Targeting Endoglin Signaling to Antagonize Androgen Receptor Splice Variants in Castrate-Resistant Prostate Cancer
Abstract
Rationale: Prostate cancer cases and tumor growth after drug treatment continue to increase in the United States. Prostate cancer rates have increased 108% since 1950, despite surgery, chemotherapy, and radiotherapy. Although the standard of care blocks androgen hormone by castration or androgen deprivation therapy, developing better treatment is still challenging. Initially, 70%-80% of prostate cancer patients respond to therapy, but some tumors become hormone-refractory, leading to poor prognosis. Androgen deprivation therapy, like enzalutamide, binds to the ligand-binding domain of androgen receptor protein. However, when androgen messenger RNA has been selectively terminated at the ligand-binding domain, enzalutamide fails to stop androgen receptor function. The proteins produced from this splicing are called androgen receptor splice variants, which have been shown to increase during drug treatment and are high in larger prostate tumors. Cells that communicate within the tumor environment are important to study to develop better treatments. Unfortunately, androgen receptor splice variants have been studied in prostate epithelial cells, although the prostate stroma is significant during tumor growth, and when these tumors leave the primary site. Endoglin is highly expressed in tumors and increase after enzalutamide treatments. RNA binding proteins are closely involved with increased splicing, and their functions need to be determined during the expression of androgen receptor splicing. Studying the adhesion molecules, like endoglin, outside of the cell and RNA binding proteins that directly control splice variant production, like RNPC1, provides insight on castrate-resistant prostate cancer. Objectives: (1) Determine how androgen receptor variants expressed in prostate tumor stroma help to promote androgen deprivation therapy resistance. (2) Sensitize prostate cancer cells to androgen deprivation therapy using species-specific endoglin antagonism. (3) Determine the role of RNA binding protein RNPC1 during androgen receptor splice variant expression and therapy response. Clinical Impact: This proposal will address the role of androgen receptor splice variants on castrate-resistant prostate cancer and the connection between prostate cancer stroma and epithelia. Patient Focus: The data generated from this proposal will help patients suffering with prostate cancer, and who are treated with antitumor drugs such as enzalutamide, where androgen receptor signaling has been altered to increase tumor growth. Potential Clinical Applications: Findings from this proposal may be used to (1) predict gene changes that may impair drug effects to reduce tumors and (2) develop a method to reverse negative effects on prostate stroma cells in patients. Based on ongoing Phase 2 clinical trials using TRC105 in sarcoma, we predict that the patient-related outcomes will be primarily positive. The safety outcomes for TRC105 are highly favorable, especially considering the negative side effects of enzalutamide that have been documented for several years. These data further demonstrate to us the potentially high level of efficacy for TRC105 during our studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710154
Entities
People
- Bethany Smith
Organizations
- Cedars-Sinai Medical Center
- United States Army