Rationale, Objective, and Aims: The spread of breast cancer to different organs, metastasis, is the cause for a majority of deaths in women with Her2+ breast cancer. The brain is increasingly the site of metastasis from primary breast cancer. Her2+ amplification occurs in 25% of primary breast carcinomas and is associated with diminished disease-free and overall survival. Unfortunately, in a past study, 50% of patients with breast cancer who had systemic metastatic Her2+ disease who were responding to chemotherapy or had stable systemic disease when brain metastases were diagnosed later died of progressive brain metastases. Our preliminary results suggest that breast cancer brain metastases cells express TrkB, a receptor commonly found in brain cells. Utilizing a combination of cell culture and animal experiments, our objective is to establish the importance and functionality of TrkB in the development of brain metastases and to investigate the effects of dual targeting the Her2 and TrkB receptors. In order to fulfill these goals, we will focus on three aims. Through Aim 1, we will show that TrkB is important for brain metastasis formation. In Aim 2, we will determine the effects of the brain on the breast cancer cells that metastasize to the brain. Lastly, in Aim 3, we will investigate the efficiency and specificity of simultaneously targeting both Her2 and TrkB receptors in the breast cancer brain metastasis cells.

The applicability of our proposed work has its basis in the investigation and discovery of novel molecular approaches to treat brain metastases that would create momentum for clinical trials for women living with advanced cancer. There is currently a clinical need for brain metastases research in the breast cancer patient community. The rising incidence of brain metastases in Her2+ patients with controlled systemic disease has broader implications because advances in systemic therapy similar to trastuzumab are being made for other subtypes of breast cancer. Current treatment options for brain metastases are limited to surgery and radiation, which is antiquated when compared to current generation molecular therapeutics. The development of new therapies targeting multiple receptors could improve existing treatment options of breast cancer brain metastases patients.