Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism

ABSTRACT Patients with HER2 positive (HER2+) breast cancer (~14% of breast cancer patients) have a high risk of developing brain metastases (34%). The development of novel HER2 targeting agents has revolutionized the treatment of patients with HER2+ breast cancer; however, the efficacy of these targeted drugs is very limited

when there is disease in the brain because the blood-brain-barrier/blood-tumor-barrier (BBB/BTB) hinders drug delivery, and the brain microenvironment confers drug resistance even when the drugs accrue in tumors. Thus, overcoming both the BBB/BTB and identifying unique brain-specific targets is required to improve the response

of breast cancer brain metastasis (BCBM) which are otherwise effective therapies. We discovered that lipid synthesis is a metabolic requirement for breast cancer cells to grow in the brain. The expression and activity of fatty acid synthase (FASN), a lipogenic enzyme, in breast cancer cells is significantly

increased in breast tumors in the brain when compared to extracranial sites. Our preliminary findings suggest that there is a limited lipid availability in the brain, making cancer cells dependent on de novo synthesis to proliferate in this site. Disrupting FASN expression in preclinical models of HER2+ BCBM decreased tumor progression in

mice with brain lesions but not mammary fat pad or liver tumors. Blocking lipid synthesis also improved the efficacy of HER2 signaling inhibitors in vitro. Based on our preliminary findings we hypothesize that the limited availability of lipids in the brain leads to dependenc eon de novo synthesis and creates a targetable metabolic

liability. We propose to unravel the mechanisms involved in allowing metabolic adaptation to the brain microenvironment and improve the treatment of HER2+ BCBM. In Aim 1, we will examine the nutrient limitations in brain that may increase lipid synthesis in BCBM. In Aim 2, we will identify brain-specific metabolic liabilities by

investigating lipid metabolism in BCBM. Lastly, in Aim 3 we will determine the effects of targeting FASN alone, or in combination with HER2-axis targeted therapies, on improving the treatment outcome. We will use focused ultrasound (FUS) to improve drug delivery to BCBM. To realize these aims, we have developed clinically relevant

animal models, optimized FUS protocol, and designed methods to study cancer metabolism in vivo and ex vivo to provide molecular, cellular, and functional insights into cancer metabolism. These innovative approaches and the unique collective expertise of our multidisciplinary team will allow us to uncover how lipid metabolism governs

BCBM progression, and to leverage this insight to improve BCBM treatment.