Precision Nutrition Increases Efficacy of DNA-Damaging Therapies in Prostate Cancer
Abstract
Rationale: Prostate cancer is a leading cause of cancer-related deaths among men with approximately 30,000 men in the United States and 360,000 globally expected to die this year of metastatic castration-resistant prostate cancer (CRPC). Currently, about 180,000 men in the United States are advanced prostate cancer survivors. Once prostate cancer progresses to a CRPC, it is incurable with no long-term effective treatments available. Therefore, new long-term effective treatments are needed. Our proposal addresses PRMRP Nutrition Optimization topic area Research into nutrition-based strategies to prevent or reduce the impact of disease in order to help hundreds of thousands of men suffering from advanced prostate cancer. One approach used to treat many cancer types is the use of therapies that will damage tumor DNA leading to the death of the tumor cells. Unfortunately, efficacy of these therapies is rather limited in CRPC. An example of such treatment is radiotherapy, which works by impairing the ability of the cancer cell to heal itself when damaged (i.e., to repair DNA). Despite efficacy of radiotherapy in many cancer types, most CRPC patients do not respond at all or experience only minimal benefits from radiation. Another type of DNA-damaging therapy that is used in clinics is PARP inhibition, which is effective in tumors with BRCA1/2 mutations. PARP inhibitors have been used for years to effectively treat breast and ovarian cancer, but PARP inhibitors were only recently approved for CRPC patients with BRCA1/2 mutations. Regrettably, only ~10%-20% of CRPC patients have tumors with BRCA1/2 mutations, and therefore the majority of CRPC patients are not treated with PARP inhibitors. This illustrates a critical need to identify a novel way of enhancing the effectiveness of currently available DNA-damaging therapies to improve survival for men with lethal CRPC. It has become increasingly clear that lifestyle-related factors, such as diet, have an effect on development and progression of prostate cancer. For example, obesity and red meat consumption are associated with higher mortality of prostate cancer patients. In our preliminary studies, we have found that prolonged consumption of a traditional Western-diet that has a lot of saturated fats causes DNA damage in patient’s tumors. When tumor cells are trying to repair this large amount of DNA damage, errors are included in DNA accelerating the prostate cancer progression. This is a bad thing. However, our preliminary data demonstrate that only a short-term (few days) consumption of saturated fats causes DNA damage and increases prostate tumors sensitivity to radiation by together creating an excessive amount of DNA damage that cancer cells cannot repair and therefore kill them. Taken together, this raises the conundrum: Could we therapeutically leverage the short-term consumption of a saturated-fat diet (hereafter referred to as precision nutrition) in combination with DNA-damaging therapies (e.g., radiotherapy, PARP inhibitors) to increase DNA damage to a point that tumor cells cannot tolerate this high volume of DNA damage and will die? Our proposal further supports our preliminary results demonstrating this efficacy of short-term high saturated fat diet to increase effectiveness of DNA-damaging therapies. Our ultimate goal is to translate this approach into the clinic and develop a novel treatment combining defined diet with DNA damage therapies to improve the survival of patients with lethal CRPC. Most importantly, this treatment strategy has a promise to benefit all prostate cancer patients, without the requirement of underlying alterations in genes related to DNA repair. Objective: The objective of our highly innovative studies is to identify a precision nutrition strategy that will improve the efficacy of DNA-damaging therapies in prostate cancer. To address this objective, we developed three specific aims: Specific Aim 1: Evaluate precision nutrition a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210586
Entities
People
- Eva Corey
Organizations
- United States Army
- University of Washington