Novel Mechanism and Targeting of Neuroendocrine Prostate Cancer
Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in American men. Androgen- deprivation therapies (ADTs) are commonly used against advanced PCa; however, patients still die of the growth of castration-resistant PCa (CRPC) and/or therapy-induced neuroendocrine PCa (t-NEPC). Therefore, novel and effective therapies are needed to combat CRPC/t-NEPC growth by eradicating PCa cells. Studies have revealed that cancerous cells have networks (or pathways) of molecules that sometimes turn on in response to hormone- or chemo-therapies in PCa patients with advanced disease, causing the treatments to fail. In CRPC/t-NEPC malignancy, the advanced stages of PCa, these networks are more complicated than those in early-stage disease; therefore, new strategies and drugs hitting the critical cancer-promoting pathways should kill cancer cells more effectively. Elevation of KDM5B (an oncogenic factor) is frequently found in PCa patients with advanced disease, including CRPC/t-NEPC. KDM5B signaling is associated with SOX9, another molecule in PCa, particularly upon loss of PTEN (a tumor suppressor) function. Targeting KDM5B should be a logical option to stall tumor growth through impairing the oncogenic pathways such as SOX9. In this proposal, we think that KDM5B elevation is crucial for the survival of PCa cells and CRPC/t-NEPC progression, and targeting KDM5B will effectively restrict PCa progression and CRPC/t-NEPC growth. We will test this proposed theory in three aims by performing experiments using laboratory human PCa cells (PC3, LNCaP-MDV, and NCI-H660), experimental mice designed to grow human PCa cells, genetically engineered mice that develop PCa with NEPC features, and PCa patient-derived xenografts (PDXs). First, we will investigate the functional role of KDM5B in the development and growth of NEPC malignancy in the experimental mice. Second, we will elucidate the molecular contributions of KDM5B to the regulation of SOX9 signaling in human PCa cells. Third, we will evaluate the anticancer effects of KDM5B inhibition with specific drugs (small molecule inhibitors) on the growth of NEPC tumors in the experimental mice. If successful, our findings will surely lead to greater understanding of these networks of molecules in PCa and may reveal more effective treatments against CRPC/t-NEPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210818
Entities
People
- Zhenbang Chen
Organizations
- Meharry Medical College
- United States Army