Grant: Project Grant

Brain metastases (BM) are brain tumors arising from primary cancer cells from different organs in the body that escape and travel to the brain. Lung cancer, the most common cause of cancer-related deaths in adults is the most common cause of BM. As therapies for the treatment of primary cancers are becoming more effective at controlling a patient's primary disease, they are ironically dying from metastatic disease to the brain, therefore the ability to prophylactically prevent the formation of BM altogether can be a game-changer for cancer patients. Using the genome-editing technology CRISPR, we screened for genes whose increased expression would increase the spread of lung cancer to the brain. We found that increased expression of Beta secretase 1 (BACE1) facilitated the spread of lung cancer cells to the brain. We found that increased expression of BACE1 enhanced activation of the epidermal growth factor receptor (EGFR), a major player in lung cancer, where activating mutations lead to increased likelihood of developing BM. We hypothesize that BACE1 directly cleaves EGFR to activate a metastatic program to facilitate lung cancer BM and therapeutically targeting BACE1 will reduce the growth/formation of BM. We will perform proteomic screens to identify the cleavage site in EGFR as well as binding partners of BACE1. We will then test if existing potent BACE-1 drugs that are already in Phase 3 clinical trials for Alzheimer's disease patients will prevent the formation of BM using our preclinical mouse models. We envision that this approach will lead to rapid translation of repurposed potent drugs into clinical trials for BM patients to improve patient survival.