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 and 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. Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biological agents. Several new docetaxel-based combinations and novel agents are under evaluation in both the preclinical and clinical setting with promising results. We investigated the selectivity and efficacy of new drug combinations for CRPC. We combined three compounds: paclitaxel (PTX: taxane that inhibits microtubule polymerization); 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole- 1,3(2H)-dione (CPS49; redox-reactive thalidomide analog with anti-angiogenic properties) and flavopiridol (flavo: semisynthetic flavonoid that inhibits cyclin dependent kinases). We found that CPS49 enhanced flavo or PTX cytotoxicity in human PCa cell lines while showed resistance in a non-tumor cell line. Xenografts generated by inoculation of human prostate carcinoma PC3 cells in nu/nu mice showed that CPS49/flavo administration reduced tumor growth both after 2 weeks of co-treatment and after 1 week of pretreatment with a low dose of flavo followed by 2 weeks of co-treatment. PTX and CPS49 combination did not significantly reduce tumor growth in PC3 xenografts. Histological analysis of xenograft PC3 tumor samples from CPS49/flavo combination showed extensive areas of necrosis induced by the treatment. RT-qPCR array containing 23 genes from PC3 cells or PC3 xenografts exposed to CPS49/flavo combination showed that this treatment shut down the expression of several genes involved in adhesion, migration or invasion. In summary, the antitumor activity of CPS49 or flavopiridol was improved by the combination of these compounds and using half dose of that previously reported. Hence, CPS49-flavo combination is a promising new alternative for PCa therapy. 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 metastatic castrate-resistant prostate cancer (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-1 alpha (HIF-1a) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1a signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1a inhibition was achieved by siRNA silencing HIF-1a or via chetomin, a disruptor of HIF-1a-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1a target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1a inhibition attenuated AR-regulated and HIF-1a-mediated gene transcription. The combination of enzalutamide and HIF-1a inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor 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. 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. 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. Analysis of the trial data 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. Analysis of the trial data is ongoing.
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