Rationale, Objective, and Aims: Brain metastasis, the spread of cancer to the brain, is a leading cause of death in breast cancer patients. Despite the application of multiple treatment modalities, breast cancer brain metastasis (BCBM) has an extremely grim prognosis with overall survival ranges from only 2 to 16 months, depending on the subtype of the tumor. Importantly, more and more breast cancer patients are diagnosed and die from brain metastasis due to improved survival from newly developed treatments. Despite ongoing research efforts, the factors that attract breast cancer cells to the brain are not fully understood. Recent studies suggest crucial roles for extracellular vesicles (EVs) to mediate tumor growth, therapeutic resistance, and distant metastasis. These small particles are secreted by cancer cells and carry different molecules that are characteristic of the parental cell and transfer these to the surrounding and distant cells. The role of EVs in the development of BCBM has not been fully understood. Growing evidence suggests that neuronal activity significantly promotes the growth of cancer cells. Despite extensive presence of neurons in the brain, little is known about the impact of cancer cell-secreted EVs on neurons. We recently showed DGKalpha pathway activation as a crucial resistance mechanism to radiation treatment in several cancers including glioblastoma and breast cancer. Our new findings suggest a crucial role for DGKalpha to regulate the production and secretion of EVs from cancer cells. Using novel methodology, we propose to determine the role of DGKalpha to drive brain metastasis from breast cancer through regulating the synthesis and secretion of EVs. We will achieve this objective through pursuing these aims: In Aim 1, we will show that DGKalpha activity regulates EV production and secretion from breast cancer cells. In Aim 2, we will evaluate the impact of breast cancer cell-secreted EVs on neurons and their activity, and in Aim 3, we will evaluate the therapeutic potential of clinically applicable DGKalpha inhibitor against primary and brain metastatic breast cancer.

Applicability of the Research: The treatment of breast cancer brain metastases remains an unmet clinical need. Despite significant advances in the treatment of primary breast cancer, there is a remarkable lack of chemotherapeutic options against brain metastases. Given its increasing incidence and grim prognosis, new therapeutic strategies for the prevention and treatment of BCBM are urgently needed. Our proposed studies would discover a novel mechanism for EVs to promote the establishment and growth of BCBM. These findings could help develop new therapeutic strategies for the prevention and treatment of brain metastasis that can eventually be brought to the clinic. Establishing the DGKalpha pathway as a crucial therapeutic target would rapidly lead to clinical trials for breast cancer patients, as clinically applicable DGKalpha inhibitor ritanserin has already been tested for other indications and proven to be safe in humans. Ritanserin is highly brain penetrant and well tolerated, with minimal side effects. Altogether, these studies could significantly reduce breast cancer-related morbidity and mortality, and improve the quality of life.