Developing Precision Oncology Tools for Guiding Prostate Cancer Immunotherapy
Abstract
Scientific Objectives/Rationale: Prostate cancer (PC) is the most frequently diagnosed tumor in men, with incidence rates rising dramatically with advancing age. Though most of the detected PCs never spread beyond the confines of the prostate gland, a significant proportion of patients show metastatic propagation of the disease, leading to tens of thousands of deaths yearly. With new treatments there have been improvements in extending the survival of men with metastatic PC and castration-resistant PC (mCRPC), but very few men are cured. Recent progress in understanding the molecular drivers of PC have led to precision oncology approaches to exploit particular tumor vulnerabilities with selected drugs. A notable example involves PARP inhibitors for tumors with specific types of DNA repair defects. Another exciting area centers on methods to enhance immune responses toward tumors. Remarkable responses have been observed in some tumor types using immune checkpoint inhibitors. However, these agents have not shown consistent responses in mCRPC. Recent studies have determined that tumors with high mutation loads may be particularly responsive to immune checkpoint inhibitors. We have recently determined that a subset of men with mCRPC have tumors with high mutation loads. The objective of this research proposal is to determine if mCRPC tumors with high mutation loads, termed hypermutated tumors, will respond to immune checkpoint blockade. Applicability of Research: This proposal has three specific aims in addition to specific plans for my training in scientific methods related to PC biology and clinical treatment. In Aim 1, I will ascertain the prevalence of hypermutated tumors in men with mCRPC and determine if there is a relationship between mutation status and the quantity and type of immune cells infiltrating into the tumor. In Aim 2, I will evaluate tumor samples from a clinical trial of an immune checkpoint inhibitor (Durvalumab) to determine if men with hypermutated PCs exhibit clinical responses to this drug and assess the immune cell infiltration in these tumors. In Aim 3, I will develop a minimally invasive blood-based assay to identify tumors with high mutation loads, and avoid the need for an invasive tumor biopsy procedure. This proposal will specifically assist men with metastatic PC by identifying a treatment approach (immune checkpoint blockade) likely to work in some (those with hypermutated tumors) and not in others (those without hypermutated tumors). A blood test to identify the tumor mutation load status would help all men with metastatic PC by assisting them with treatment decisions. A patient-related outcome can possibly be achieved within a 2-year time frame (the development of a blood-based assay) and with 3-4 years (clinical studies demonstrating benefit from checkpoint blockade in this patient subtype). Career Goals: My long-term career goals are to direct a scientific team focused on using genomics-based tools to define subtypes of prostate cancer, predict their vulnerabilities, and assist in developing therapeutic strategies to target them. The experiments comprising the specific aims of the proposal will expand my repertoire of computational and wet-bench skills and provide a foundation for leading a scientific team directed toward developing translational precision genomic tools in different avenues of cancer surveillance and therapy. For this Prostate Cancer Research Program postdoctoral training proposal, I have developed a multi-component strategy for developing critical skills and a knowledge base with my mentor (Dr. Nelson) and will interact extensively with a highly collaborative research team (including mentors and advisors in laboratory medicine, pathology, and medical oncology) that will serve as the foundation for sustained success in prostate cancer-related biomedical research. Contributions Toward Advancing Prostate Cancer Research: Collectivel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710380
Entities
People
- Navonil De Sarkar
Organizations
- United States Army
- University of Washington