Exploiting metabolic vulnerabilities of breast cancer brain metastases for therapy

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Metastatic spread of breast cancer cells to the brain is universally fatal. Despite new therapies targeting oncogenic drivers in breast cancer that are effective in controlling systemic disease, these drugs fail to treat breast cancer tumors in the brain. Two important reasons why brain metastases are difficult to treat are that it is challenging to deliver drugs across the blood-brain barrier and that the brain microenvironment impacts the biology of breast cancer cells to render therapies ineffective even when adequately delivered to brain tumors. Therefore, improving drug delivery to brain metastatic tumors and understanding how breast cancer cells adapt to the brain environment are necessary to improve treatment of breast cancer brain metastases. In order for cancer cells to proliferate, they must duplicate their biomass by acquiring macromolecular precursors from their surroundings. Local availability of nutrients, as well as a cell’s biosynthetic capacity, influences its ability to colonize unique tissue environments and grow. The blood-brain barrier limits which nutrients are available to cells in the brain and creates a unique challenge for cancer cells to thrive at this site. Specifically, we found that breast cancer cells implanted into the brain, but not in extracranial sites, require de novo lipid synthesis that involves the enzyme FASN for growth and survival. This occurs because lipids that can be used by breast cancer cells are at lower levels in the brain environment than they are in other tissues. As a consequence, treatment of breast cancer tumors with brain-permeable FASN inhibitors moderately reduces tumor burden in the brain. I hypothesize that the brain-specific nutrient microenvironment imposes unique constraints on cancer cell metabolism that can be targeted to improve treatment of breast cancer brain metastases. In Aim 1, I will investigate whether FASN-null breast cancer cells are able to adapt to the brain environment through upregulation of lipid uptake mediated by the lipid transporter CD36. In Aim 2, I will perform a CRISPR/Cas9-based screen targeting nonessential metabolite synthesis pathways in breast cancer cells in order to identify additional metabolic dependencies of breast cancer cells growing in the brain. In Aim 3, I will improve the delivery of drugs targeting metabolic dependencies to the brain by formulating nanoparticles encapsulating the relevant inhibitors and assessing their effect on breast cancer brain tumor growth. I anticipate that the results from this study will directly inform future clinical studies to improve treatment of breast cancer brain metastases. My goal for the F31 training award is to gain the expertise I need to become an expert in investigating metabolic vulnerabilities in cancer that can be exploited to develop new therapies. The Vander Heiden laboratory and the Department of Biology at MIT provide me with a rich training environment with nearly unlimited resources and opportunities I am fortunate to be able to draw from to develop the skills I require to further develop my career as an independent research scientist.