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
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.