Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy.
Androgens play a major role in the development, growth, and maintenance of the prostate. As with normal prostate development, primary prostate cancers are largely dependent on androgens for growth and survival. Androgens exert their effects via the intracellular androgen receptor (AR), a ligand-dependent transcriptional activator. In fact, androgens and AR represent the very first class of unique targets for therapies tailored for prostate cancers. MDV3100 is an oral androgen receptor antagonist in development for the treatment of early-stage and advanced prostate cancer. It directly inhibits AR by binding the receptor irreversibly. This interaction impairs AR nuclear translocation, DNA binding, and recruitment of co-activators
The human EGFR family (HER/ErbB) receptors have been recognized as a very important family of receptor tyrosine kinases. This family comprises four closely related receptors: EGFR (HER-1/ErbB1), HER-2 (Neu/ErbB2), HER-3 (ErbB3), and HER-4 (ErbB4). It has been reported that EGFR is overexpressed in 18-37% prostate cancers. Recently, Neto et al. also reported a significant direct correlation of HER2/neu over-expression with the risk of death and recurrence in prostate cancer. HER2 is also associated with the activation of androgen receptor and androgen-induced PSA expression. These studies indicate that targeted agents for ErbB receptors, including monoclonal antibodies (Cetuximab, Trastuzumab) and small molecule tyrosine kinase inhibitors (gifitinib, erlotinib, and lapatinib), can potentially provide treatment options for prostate cancer.
Epidemiological studies indicate that circulating IGF-I levels are positively correlated with increased risk of prostate cancer. Cardillo et al. analyzed 43 paraffin-embeded prostate cancer samples and found kinetic changing of IGF system as prostate tissue progressed from a normal to malignant state, suggesting that differential expression of IGF may be associated with the malignancy of tumor phenotype. So interference with this pathway appears to be a potential approach for targeted therapies. Cixutumumab which is currently in Phase II for prostate cancer, is a monoclonal antibody directed against IGF-1R. The antibody selectively binds to the membrane-bound IGF-I receptor, thereby down-regulating the PI3K/AKT survival pathway.
Platelet-derived growth factors (PDGFs) exert their cellular effects through receptors PDGFR-α and PDGFR-β. PDGFR-α can be activated by PDGF-AA, PDGF-AB, PDGF-BB and PDGF-CC, whilst PDGFR-β is only bound and activated by PDGF-BB and PDGF-DD. There is an increasing body of evidence implicating PDGFs in the development of solid tumors. In prostate cancer, overexpression of PDGFRα has been detected in epithelial and stromal cells of prostate adenocarcinomas as well as in bone marrow of metastatic androgen–independent disease, indicating a role for this receptor in both primary and progression of prostate cancer. Expression of PDGFR in prostate tumor-associated endothelial cells was much higher than prostate tumor cells. Tumor cells appear to interact with host factors in the microenvironment to induce growth and the expansion of vasculature. PDGFR inhibitors can, therefore, be considered as a class of antivascular therapies that destroy tumor cells by blocking the required oxygen and nutrients for survival. Imatinib was found to be a potent inhibitor of PDGFR kinase, showing profound activity for prostate cancer in animal models. SU101 leflunomide is a small organic molecule that selectively inhibits PDGFRα and PDGFRβ in vitro. Tandutinib is a small-molecule inhibitor of the type III receptor tyrosine kinases, including the Fms-like tyrosine kinase 3 receptor (FLT3), platelet-derived growth factor receptor (PDGFR), and c-Kit receptor tyrosine kinase.
Angiogenesis, the process of new blood vessel formation, is a crucial step in the propagation of malignant tumor growth and metastasis. Among the multiple pro-angiogenic factors that promote the process of vessel formation, vascular endothelial growth factor (VEGF) is one of the most important. Clinical trials have demonstrated the efficacy of anti-VEGF therapy as a treatment for many types of cancers. Bevacizumab (Avastin) is a humanized murine monoclonal antibody against the VEGF receptor and has been shown to have activity in multiple cancer cell lines. Initial preclinical studies showed that VEGF inhibition by Bevacizumab prevented further tumor growth of the prostate cancer cell line DU145 implanted in nude mice. Unfortunately, use of Bevacizumab as a single agent in prostate cancer was disappointing. Sunitinib is another multi-specific tyrosine kinase inhibitor that targets VEGFR1-3, PDGFRα/β, CSF-1R, and Flt-3. In vivo studies showed additive anti-tumor effect of Sunitinib in combination with docetaxel and/or anti-EGFR antibody Cetuximab in the prostate cancer PC3 and DU145 xenografts.
Fu W et al. Progress of molecular targeted therapies for prostate cancers[J]. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2012, 1825(2): 140-152.