Targeting TPH1 in Neuroendocrine Prostate Cancer
Abstract
Scientific Objective and Rationale: Approximately 33,330 men are projected to die from prostate cancer in the United States in 2020, making it the second commonest cause of death from cancer in men of all ages and the commonest cause of death from cancer in men over age 75. Hormone therapy, which prevents androgens such as testosterone from promoting prostate cancer’s biological effects, is the current dominant therapy. Though prostate cancer patients benefit from this type of therapy at first, prostate cancer inevitably progresses to castration resistance and is then treated with more potent hormone therapies such as enzalutamide (Xtandi). However, prostate cancer can rapidly develop drug resistance to the newer hormone therapies and further progress to neuroendocrine prostate cancer. This lethal type of prostate cancer reportedly constitutes up to 25% of treatment-resistant relapsed prostate cancer. Currently, there is no effective treatment for neuroendocrine prostate cancer, and the survival of patients who suffer from this deadly disease is only ~7 months. There is an urgent clinical need to develop new and effective targeted therapies against this incurable type of prostate cancer. I recently discovered that the expression levels of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme responsible for the biosynthesis of serotonin, a well-known chemical messenger essential for maintaining a wide range of neural and physiologic activities in the body, was significantly increased in a human prostate cancer cell model that successfully mimics emergence of clinical neuroendocrine prostate cancer and in human neuroendocrine prostate cancer patient samples. My pilot studies further showed that silencing TPH1 effectively suppressed neuroendocrine prostate cancer cell growth and related neuroendocrine marker expression in experimental models. Based on these exciting data, I propose to test the hypothesis that TPH1 plays an active role driving neuroendocrine prostate cancer and that targeting TPH1 is a feasible strategy to treat neuroendocrine prostate cancer. Research Applicability: The proposed project addresses two Prostate Cancer Research Program Overarching Challenges. I aim to define the biology of lethal prostate cancer while also developing treatments for men who suffer from this terminal disease. This study will further validate the involvement of TPH1 and serotonin signaling in neuroendocrine prostate cancer and provide insights into the biology and molecular pathways that drive neuroendocrine differentiation in prostate cancer. The proposed research will lead to the development of a novel therapeutic strategy for neuroendocrine prostate cancer to improve outcomes for patients with this currently lethal disease. Ultimately, completion of the proposed research will assess the therapeutic potential of a FDA-approved TPH1 inhibitor for neuroendocrine prostate cancer in animal models. If successfully executed with the expected results, this will provide compelling preclinical evidence for quickly launching human clinical trials to repurpose TPH1 inhibitors as a neuroendocrine prostate cancer therapy in the near future. Patient Focus: The results of this work will help prostate cancer patients who received hormone therapy, also called androgen deprivation therapy, and then developed treatment-induced neuroendocrine traits that currently lack an effective treatment. Career Goals: My overarching career goal is to become an independent prostate cancer researcher. The execution of this project under the guidance of Dr. Wu will enable me to acquire the necessary knowledge and expertise to dissect biological mechanisms responsible for prostate cancer. Likewise, the mentorship of Dr. Meier will be instrumental to my initial training in prostate cancer research and the successful completion of the project aims. My career in prostate cancer research will be accomplished through the development of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110218
Entities
People
- Jing Wei
Organizations
- United States Army
- Washington State University