Project Summary In response to PQ11, “Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment?,” this proposal will determine that nutrition can be used to improve radiation (RT) response, improve outcomes and decrease toxicity for breast cancer patients with brain metastases. Breast cancer is the leading cause of brain metastases in women and is associated with a dismal prognosis despite standard therapies including radiation or surgical resection. Local control of brain metastases confers better survival and prevents neurological decline. To try and improve local control, novel targeted therapies have been added to radiation (RT); most have unfortunately resulted in little improvement while adding significant toxicity. For the first time, it will be determined if dietary modifications may play a role in the treatment of brain metastases since one of the hallmarks of both metastases and tumor cell resistance to RT, is the dysregulation of cellular metabolism. Our long-term goal is to 1) change the landscape of cancer care by empowering patients to use dietary interventions to improve outcomes, and 2) to use the discoveries from this proposal to translate findings. The objective of this grant is to determine if radiation efficacy can be increased for metastatic disease without increasing toxicity, by using dietary manipulation. The central hypothesis is that an integrated approach, one incorporating dietary changes, will alter key pro-survival pathways in metastatic tumor cells, to improve local control and, therefore, patient survival. Our specific aims will test the following hypotheses: (Aim1) Determine the contribution of dietary intervention on radiation effectiveness in treatment of breast cancer brain metastases; (Aim 2) the IGF-1R/AKT signaling pathway axis is a key node, at least in some part, in the biological response leading to the proposed molecular cytotoxic cooperation between dietary modification and RT; (Aim 3) Determine the subset of breast cancer patients with brain metastases that benefit from combined DMs and RT. This contribution is significant since it will establish that dietary modifications can target pathways (ie IGF-1R/Akt) to modulate the radiation response and affect a positive clinical change. The proposed research is innovative because diet has not been used as a “drug” during cancer therapy. This proposal will provide insight into how dietary modifications can be used to affect the radiation response, potential toxicity and outcomes in breast cancer patients with brain metastases.