Targeting FASN to eliminate metastatic breast cancer in the brain

总结

Summary Metastatic breast cancer in the brain is a deadly disease and the second most tumor incidence in the central nervous system. Although improvement of cancer treatments with targeted and immunotherapies have made some cancer curable, these new advancements and therapeutics have not been able to benefit breast cancer patients with brain metastasis primarily due to blood brain barrier (BBB). Recently, fatty acid synthase (FASN), the sole cytosolic enzyme responsible for de-novo synthesis of palmitate, was shown to upregulate in breast cancer brain metastasis (BCBM) but not in metastatic breast cancer in other organs and its inhibition limited breast cancer growth in the brain. Although FASN as a target has been established and inhibitors targeting FASN have been identified, no therapeutics targeting FASN have been approved for cancer treatments due to various reasons including toxicity and bioavailability. In attempting to repurpose FDA-approved drugs to overcome the past hurdles in targeting FASN, we recently showed that proton pump inhibitors (PPIs), approved for treating digestive disorders, effectively bind to and inhibit FASN. They also prohibit breast cancer cell proliferation in a laboratory study. In a phase II trial of triple negative breast cancer (TNBC) patients, supplementation of a PPI, omeprazole, at high dose (80 mg/day) inhibited FASN activity in the tumors and nearly doubled the pathological complete response with the standard of care neoadjuvant AC-T (Adriamycin cyclophosphamide-taxane) chemotherapy. It is also noteworthy that PPIs have been shown to be BBB permeable and have neuroprotective effects, providing an opportunity to develop PPIs as BCBM therapeutics targeting FASN. The long-term goal of this line of research is to eliminate metastatic breast cancer mortality by repurposing PPIs targeting FASN. The overall hypotheses to be tested in this explorative phase are that FASN protects BCBM by up-regulating DNA damage repair activity against excessive oxidative stress-induced DNA damage in the brain and that PPIs could be developed as BCBM therapeutics by targeting FASN to elicit oxidative stress-induced cancer cell death in the brain. To this end, we will accomplish two specific aims to (1) determine the molecular mechanism of FASN function in regulating repair of DNA damages induced by oxidative stress and (2) repurpose PPIs to treat BCBM by targeting FASN. We trust that the successful outcome of this explorative study will reveal a novel mechanism on how FASN protects breast cancer cells in the brain and provide preliminary data on targeting FASN by repurposing PPIs that will enable us to conduct a full-scale study. The positive outcome may also lead to a clinical trial testing PPIs on breast cancer patients with brain metastasis, which will immediately and profoundly impact the BCBM treatment landscape.