Defining and Targeting Genomic Mechanisms Driving Resistance to AR Signaling Inhibitors
Abstract
Scientific Objective and Rationale: Prostate cancer (PC) is the most commonly diagnosed solid cancer in U.S. men and the second leading cause of cancer-related death. Men with primary PC often receive surgery or radiation therapy and cures are common. However, once PC spreads to distant sites, cures are very rare. However, systemic treatments, primary those that interfere with androgen receptor (AR) signaling, can extend survival by many years. However, the depth and duration of AR targeted treatments – including androgen deprivation therapy (ADT) and the use of AR signaling inhibitors (ARSIs) vary substantially from individual to individual. Recent studies detailing the molecular composition of metastatic PC has determined that these advanced tumors are driven by recurrent genomic alterations across of a spectrum of genes. A subset of these genomic alterations involve genes uniquely altered in PC such as TMPRSS2-ERG rearrangements and mutations in the AR, whereas others have well-described roles across many types of cancer. Importantly, a number of these well-known cancer-associated genes appear to functionally modify important aspects of AR signaling, and influence response rates to AR directed treatment. This proposal is specifically focused on understanding and exploiting the role of the important tumor suppressor gene TP53 with respect to AR function. Alterations in TP53 occur in ~50% of all metastatic PCs, emphasizing the key role for this key guardian of the genome in PC biology and potentially in therapy resistance. In this proposal, I will test the hypothesis that genomic alterations commonly observed in PC – specifically alterations in TP53 – influence AR signaling and promote resistance to AR pathway-directed therapy. I further hypothesize that TP53 alterations exert effects via reprogramming the PC cell epigenome and that specific signaling pathways altered through this reprogramming can be targeted to overcome resistance to AR-directed treatment. The specific aims of the project are designed to directly test the above hypotheses. In Aim 1, I will identify alterations in the PC AR cistrome resulting from inactivation of TP53. In Aim 2, I will determine how TP53 loss promotes PC cell survival in the context of AR pathway repression. In Aim 3, I will develop a therapeutic approach co-targeting AR signaling and TP53-regulated resistance pathways. The experimental strategy will use controlled experiments with novel PC model systems and patient-derived tumors with attention to rigor and reproducibility. Applicability of the Research: This project directly relates to the overarching challenge – define the biology of lethal prostate cancer to reduce death. The research is applicable to patients diagnosed with PC that have progressed to a state where the cancer has spread to distant sites (metastases), but may also have relevance to high-risk localized disease. Understanding why and how PC behaves differently in different men is important for understanding prognosis and also provides key insights for developing new treatment strategies. In this context, TP53 is an important gene involving in suppressing tumor development, growth and spread. While it has been challenging to develop treatments that directly target/exploit TP53 itself, downstream pathways regulated by TP53, and particularly interactions with the AR pathway present new opportunities. Consequently, the anticipated results of this research project will contribute vital information towards personalized therapeutic strategies for patients, and potentially identify new drug combinations that could improve responses and/or extend survival. The planned work utilizes preclinical models that reflect the biology of human prostate cancer. The near-term output will include biomarkers of resistance/response to ARSIs and the identification of combination therapeutics that demonstrate preclinical activity. As clinically approved compounds
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310462
Entities
People
- Wanting Han
Organizations
- Fred Hutchinson Cancer Center
- United States Army