Systems Medicine Approaches to Improving Understanding, Treatment, and Clinical Management of Neuroendocrine Prostate Cancer.

BACKGROUND Prostate cancer is the most commonly diagnosed cancer in men. More than 200,000 new cases are added each year in the US, translating to a lifetime risk of 1 in 7 men. Neuroendocrine prostate cancer (NEPC) is an aggressive and treatmentresistant form of prostate cancer. A subset of patients treated with aggressive androgen deprivation therapy (ADT) present with NEPC. Patients with NEPC have a reduced 5-year overall survival rate of 12.6%. Knowledge integration from genetic, epigenetic, biochemical and therapeutic studies suggests NEPC as an indicative mechanism of resistance development to various forms of therapy. METHODS In this perspective, we discuss various experimental, computational and risk prediction methodologies that can be utilized to identify novel therapies against NEPC. We reviewed literature from PubMed and computationally analyzed publicly available genomics data to present different possibilities for developing systems medicine based therapeutic and curative models to understand and target prostate cancer and NEPC. RESULTS We discuss strategies including gene-set analyses, network analyses, genomics and phenomics aided drug development, microRNA and peptide-based therapeutics, pathway modeling, drug repositioning and cancer immunotherapies. We also discuss the application of cancer risk estimations and mining of electronic medical records to develop personalized risk predictions models for NEPC. Preemptive stratification of patients who are at risk of evolving NEPC phenotypes using predictive models could also help to design and deliver better therapies. CONCLUSION Collectively, understanding the mechanism of NEPC evolution from prostate cancer using systems biology approaches would help in devising better treatment strategies and is critical and unmet clinical need.