Overcoming mechanisms of PTPN1 driving therapy- and castration- resistant prostate cancer with novel theranostics

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

Project Summary/Abstract Overwhelming data from clinical experience clearly indicate that the recurrent therapy- and castration-resistant prostate cancer (t-CRPC) is responsible for the majority of these deaths because these cells exhibit resistant phenotype to hormonal therapy as well as conventional chemotherapy. Thus, new therapeutic target(s) based on molecular mechanisms leading to resistant phenotype is urgently needed for prolong the survival of prostate cancer (PCa) patients. More than 25% of the metastatic CRPC patients on highly potent new-generation anti-androgen therapies end up with neuroendocrine prostate cancer (NEPC). Currently, NEPC is considered as an end stage disease because only few chemotherapeutics for NEPC with unsatisfied outcome. From several tissue culture and transgenic animal models, data suggest that hormonal therapy promotes androgen-dependent prostate adenocarcinoma (ADPC) cells to undergo transdifferentiation then become therapy resistant NEPC. Nevertheless, the underlying molecular mechanism remain largely uncharacterized. In this study, we provide strong evidence that the protein tyrosine phosphatase non-receptor 1 (PTPN1) plays a critical role in PCa transdifferentiation. For example, Increased PTPN1 expression in ADPC promotes the onset of NEPC. In contrast, knocking down PTPN1 expression in NEPC cells can restore ADPC phenotype. Thus, this project is to examine the regulation of PTPN1 gene expression by anti- androgens and unveil the reciprocal regulatory network among PTPN1-androgen receptor- RE1- silencing transcriptional factor then identify the downstream effector(s) of PTPN1 in promoting NEPC. Most importantly, it is to develop a new NEPC-specific theranostic strategy by engineering NEPC-specific small drug conjugate with molecular imaging capabilities. The ultimate goal is to explore clinical translation by formulating a new therapeutic regimen with PTPN1 theranostics and anti-androgen agent in clinically relevant animal models. The outcome gained from this project will revolutionize the current concept of recurrent t-CRPC therapy in order to improve overall survival of patients.