Novel Therapeutic Targets in Neuroendocrine Prostate Cancer
Abstract
Our team is exploring novel research in the field of prostate cancer with the goal of developing an effective approach to cure an especially lethal and dangerous form of this cancer, termed neuroendocrine prostate cancer (NEPrCa). NEPrCa is a highly aggressive and metastatic subtype of prostate cancer that arises from a precursor form of this disease known as castrate-resistant prostate cancer. From a clinical perspective, NEPrCa is extremely difficult to treat and is associated with a very poor life expectancy of less than one year. The proposed research is based upon several novel and exciting findings from our research team. First, we have shown through several lines of investigation that a molecule on the outer surface of the cells, known as NgR2, promotes the progression of prostate cancer to the more aggressive NEPrCa form. Second, we have recently identified another protein at the cell surface, alphavbeta3 integrin, as a potential partner of NgR2. We propose that NgR2 acts to transmit a signal from alphavbeta3 into cells, triggering them to transform into NEPrCa cancer. Thus, our recent research strongly indicates that this newly discovered alphavbeta3/NgR2 association represents a key signaling pathway that is responsible for the development of aggressive NEPrCa. Therefore, investigating this pathway might offer new avenues for predicting and/or detecting early stages of NEPrCa in patients (through developing biomarkers to monitor this pathway) as well as preventing and treating NEPrCa (through targeting this pathway with chemotherapy drugs or other medical interventions). We propose to build upon these basic science observations by clinically validating our findings in primary and metastatic tumors from a large cohort of affected NEPrCa patients. We will perform detailed studies of the amount of alphavbeta3 and NgR2 proteins in these tumor samples, and cross-reference this information to the detailed clinical features of the corresponding patients, including their disease courses, responses to therapy, and health outcomes. In addition, we will genetically eliminate the activity of alphavbeta3 and NgR2 in a mouse model for NEPrCa to rigorously assess the causative roles of these two proteins in NEPrCa development. Together, these studies in human patients and in a closely related mouse model will enable us to determine the functional importance of both alphavbeta3 and NgR2 in this aggressive NEPrCa form of prostate cancer. Our team is composed of several highly regarded preclinical and clinical investigators, including Drs. Lucia Languino (Cancer Biology), William Kevin Kelly (Medical Oncology), Peter McCue (Pathology), Thenappan Chandrasekar (Urology), and Fabio Quaglia (Cancer Biology). All of these investigators are located at Thomas Jefferson University in Philadelphia, which will enhance the cooperation and collaboration among the researchers involved in this proposed project. Given their complementary expertise in basic mechanisms as well as translational and clinical research in prostate cancer progression, their combined efforts on the project will strongly synergize to produce an outcome greater than that which could be achieved by their independent efforts. In summary, our application addresses an important area of research that is under-investigated and has significant unmet clinical need; the challenge is to develop effective diagnostic and therapeutic tools for NEPrCa. Our research focus is thus closely aligned with the FY21 Overarching Challenge Statement of the DOD Prostate Cancer Research Program to Define the biology of lethal prostate cancer to reduce death. Overall, our study will provide novel insights into the identification of a new pathway mediated by alphavbeta3 and NgR2 that promotes an aggressive prostate cancer subtype for which currently there is no effective therapeutic approach. Through our proposed studies, we hope to identify molecular biomarkers that can be
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210826
Entities
People
- Lucia R. Languino
Organizations
- Thomas Jefferson University
- United States Army