High Potency Drug Screening in Neuroendocrine Prostate Cancer

Abstract

Neuroendocrine Prostate Cancer (NEPC) is an aggressive subtype of prostate cancer, affecting approximately 2% of all prostate cancer patients. While NEPC is a rare disease, it has no known treatment and often leads to death within a year of diagnosis. As result of low incidence rates, these rare conditions typically do not get the same pharmaceutical interest, as discovery research rarely recovers the cost for development and clinical trials. Drug repurposing is a viable option for rare conditions and the use of high-throughput screens can lead to drug repurposing discovery. Chemotherapy has moved to personalize therapy, focusing on molecular alterations for specific tumors. NEPC cell lines (specifically, LnCAP and 22rv1) have been shown to overexpress n-MYC (MYCN), which is a proto-oncogene not typically expressed in adult tissue. This transcription factor is typically present in developing tissue that results in neural tissue. The LnCAP cell lines (LnCAP-P and LnCAP-n-MYC) have been shown to be a in vitro NEPC model, and along with Benign Prostate Hyperplasia tissue (BPH-1) as a control, these cell lines were screened using the Targetmol Drug library, which contained 1813 small molecules at concentrations of 100 nM, 500 nM and 1000 nM in 384-well optic plates using high-throughput microscope and RFP fluorescence in cell lines. Fludarabine and Fludarabine phosphate were identified as potential n-MYC selective hits and validation of Fludarabine phosphate using Alamar Blue viability reagent in 96-well plates were done using BPH-1, LnCAP, and 22rv1. Result confirmed Fludarabine phosphate selectively inhibited cell viability in n-MYC overexpressed cells in both LnCAP and 22rv1.