Is the Bench Getting Closer to the Bedside in the War on Cancer? A Quick Look at Prostate Cancer

officially inaugurated in the early seventies by Richard Nixon, research priorities to identify and attack the main weaknesses of tumor cells have evolved, following the rhythm of technology. From the use of overtly toxic and undiscriminating drugs to the detailed annotation of cancers on a patient-to-patient basis through the use of “Omics” approaches, research has struggled in the search for a cure. Is current basic research having a more immediate impact on nurturing clinical work? Here we discuss the recent contributions of basic research to prostate cancer therapy, and the factors contributing to a change in the way we fight this disease, with a focus on hormone signaling and metabolism. Prostate cancer is the fifth cause of death by cancer worldwide (data retrieved from the WHO), second in the male population. Prostate cancer arises from the aberrant proliferation of epithelial cells, termed prostate intraepithelial neoplasia (PIN). Cancer cells can further alter the structure of the gland, leading to the disruption of the basal cell layer and loss of basement membrane integrity and the onset of invasive prostate cancer lesions. Upon sustained hormone-ablation therapy, invasive prostate cancer frequently acquires castration-resistant features and gains metastatic potential, which accounts for a large fraction of morbidity (Moul and Dawson, 2012). Much of the effort dedicated to prostate cancer research has been oriented at developing efficient therapies for the most deadly form of the disease, castration-resistant prostate cancer (CRPC), which often exhibits aberrant production of androgens or activating mutations in the Androgen Receptor (AR) gene, together with inactivating mutations in genes such as the tumor suppressor PTEN (Friedlander et al., 2012). Recent studies indicate that inhibitors of androgen synthesis (CYP17) and AR signaling exhibit antitumoral activity in CRPC patients. Thus, compounds targeting the androgen pathway have emerged as leading anticancer agents. CYP17 exhibits both 17,20 lyase and 17-hydrolase activity. Whereas the 17,20 lyase activity of CYP17 is involved in androgen synthesis, the 17-hydrolase activity is relevant for glucocorticoid synthesis. Therefore, inhibition of both CYP17 activities results in the reduction of both androgen and glucocorticoid synthesis, which has led to the need of combining CYP17 inhibitors ith glucocorticoid supplementation, in order to avoid undesirable side effects (Attard et al., 2012). The US FDA recently approved the CYP17 inhibitor abiraterone acetate (Zytiga) for the treatment of CRPC (De Bono et al., 2011). In addition, there are inhibitors targeting the 17,20 lyase activity of CYP17 (rather than the 17-hydrolase activity, hence eliminating the need for glucocorticoid supplementation), such as TAK700, in Phase III clinical trials (refs. NCT01193244 and NCT01193257) and galeterone, a dual CYP17/AR inhibitor in Phase I (see text footnote 1 ref. NCT00959959), that could be adopted as first line therapies for CRPC in the near future. To date, targeting androgen signaling in CRPC appears to be one of the most attractive approaches, due to the fact that resistance to castration is often associated to extra-gonadal androgen synthesis (adrenal glands, intracrine de novo synthesis) that can be targeted with these new pharmacological inhibitors (Attard et al., 2012). However, these exciting new drugs might still fail to function upon the emergence of resistant cancer cells (Mostaghel et al., 2011). Therefore, and in line with the notion that single anticancer therapy will only be an efficient anticancer approach in a handful of cancers with a clear oncogene addiction (Weinstein, 2008; Weinstein and Joe, 2008), the question arises: what will be the best drug combination to cure prostate cancer? Genetically engineered mouse models provide us with a fantastic opportunity to study and understand the biological alterations that occur in the disease, and in turn might facilitate predicting the best pharmacological combination on the basis of the genetic make-up of the cancer. The tumor suppressor PTEN is among the most mutated/inactivated genes in prostate cancer, with up to 70% of tumors harboring partial or complete loss of PTEN at presentation (Salmena et al., 2008). While PTEN frequently undergoes loss of heterozygosity, it is mostly in advanced cancers that complete loss is observed. On this basis, a genetic mouse model driven by prostate epithelium-specific loss of Pten was anticipated to be a faithful model for this disease. Indeed, Pten heterozygous mice present PIN lesions in the prostate with long latency (Di Cristofano et al., 1998; Trotman et al., 2003), whereas complete loss of PTEN in the prostate epithelium results in full-penetrance PIN in early stages, and invasive cancer later on, once the underlying senescence response has been evaded (Chen et al., 2005; Alimonti et al., 2010). This mouse model therefore offers two flavors of prostate cancer, onset and progression, which is extremely useful both for biological understanding and therapeutic initiatives. Indeed, this model has led to the characterization of the intimate association between the PI3K pathway and androgen signaling in prostate cancer, with reciprocal feedback loops triggering compensatory activation of these pathways when pharmacological inhibitors are employed (Carver et al., 2011; Mulholland et al., 2011). The idea that emanates from these studies is Is the bench getting closer to the bedside in the war on cancer? A quick look at prostate cancer