Targeted Inhibition of Neuropilin-2 to Enhance Immunotherapy of Lethal Prostate Cancer
Abstract
Scientific Objective and Rationale: The objective of this proposal is to understand the role of the proteins vascular endothelial growth factor (VEGF) and neuropilin-2 (NRP2) in regulating the aggressive behavior of a lethal form of prostate cancer (PCa) called neuroendocrine PCa and to develop new treatment strategies for this lethal disease. Neuroendocrine PCa is an aggressive form of PCa that is associated with rapid progression, resistance to treatments, and a very poor outcome, with most patients surviving less than 1 year. One of the factors contributing to the aggressive behaviors of neuroendocrine PCa is by changing the cancer cells to behave similarly to stem cells. Our laboratory showed that NRP2 can bind with VEGF and can change the cancer cells to be similar to stem cells. Neuroendocrine PCa cells have extra copies of both VEGF and NRP2 genes compared to normal cells. Further, the expression of NRP2 can help PCa cells escaping destruction by the immune system. Thus, NRP2 may contribute to the stem cell behaviors underlie the aggressive nature of neuroendocrine PCa and the cancer cells’ ability to escape immune destruction. Currently, there is no effective treatment for neuroendocrine PCa. Importantly, treatments are needed that can inhibit the stem-cell behaviors of cancer cells, make the cancer cells more vulnerable to therapies, and increase the therapeutic efficiency. Since NRP2 is over-expressed in cancer cells and is not expressed in normal cells, NRP2 can be a safe and effective therapeutic target using function-blocking antibodies, making it a promising target to reduce the aggressive behavior of neuroendocrine PCa and increase the efficiency of treatment to activate immune system to kill the cancer cells. Ultimate Applicability of the Research: This research will primarily address the Overarching Challenge to “Develop treatments that improve outcomes for men with lethal prostate cancer” by evaluating the therapeutic potential of targeted NRP2 inhibition in reducing stem-cell behaviors, activating the anti-tumor immunity of neuroendocrine PCa, and the effect of combination therapy using both NRP2 inhibition and immune therapies. Furthermore, this work will address the Overarching Challenge, “Define the biology of lethal prostate cancer to reduce death,” by understanding the role of VEGF and NRP2 in promoting the aggressive behavior and stem-cell behavior of neuroendocrine PCa. The proposed research will help patients with neuroendocrine PCa, which is a lethal form of advanced PCa, by studying the drivers contributing to the aggressive behaviors of cancer cells and developing new therapeutic strategies. It has significant clinical implications because it can be efficiently inhibited using available antibodies. Further, it can be combined with immune therapies to improve the efficacy of these therapies. Importantly, it is highly expressed in cancer cells and not expressed in normal cells, making it a safe and promising target specific in cancer cells. The projected timeline for this study is 2 years. I will use both cell models and animal models to test my hypothesis. If the results of this study show NRP2 is a promising target and can be combined with immune therapies to improve treatment outcome, it should be readily translatable to the clinic upon finishing the project to achieve a patient-related outcome. Principle Investigator and Mentorship: My long-term career goal is to become an independent PCa researcher focusing on studying molecular and cellular mechanisms that drive PCa progression and to uncover new targets for therapy. This proposed research plan will support me in achieving these goals because it utilizes different research approaches that will benefit my future career, and it will advance my knowledge and expertise on different fields of PCa, including PCa pathology, PCa biology, cancer immunology, and immuno-therapy, to accomplish this study and to become an indepen
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110123
Entities
People
- Mengdie Wang
Organizations
- United States Army
- University of Massachusetts Medical School