Exploiting Prostate Cancer Metabolic Dependencies to Develop New Therapeutics and Circulating Prognostic and Predictive Biomarkers
Abstract
Due to the dependence of prostate cancer (PCa) cells on androgens for growth and survival, androgen deprivation therapy has remained the frontline strategy for management of advanced PCa since the 1940s. Although androgen deprivation therapy is initially effective in most patients, it fails to achieve an enduring remission, with a predictable disease recurrence in a median time of 18-20 months. The stage of the disease after androgen deprivation therapy failure is termed castration-resistant prostate cancer (CRPC), and it remains incurable. Furthermore, almost one fifth of CRPC develop small-cell neuroendocrine pathologic features after AR inhibition treatment that are resistant to AR-targeted therapy (NEPC). There is an urgent need to identify new therapeutic targets and introduce new drugs that are effective in the advanced stages of the disease. Drug treatment of cancer cells usually kills most cells; the ability of the remaining cells to resist drug treatment is attributed to their ability to activate survival pathways. Disclosing and understanding the biology of these activated pathways and then trying to discover ways to target these pathways will lead to the eradication of more cancer cells and delay disease relapse. My published research has contributed substantially to a body of work indicating that PCa cells activate a process called fatty acid oxidation to generate the energy to support cancer cell proliferation and drug resistance. In addition to energy production, fatty acid oxidation products modulate cancer cell gene expression, which might enable cancer cells to progress to a more aggressive form. In this project, I will study the impact of fatty acid oxidation on PCa biology to understand how this process supports cancer progression. In addition, this proposal aims to discover new, clinically safe fatty acid oxidation targets and evaluate the efficacy of inhibition of these targets to suppress tumor growth and progression. I will employ in vitro studies that include cell lines representative of all PCa stages, in vivo patient-derived xenograft models, and human prostate tumors that mimic the disease biology and better predict drug efficacy in the in the human body. Therefore, this project will address these FY21 PCRP Overarching Challenges: 1. Define the biology of lethal PCa to reduce death. 2. Develop treatments that improve outcomes for men with lethal PCa. In my pilot studies, I treated PCa cells with clinical anti-androgens, and analyzed the changes that took place in the cancer cells that remained viable after treatment. I revealed that the abundance of two proteins, HADHB and DECR1, which are involved in fatty acid oxidation, was increased in the cells that resist the treatment. Further analysis of a large public biorepository of information collected from PCa tissues revealed that the abundance of the HADHB and DECR1 enzymes is increased in PCa tissue compared to normal tissue, and their abundance is further increased with disease progression and in drug resistant and NEPC tumors. I hypothesize that targeting HADHB or DECR1 enzymes would starve PCa cells to overcome drug resistance and slow tumor growth and metastasis. While developing new drugs requires approximately 15 years, two key aspects of this project will facilitate more rapid clinical translation of my research outcomes. First, drug repurposing is an emerging strategy where existing medicines, having already been tested as safe in humans, are reassigned to combat difficult-to-treat diseases. Fortunately, there is a drug inhibitor available for HADHB called trimetazidine, which is currently used to treat angina. If this project is successful, trimetazidine could be readily tested clinically for PCa because we already know that this drug is safe and how it behaves and is distributed in the human body. Second, I will develop blood predictive/prognostic biomarkers to detect altered fatty acid oxidation. Thi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210967
Entities
People
- Zeyad D Nassar
Organizations
- United States Army
- University of Adelaide