Pharmacologic Downregulation of SOX2 to Enhance Efficacy of Anti-AR Therapies in Prostate Cancer
Abstract
As a son and son-in-law of prostate cancer survivors, I am keenly aware of the deficiencies in our ability to treat prostate cancer. Having walked through their cancer journeys with them, it is clear that we have a long way to go for us to overcome the scourge of lethal prostate cancer. The sole purpose of my research program is to develop new ways to combat prostate cancer, from early-stage tumors to advanced metastatic disease. In particular, there is a dire need to provide surgeons and oncologists with more options for patients to aid in: (1) whether to pursue surgery, radiation, or active surveillance after an initial diagnosis and (2) what to do when the cancer returns and progresses to metastatic disease. My lab has worked to accelerate the discovery of new biomarkers and drugs using bio-informatics, cell biology, publicly-available patient-derived gene array datasets, drug screening, and research collaboration to identify new signaling pathways in prostate cancer that can be translated into biomarkers and drug targets. The SOX2 protein is an important driver of prostate development, and when expressed in tumors, it drives tumor growth and metastatic progression. In our ongoing work we have used bioinformatic, clinical, and molecular approaches to discover that SOX2 proteins mark aggressive, metastatic prostate tumors, and that blocking SOX2 protein expression blocks tumor growth, metastasis, and makes cells much more sensitive to enzalutamide. Further, we have identified a class of drugs targeting the Insulin Growth Factor Receptor 1 (IGF1R) that decrease SOX2 expression in prostate cancer cells. This prioritizes SOX2 as a critical determinant of lethal, drug-resistant metastatic disease. Thus, understanding how it functions has the high probability to identify new targets for therapy and to galvanize SOX2 expression as novel staging tools for men diagnosed with prostate cancer. The work proposed here has three main purposes: 1. To further understand how SOX2 promotes lethal prostate cancer and identify new strategies for preventing drug resistance and treating advanced prostate cancers. 2. To understand what regulates SOX2 in prostate tumors, and to develop new strategies for decreasing SOX2 expression and blocking its activity. Our recent drug screening efforts have identified IGF1R signaling (Insulin Growth Factor 1 Receptor) as a key driver of SOX2 expression. Importantly, there are many available inhibitors of IGF1R under clinical development, and we have found that these re-sensitize SOX2-positive prostate cancer cells to enzalutamide. Thus, work proposed here has the high potential to lead to clinical trials targeting IGF1R, SOX2, and the Androgen Receptor (AR) to prevent or overcome resistance to AR-targeted therapies. 3. To develop and characterize robust biomarker approaches that can be utilized in a clinical trial to identify patients with SOX2-positive tumors that may benefit from our potential new approaches. It is my plan and sincere ambition that completion of the work proposed here represents a significant benefit to prostate cancer patients at both early and advanced stages of disease, and also benefits future prostate cancer researchers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310619
Entities
People
- Donald Vander Griend
Organizations
- United States Army
- University of Illinois at Chicago