Identify the Metabolic Dependencies of Obesity-Associated Aggressive Prostate Cancer to Develop Tailored Imaging and Therapeutic Approaches
Abstract
Prostate cancer is the most commonly diagnosed tumor in men and the second leading cause of cancer-related deaths in the United States. Curative treatments for the advanced forms of the disease are still not available; thus, novel therapeutic strategies are needed. Environmental factors including diet, lifestyle, and metabolic diseases, such as obesity, are known to affect the development and progression of prostate cancer. The obesity epidemic in the United States has become a major concern not only for the deleterious health problems associated with this condition like diabetes and cardiovascular diseases but also for its association with more aggressive cancer. Prostate cancer arising in obese patients is generally more aggressive and more often associated with death from the disease. Moreover, diets enriched in saturated or animal fatty acids have also been associated with more aggressive behavior of the tumor. However, the biological and molecular mechanisms that are responsible for this are largely unknown. This is of paramount importance because once these pathways are unraveled, they can be used as biomarkers, targeted therapeutically, or utilized to identify tumor sites in patients with novel or already established noninvasive imaging tools. Our study is based on the evidence that others and we have generated demonstrating that genetic alterations require and bring about a unique metabolic infrastructure for the cancer cell to survive and thrive. Genetic alterations do so to sustain the increased growth they induce. We hypothesize that high fat intake or established obesity potentiates this metabolic support, providing additional fuel for a more aggressive tumor growth. The main objectives of this study therefore are (a) to identify metabolic genes/pathways that drive aggressive prostate cancer arising in the context of high fat diet/obesity and (b) to apply the results obtained in laboratory experiments to patients cohorts and link these key alterations to clinical outcomes for ultimate targeting. To this end, we propose to look at changes in metabolites in general and fats in particular that are unique in the context of high fat intake or increased body weight to see if these and the enzymes that produce them are responsible for accelerating growth and aggressiveness of prostate cancer. The identification of specific metabolic liabilities will thus guide personalized therapeutic strategies and pave the way for the use of tailored imaging biomarkers of aggressive prostate cancers, in particular, those arisen in obese/overweight patients. To accomplish this, we will utilize mouse models driven by the well-known oncogene MYC, metabolic profiling, bioinformatics analyses, as well as a novel, high-throughput genetic (DNA-editing) approach in cells cultured in the serum from mice to recapitulate the in vivo high fat diet/obesity condition. If our data point to a perturbation of lipid metabolism/uptake induced by high fat diet/obesity in aggressive tumors, we will also test the feasibility to use non-invasive imaging with lipid-based tracers to monitor these tumors. If this can be achieved, these approaches can be immediately translatable into the clinic. Importantly, we aim to integrate the molecular findings obtained from preclinical studies with human data from large and well-annotated prospective cohorts with long-term follow-up. The resulting discoveries will be instrumental in: (1) identifying novel metabolic targets for therapy and imaging; (2) understanding whether high fat diet/obesity affect pathological features of prostate cancers harboring MYC alterations and clinical outcomes; and (3) clarifying whether weight loss or changes in diet behaviors can improve the clinical history and prognosis of prostate cancer patients. The ability to integrate experimental and human models in our study provides a stronger likelihood for the clinical translation of our findings in the short term.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610645
Entities
People
- Giorgia Zadra
Organizations
- Dana–Farber Cancer Institute
- United States Army