Trop2 as a Novel Driver and Therapeutic Target for Castration-Resistant Prostate Cancer
Abstract
Rationale, Objective, and Specific Aims: Androgen deprivation therapy is the first line of treatment for men with advanced prostate cancer. Unfortunately, the disease commonly relapses in its lethal metastatic form, referred to as castration-resistant prostate cancer (CRPC). Thus, there is an urgent needed to identify novel therapeutic targets and therapeutic strategies for advanced prostate cancer. Trop2 is a cell surface transmembrane glycoprotein found highly expressed and associated with an unfavorable outcome in various human cancers. We have discovered that Trop2 is activated by sequential cleavages, which leads to generation of two products: extracellular domain and an intracellular domain. We also demonstrated that overexpression of these two cleavage products promotes prostate tumorigenesis in vivo. Our preliminary results demonstrate that Trop2 is elevated in metastatic CRPC, and its expression correlates with an unfavorable clinical outcome. We have recently demonstrated that Trop2 is essential for prostate cell proliferation, migration, and invasion in vitro and tumor formation in vivo. Moreover, our preliminary results suggest that Trop2 drives CRPC. These findings provide strong functional evidence that Trop2 may represent a new rational therapeutic target for aggressive prostate cancer. In addition, we generated 16 humanized anti-Trop2 antibodies as a new strategy to block Trop2 activation. The major goals of the proposed projects are as follows: Specific Aim 1: Evaluate the role of Trop2 in castration resistance and metastasis in vivo. Specific Aim 2: Define the molecular mechanisms through which Trop2 signals in prostate cancer. Specific Aim 3: Evaluate novel therapeutic strategies to target Trop2 activity in cancer. The proposed study will facilitate our understanding of fundamental molecular mechanisms driving advanced prostate cancer and test novel therapeutic strategies for aggressive prostate cancer. Clinical Applications: Defining new therapeutic strategies for advanced prostate cancer will result in a significant decrease in deaths associated with aggressive prostate cancer. The proposed study will facilitate our understanding of fundamental molecular mechanisms driving advanced prostate cancer. Understanding how Trop2 signals in prostate tumorigenesis will give us new insights on the development of novel therapies for aggressive prostate cancer. Finally, antibodies that inhibit Trop2 activation may be used for patients with aggressive prostate cancer and may significantly reduce deaths associated with advanced prostate cancer. Contributions to the Field of Prostate Cancer Research: The proposed research aims to evaluate a new therapeutic strategy for advanced prostate cancer. We recently demonstrated that Trop2 represents a new promising therapeutic target for advanced prostate cancer. Identifying therapeutic strategies and new pathways and mechanisms that contribute to the development of aggressive prostate cancer will significantly advance the field of prostate cancer research. The proposed project is the first study to date to evaluate the therapeutic potential of antibody-based strategies to inhibit Trop2 activation. This innovative strategy will identify novel therapies for aggressive prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810323
Entities
People
- Tanya Stoyanova
Organizations
- Stanford University
- United States Army