Mechanisms Controlling the Progression of Prostate Adenocarcinoma to Neuroendocrine Cancer
Abstract
This project directly addresses the FY22 PCRP Overarching Challenge to Define the biology of prostate cancer progression to lethal prostate cancer to reduce death. It will contribute to our understanding of how neuroendocrine prostate cancer forms and will test multiple molecular pathways as vulnerabilities for future therapies targeting this form of prostate cancer. Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that may arise de novo (less than 1% of prostate cancer), or it may arise in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. The latter is an emerging clinically relevant problem since so called therapy- emergent neuroendocrine prostate cancer (tNEPC) is a lethal disease with a median overall survival of less than 1 year from the time of detection. Given the aggressive clinical course and poor outcomes of tNEPC patients, it is essential to better understand the biological basis for the progression from prostate adenocarcinoma to lethal tNEPC. Identifying the molecular drivers of the progression from an adenocarcinoma to a neuroendocrine cancer will provide new strategies for development of therapeutic agents to block the progression and/or growth of the cancer. Development of new therapeutic approaches to tNEPC is severely limited by a lack of molecular insight into factors required for the transition of non-neuroendocrine tumors to the neuroendocrine identity. This project provides development of a new mouse model to be used to gain biological insights and identify vulnerabilities in tNEPC. In doing so, new opportunities for therapeutic intervention will be identified, which is critical for changing the mortality curve for therapy- resistant prostate cancer. We will leverage our knowledge of key molecular drivers of neuroendocrine lineages in normal development and disease and our expertise with genetically engineered mouse models to gain access to this understudied area. The first aim of this project will be to identify the types of cells that transition to tNEPC using newly developed genetically engineered mouse models to study this process in the intact animal. We will use these same mouse models to test whether a factor that is known for its function in controlling the generation of neuroendocrine cell types in multiple organs during normal development is required for the transition of prostate cancer to NEPC. Finally, we will explore the role of a signaling pathway that connects molecular information from outside the cell to changes in the nucleus that may be required for the aggressive characteristics of tumors with neuroendocrine features. The importance of the latter aim is that the signaling pathways comprise the largest multigene family of known drug targets and, thus, provide potential therapeutic implications for future exploitation. The anticipated near-term impact of this program includes providing much-needed new models to study the progression of prostate adenocarcinoma to a neuroendocrine tumor in an intact system to probe key molecular vulnerabilities. These advances will provide a foundation for future research projects to develop therapeutic strategies directly targeting identified vulnerabilities that will enable progress towards eliminating death from prostate cancer and enhancing the well-being of all the men and their families who are experiencing the impact of the disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310285
Entities
People
- Jane Johnson
Organizations
- United States Army
- University of Texas Southwestern Medical Center