Metabolic implications of radiation response in oligometastatic prostate cancer.

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Altered metabolism in cancer cells is recognized as a hallmark of malignant transformation and has been shown to be in part responsible for metastatic spread due to its role in the fate of anchoring metastases to the tumor microenvironment. Therefore, understanding radiation response as it relates to the tumor and patient metabolism will be key in determining the subset of patients who will require metabolic interventions to optimize outcomes for prostate cancer patients with oligometastatic disease. It has been discovered that genomic drivers of prostate cancer can cause metabolic reprogramming of both the tumor and its microenvironment to create niches with specific nutrient requirements that enrich for key pro-survival pathways. For example, that c-myc driven tumors thrive best when activating lipogenic metabolism while akt activated tumors thrive by activating the classic glycolytic switch. Understanding how to specifically reprogram the metabolic pathways that the tumor is preferentially using to create a favorable growth environment, could decrease prostate cancer tumor progression, metastases and increase sensitivity to radiation therapy. Preliminary data demonstrates the ability to use dietary alterations to metabolically alter the tumor and its environment to decrease tumor progression and metastases. Coupled with radiation, our data shows that caloric restriction increases anti-tumor immunity by increasing effector T-cells and decreasing T-regulatory cells. A first in-human pilot clinical trial using caloric restriction before prostatectomy for prostate cancer patients has confirmed this with a downregulation of c-myc and akt with metabolomic evaluation revealing decreased lipogenesis and glucogenesis. Pathway analysis of serum profiling demonstrates that caloric restrictions most significant effect was in upregulating anti-tumor immunity. Since it has been established that myc driven cancers have altered Treg response and akt driven tumors have altered Teff profiles, we hypothesize that precision nutrition can be used to reprogram the metabolic alterations induced by the driver oncogenes to improve radiation response and oligometastatic prostate cancer outcomes by affecting a positive change in the patients’ anti-tumor immunity. To study this, we will first determine radiation response of consolidative SABR on oligometastatic prostate cancers that have lipogenic versus glucogenic metabolic profiles. Next, we will use preclinical models to determine effects of metabolic reprogramming of prostate cancer cells and tumor microenvironment on radiation-induced anti-tumor immunity and consequences on metastatic potential. Finally, we will determine the influence of social determinants of health, including race, on radiation response in prostate cancer patients with oligometastatic disease treated with radiation. Our diverse patient population will allow for the understanding on the contribution of patient stressors on radiation outcomes. Results from this proposal will allow for future trial design using a precision approach to metabolically impact patients and improve outcomes with radiation.