Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

Abstract

Androgen deprivation therapy (ADT) has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer (PCa). However, this approach is rarely curative. Recent clinical trials have demonstrated that ADT combined with other agents, notably docetaxel and abiraterone, lead to improved survival. The mechanisms surrounding this improved cancer outcomes are incompletely defined. The response of cancer cells to ADT includes apoptosis and cell death, but a significant fraction remains viable. Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells. Cellular senescence is a phenotype characterized by cell cycle arrest, senescence-associated β-galactosidase (SA-β-gal), and a hypermetabolic state. Positive features of cellular senescence include growth arrest and immune stimulation, although persistence may release cytokines and growth factors that are detrimental. Senescent tumor cells generate a catabolic state with increased glycolysis, protein turnover and other metabolic changes that represent targets for drugs, like metformin, to be applied in a synthetic lethal approach. This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.

Keywords: Androgen deprivation therapy; Cellular senescence; Combination therapy; Metformin; Prostate cancer; Statins; Synthetic lethal targeting.

Figure 1

Synthetic lethal targeting of ADT induced cellular senescence for improved prostate cancer cell killing. ADT, androgen deprivation therapy.