Developing New Therapeutic Strategies to Target Trop2 in Aggressive Prostate Cancer
Abstract
Prostate cancer is the leading cause of cancer among men worldwide. Current treatment for prostate cancer diagnosis is through surgical removal of the tumor and radiation therapy, with androgen-deprivation therapy (ADT) given if the cancer returns after prostatectomy and radiotherapy. Over the course of ADT, some tumors can mutate and evolve to become castration-resistance prostate cancer (CRPC), a metastatic and lethal form of prostate cancer. The current therapies for CRPC include treatment with second-generation anti-androgen drugs, but they only improve median overall survival by a few months and new therapeutical methods are needed to address metastatic CRPC. Furthermore, a subset of CRPC gains neuroendocrine phenotype and expresses neuroendocrine markers after being treated with second-generation anti-androgen drugs. These neuroendocrine prostate cancer (NEPC) cells are not sensitive to any anti-androgen drugs because their growth is independent of androgen signaling, and they are considered the most difficult to treat and a lethal form of prostate cancer. Therefore, there is an immediate need to establish new therapeutical methods against mechanisms that promote advanced prostate cancer. We previously found a high level of Trop2 expression in advanced prostate cancer patients’ tumors. Trop2 is a cell membrane protein that is also highly expressed in advanced breast, colorectal, and lung cancer. When activated, Trop2 is cleaved into two parts: the extracellular domain (TECD) and the intracellular domain (TICD). We found that active Trop2 leads to faster cell growth and increases the ability of these Trop2 high-expressing cancer cells to invade and metastasize in locations such as bones and lungs. Depletion of Trop2 expression leads to inhibition of cell growth and a decrease in the numbers of metastases in our preclinical metastatic prostate cancer patient-derived xenograft (PDX) models. Therefore, we hypothesize that targeting Trop2 and inhibiting Trop2 signaling represent a novel therapeutic strategy for targeting advanced prostate cancer. We utilized a high-throughput compound screen for Trop2 inhibitors at the Stanford High-Throughput Bioscience Center. Over 2,500 compounds were screened, and 30 potential Trop2 inhibitors were found that have specific toxicity towards prostate cancer cell lines. Our goals for this study are (1) to develop small molecule inhibitors that target Trop2 activation and function and (2) to test these compounds’ therapeutic potential through inhibiting Trop2-driven tumor growth and metastasis. The results from this study will directly impact the prostate cancer community by providing the health community with new therapeutic methods in targeting a protein, Trop2, which is necessary for advanced prostate cancer to grow. Developing a Trop2-specific inhibitor will also be a useful tool for the research community in investigating the mechanisms by which Trop2 exerts its oncogenic role in cancer. My future goal is to establish an academic translational research lab as an independent investigator. As a molecular biologist, I am excited to investigate the oncogenic properties of Trop2 in advanced prostate cancer development. The proposed project focuses on developing novel inhibitors to Trop2, and the translational aspect of the project is in line with my growing interest in exploiting disease-specific biomarkers as therapeutic targets. My mentor, Dr. Tanya Stoyanova, has over 12 years’ experience in prostate cancer signaling and has characterized some of Trop2’s oncogenic properties in prostate cancer. Her guidance and expertise in prostate cancer preclinical models will be invaluable for this project. I will also collaborate with Dr. James Brooks, a surgical urologist with over 20 years’ experience in mentoring young scientists. His expertise in prostate cancer patient treatment will be useful as I learn more about translating findings in the laboratory setting and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310237
Entities
People
- Alifiani Hartono
Organizations
- United States Army
- University of California, Los Angeles