Targeting Prostate Cancer Metabolic Vulnerabilities in the Bone Microenvironment to Circumvent Lethal Metastatic Disease
Abstract
Challenge Addressed: This application addresses the Prostate Cancer Research Program’s (PCRP) overarching challenge to Define the biology of prostate cancer progression to lethal prostate cancer to reduce death. Rationale: Prostate cancer is the second leading cause of cancer death in American men. Despite medical advances over the past decade, prostate cancer (PCa) continues to cause over 30,000 deaths per year in the United States. The vast majority of PCa-related deaths are caused by metastases, not by primary tumors. Compared with the relative low occurrence of visceral metastases (i.e., cancer cells that have spread to soft organs like the brain, liver, lung) in PCa, bone metastases (BoM) predominantly occur in up to 90% of patients at autopsy and represent the most lethal form of PCa. Based on a cohort study of 23,087 patients in Denmark, the 5-year survival rate is 56% in PCa patients without BoM, but it is as low as 3% in patients with BoM. Therefore, BoM represent an attractive focus for research aimed at improving survival rates in PCa patients, for whom current clinical treatments do not work well. In particular, research is needed to better understand the biology of PCa during BoM progression, which will be critical for identifying novel druggable targets in cells that can form the basis for new therapies. Presently, knowledge about the progression processes involved in the growth and persistence of BoM is extremely limited, probably because of the lack of appropriate models to study PCa BoM. Here, we propose to use our newly established BoM models to study the biology of PCa during the progression of BoM, with the hope that this knowledge can ultimately be used to address the unmet needs of patients that do not respond well to current treatments. In this BoM-focused application, we propose to address this need for more information by exploiting our recent discovery about how PCa cells adapt to the environmental stresses in the bone milieu in a non-conventional way and gain the capacity to convert nutrition to energy and basic cellular building blocks, namely, metabolic adaptation. We hypothesize that this process is double-regulated by the hyper-activation of organ-specific, oncogenic NFAT (nuclear factor of activated T cells) signaling in combination with the suppression of metabolic repressor Sirtuin 3 (SIRT3). Interestingly, our early work disclosed an unexpected role for SIRT3 in the regulation of NFAT levels. Additionally, our studies, for the first time, have identified a collaborative and mutually interfering regulatory cascade as a critical mechanism that supports the metabolic adaptation and metastatic progression of PCa cells, thereby allowing PCa cells to survive amidst a limited nutrition supply and environmental stresses in the bone milieu. The involvement of the indicated genes was supported by public genomics data and pilot biological studies. These findings provide a compelling rationale to investigate and target the indicated metabolic axis for BoM treatment. This study represents pioneering work on the metabolic biology in PCa BoM, which has remained an extremely unappreciated focus area in cancer research. Importantly, new understanding of the unorthodox metabolic behavior in bone metastatic PCa could ultimately lead to the discovery of novel therapeutic strategies to improve survival rates and the quality of life in patients with lethal/metastatic PCa. We expect to complete this mechanistic study within 3 years. The proposed effort, albeit at a basic cancer biology level, has promising potential to lead to rapid translation with a clinical impact. Most compounds tested in this project have currently entered clinical trials—in fact, some have already been approved by the U.S. Food and Drug Administration to treat other diseases. Thus, success in our studies would have near-term clinical relevance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310417
Entities
People
- Hai Wang
Organizations
- United States Army