Following the publication of two landmark randomized trials, docetaxel chemotherapy is now the standard of care for men with metastatic CRPC. 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 metastatic castration-resistant prostate cancer (CRPC). 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 (p <0.01). 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.Thalidomide inhibits TGFb-1-mediated synthesis of testosterone from DHEA in prostate cancer: Recent studies have suggested that TGFb-1 induces formation of reactive stroma and conversion of DHEA to testosterone in prostate cancer stromal cells. We hypothesized that thalidomide would inhibit this process through its anti-inflammatory activity. Our results show that DHEA induced an approximate 4-fold median increase in the formation of testosterone over untreated cocultured cells while TGFb-1 induced a further dose-dependent increase in the formation of testosterone (5-6 fold;P<0.0001). Thalidomide inhibited the formation of testosterone in cocultured cells treated with DHEA and TGFb-1 by 35%. The thalidomide analogues, CPS49 and lenalidomide also had activity in cocultured cells;however, only thalidomide and CPS49 decreased median PSA secretion. Interestingly, other angiogenesis inhibitors (i.e., suramin and sorafenib) had no effect on testosterone synthesis, suggesting that anti-androgen activity was restricted to thalidomide analogues in cocultured cells. Ketoconazole also did not have activity suggesting that TGFb-1-induced testosterone synthesis from DHEA evades standard therapies designed to inhibit androgen synthesis enzymes (i.e. CYP3A4 and CYP17 inhibitors). Molecular studies revealed that thalidomide inhibits the phosphorylation of ERK without affecting total ERK levels;however, Raf inhibition (via sorafenib) did not result in anti-androgenic effects suggesting that the canonical RAF/MEK/ERK pathway is not responsible for the difference in testosterone secretion phenotype. These results indicate that thalidomide and its analogues have anti-androgen activity and may explain the success of thalidomide and its analogues in clinical treatment of hormone-dependent and castration-resistant prostate cancer. Future studies will be directed towards determining the molecular mechanism behind the inhibitory effect of thalidomide and its analogues on testosterone synthesis from DHEA. 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. In fact, the correlation between HIF-1a and AR was stronger than that between HIF-1a and vascular endothelial growth factor (VEGF), which is one of the well-validated HIF-1a target genes. This relationship between HIF-1a and AR in prostate cancer cells has been suggested by several previous in vitro studies. We hypothesize that 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 by identifying the regions of HIF-1a and AR that facilitate their interaction, identifying the genes that are upregulated by DHT and CoCl2 treatment containing both an ARE and HRE, and determining if HIF-1a and AR bind to the promoter of genes containing both an HRE and ARE. 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, if our experiments demonstrate a crucial role for HIF-1a in prostate cancer, 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. TRC105 and metastatic castrate-resistant prostate cancer:TRC105 is a human/murine chimeric IgG1 monoclonal antibody to CD105 (endoglin) that inhibits angiogenesis and tumor growth through inhibition of endothelial cell (EC) proliferation, antibody-dependent cellular cytotoxicity and induction of apoptosis. CD105 is highly expressed on proliferating vascular ECs. A phase I study of TRC105 is currently being evaluated in mCRPC patients with the primary objective to evaluate safety and identify the maximum tolerable dose of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate and overall response rate (ORR). Accrual is ongoing.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010547-10
Application #
8552730
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2012
Total Cost
$440,267
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Beedie, Shaunna; Figg, William D (2016) Resisting resistance: Establishing new treatment options for CRPC patients. Cancer Biol Ther 17:337-8
Madan, Ravi A; Karzai, Fatima H; Ning, Yang-Min et al. (2016) Phase II trial of docetaxel, bevacizumab, lenalidomide and prednisone in patients with metastatic castration-resistant prostate cancer. BJU Int 118:590-7
Leibrand, Crystal R; Price, Douglas K; Figg, William D (2016) Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: Biomarker for treatment selection exclusion or inclusion? Cancer Biol Ther 17:467-9
Schmidt, Keith T; Chau, Cindy H; Price, Douglas K et al. (2016) Precision Oncology Medicine: The Clinical Relevance of Patient-Specific Biomarkers Used to Optimize Cancer Treatment. J Clin Pharmacol 56:1484-1499
Polman, David J; Price, Douglas K; Figg, William D (2015) New bigenic mouse model increases the understanding of genetic synergism in the progression of prostate cancer. Cancer Biol Ther 16:1702-3
Karzai, Fatima H; Madan, Ravi A; Figg, William D (2015) Beyond PSA: managing modern therapeutic options in metastatic castration-resistant prostate cancer. South Med J 108:224-8
Figg, William D; Thompson, Ian M (2015) Effect of 5α-Reductase Inhibitor Use on Mortality From Prostate Cancer. JAMA Oncol 1:321-2
Fernandez, Elena V; Reece, Kelie M; Ley, Ariel M et al. (2015) Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells. Mol Pharmacol 87:1006-12
Strauss, Julius; Madan, Ravi A; Figg, William D (2015) Evaluating immune responses after sipuleucel-T therapy. Cancer Biol Ther 16:1119-21
Lochrin, Sarah E; Price, Douglas K; Figg, William D (2014) BET bromodomain inhibitors--a novel epigenetic approach in castration-resistant prostate cancer. Cancer Biol Ther 15:1583-5

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