The changing therapeutic landscape of castration-resistant prostate cancer.
ABSTRACT Castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Before 2010, only docetaxel-based chemotherapy improved survival in patients with CRPC compared with mitoxantrone. Our improved understanding of the underlying biology of CRPC has heralded a new era in molecular anticancer drug development, with a myriad of novel anticancer drugs for CRPC entering the clinic. These include the novel taxane cabazitaxel, the vaccine sipuleucel-T, the CYP17 inhibitor abiraterone, the novel androgen-receptor antagonist MDV-3100 and the radioisotope alpharadin. With these developments, the management of patients with CRPC is changing. In this Review, we discuss these promising therapies along with other novel agents that are demonstrating early signs of activity in CRPC. We propose a treatment pathway for patients with CRPC and consider strategies to optimize the use of these agents, including the incorporation of predictive and intermediate end point biomarkers, such as circulating tumor cells.
- SourceAvailable from: Asim B Abdel-Mageed[Show abstract] [Hide abstract]
ABSTRACT: Despite its side-effects, docetaxel (DTX) remains a first-line treatment against castration resistant prostate cancer (CRPC). Therefore, strategies to increase its anti-tumor efficacy and decrease its side effects are critically needed. Targeting of the constitutive endoplasmic reticulum (ER) stress in cancer cells is being investigated as a chemosensitization approach. We hypothesized that the simultaneous induction of ER-stress and suppression of PI3K/AKT survival pathway will be a more effective approach. In a CRPC cell line, C4-2B, we observed significant (p<0.005) enhancement of DTX-induced cytotoxicity following coexposure to thapsigargin and an AKT-inhibitor. However, since these two agents are not clinically approved, we investigated whether a combination of nelfinavir (NFR) and curcumin (CUR), known to target both these metabolic pathways, can similarly increase DTX cytotoxicity in CRPC cells. Within 24 hrs post-exposure to physiologic concentrations of NFR (5 µM) and CUR (5 µM) a significantly (p<0.005) enhanced cytotoxicity was evident with low concentration of DTX (10 nM). This 3-drug combination rapidly increased apoptosis in aggressive C4-2B cells, but not in RWPE-1 cells or in primary prostate epithelial cells (PrEC). Comparative molecular studies revealed that this 3-drug combination caused a more pronounced suppression of phosphorylated-AKT and higher induction in phosphorylated-eIF2α in C4-2B cells, as compared to RWPE-1 cells. Acute exposure (3-9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3. At much lower concentrations, chronic (3 wks) exposures to these three agents drastically reduced colony forming units (CFU) by C4-2B cells. In vivo studies using mice containing C4-2B tumor xenografts showed significant (p<0.05) enhancement of DTX's (10 mg/kg) anti-tumor efficacy following coexposure to NFR (20 mg/kg) & CUR (100 mg/kg). Immunohistochemical (IHC) analyses of tumor sections indicated decreased Ki-67 staining and increased TUNEL intensity in mice exposed to the 3-drug combination. Therefore, subverting ER-stress towards apoptosis using adjuvant therapy with NFR and CUR can chemosensitize the CRPC cells to DTX therapy.PLoS ONE 01/2014; 9(8):e103109. · 3.53 Impact Factor
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ABSTRACT: To date, limited options are available to treat malignant prostate cancer, and novel strategies need to be developed. Oncolytic viruses (OV) that have preferential replication capabilities in cancer cells rather than normal cells represent one promising alternative for treating malignant tumors. Vesicular stomatitis virus (VSV) is a non-segmented, negative-strand RNA virus with the inherent capability to selectively kill tumor cells. The aim of this study was to evaluate the potential of VSV-ΔM51-GFP as an effective therapeutic agent for treating prostate tumors.International Journal of Clinical and Experimental Medicine 01/2014; 7(5):1204-13. · 1.42 Impact Factor
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ABSTRACT: Novel therapeutic options beyond hormone ablation and chemotherapy are urgently needed for patients with advanced prostate cancer. Tyrosine kinase inhibitors (TKIs) are an attractive option as advanced prostate cancers show a highly altered phosphotyrosine proteome. However, despite favorable initial clinical results, the combination of the TKI dasatinib with docetaxel did not result in improved patient survival for reasons that are not known in detail.Urologic oncology. 07/2014;