Transcriptional Reprogramming of Lethal Small Cell Prostate Cancer
Abstract
For decades, researchers have been trying to understand the development and treatment resistance mechanisms of prostate adenocarcinoma (PrAd) in order to develop and improve targeted therapies. These efforts led to the current treatment for lethal and metastatic PrAd patients. However, we are facing another highly aggressive prostate cancer variant called small cell prostate cancer (SCPC) in the clinic. This SCPC is increasingly recognized in up to 20% of PrAd patients with the current treatment. SCPC has distinct cellular and molecular characteristics compared to conventional PrAd. Thus, our current knowledge and treatment for PrAd cannot be applied to combat this SCPC. Unfortunately, SCPC patients have a very dismal prognosis because no effective treatments exist. The median overall survival of SCPC patients is less than 1 year. Recent studies suggest that this lethal prostate cancer variant may arise as an adaptive treatment resistance mechanism to current androgen-deprivation therapies. In this proposed research, we will interrogate two aspects in SCPC development: (1) how PrAd becomes SCPC, which could be a current treatment-escaping mechanism, and (2) how SCPC grows rapidly, which leads to poor prognosis. We have developed a unique human prostate organ-in-a-dish transformation system that can transform normal cells into prostate cancer by adding cancer-driving genes. This novel approach will provide the unique and necessary materials to investigate and to manipulate SCPC development. Our preliminary study showed that we can capture the molecular characteristics of human prostate cancer development from normal human prostate cells, PrAd to SCPC. We will define essential genetic/molecular switches (called transcription factors) for SCPC development and aggressive cell growth. If successful, this project will increase our understanding of key genetic/molecular switches that can regulate SCPC development and rapid growth in androgen-independent SCPC. In the future, we will use large-scale screens to look for drugs that disrupt these molecular switches. This will provide insights into the development of new therapeutic interventions for preventing or reversing SCPC development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110806
Entities
People
- Jung Wook Park
Organizations
- Duke University
- United States Army