1B3 (OATP1B3) is a testosterone transporter expressed de novo in prostate tumors that represents a possible mechanism of prostate tumor growth even in the setting of ADT due to the ability of the cancer cells to scavenge additional testosterone despite low serum testosterone concentrations. There is no current imaging method capable of evaluating the status of the OATP1B3 transporter. Such a method may be important in stratifying risk factors in patients by OATP1B3 status, both with localized and metastatic disease. Eovist is a gadolinium-based contrast agent, which was approved by the FDA in 2008. It is indicated for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease, particularly in the diagnosis of hepatocellular carcinoma. Because Eovist is a low molecular weight imaging agent it rapidly enhances all vascular organs and structures. However, Eovist is not retained by non-OATP1B3 expressing tissue and so at 20 minutes a correlation can be made between OATP1B3 expressing lesions (persistent enhancement) and non-OATP1B3 expressing lesions (washout of enhancement). Thus, we are using Eovist in patients with localized and metastatic prostate cancer in order to determine if this method is feasible to observe differences in uptake times in prostate cancers and whether these differences correlate with OATP1B3 expression in prostate cancer and therefore might serve as a predictive biomarker. Accrual is ongoing. Preclinical studies support the use of an antiangiogenic approach in the treatment of prostate cancer. Trebananib (AMG386) is a novel peptide-Fc fusion protein that sequesters angiopoeitin 1 and angiopoeitin 2, thereby preventing their interaction with their common receptor Tie2, and inhibiting tumor endothelial cell proliferation and tumor growth. Dual inhibition of the androgen and angiogenic axis represents a novel strategy of combined targeted therapy for patients with mCRPC. We hypothesize that the addition of trebananib to CYP17 inhibitor abiraterone and prednisone will increase the median progression free survival in chemotherapy-naive mCRPC. This phase 2 study will evaluate the treatment effect as measured by progression free survival in patients treated with trebananib plus abiraterone/prednisone relative to abiraterone/prednisone alone. We are also involved in the biomarker studies in this trial. Accrual is ongoing. Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its resistance mechanism. It is an inhibitor of multiple receptor tyrosine kinases including c Met, VEGFR2 and RET. In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities across many solid tumor types. Cabozantinib has yielded one of the highest rates of response with disease control rate, defined as SD or confirmed response, of 68% in CRPC patients. We are involved in a single arm phase I study of fixed dose of docetaxel and prednisone in combination with cabozantinib at three escalating doses too determine the safety profile of cabozantinib in combination with docetaxel and prednisone, and to determine the maximal tolerated dose as recommended phase II dose in combination with docetaxel. Accrual is ongoing.
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