Exploiting metabolic vulnerabilities of breast cancer brain metastases for therapy

乳腺癌细胞向大脑的转移性扩散是普遍致命的。尽管新的治疗方法 乳腺癌中的致癌驱动因素在控制全身性疾病方面是有效的，这些药物不能治疗 乳腺癌肿瘤在大脑中。脑转移瘤难以治疗的两个重要原因是， 具有挑战性的是，通过血脑屏障递送药物，并且大脑微环境会影响药物的作用。 乳腺癌细胞的生物学，使治疗无效，即使充分交付给脑肿瘤。 因此，改善药物输送到脑转移瘤和了解乳腺癌细胞如何适应 改善脑内环境是提高乳腺癌脑转移治疗的必要条件。 为了使癌细胞增殖，它们必须通过获得大分子来复制它们的生物量。 从周围的环境中。营养的局部可用性，以及细胞的生物合成能力， 影响其在独特的组织环境中定植和生长的能力。血脑屏障限制了 大脑中的细胞可以获得营养，这对癌细胞在该部位的生长形成了独特的挑战。 具体地说，我们发现，乳腺癌细胞植入大脑，但不是在颅外部位， 新的脂质合成，涉及生长和生存的酶Festival。这是因为脂质可以 乳腺癌细胞在大脑环境中的使用水平低于其他组织。作为 因此，用脑渗透性FXR抑制剂治疗乳腺癌肿瘤适度降低了 肿瘤在大脑中的分布我假设大脑特有的营养微环境 对癌细胞代谢的限制，可以有针对性地改善乳腺癌脑的治疗 转移在目标1中，我将研究FASN缺失的乳腺癌细胞是否能够适应大脑 通过上调脂质转运蛋白CD 36介导的脂质摄取来调节环境。在目标2中，我将执行 基于CRISPR/Cas9的筛选靶向乳腺癌细胞中的非必需代谢物合成途径， 以确定乳腺癌细胞在大脑中生长的额外代谢依赖性。在目标3中，我将 通过配制纳米颗粒改善靶向代谢依赖性药物向大脑的递送 包封相关抑制剂并评估它们对乳腺癌脑肿瘤生长的作用。我预计 这项研究的结果将直接为未来的临床研究提供信息，以改善乳腺癌的治疗 脑转移 我获得F31培训奖的目标是获得成为调查专家所需的专业知识 癌症中的代谢脆弱性，可以用来开发新的疗法。范德海登实验室 和麻省理工学院的生物系为我提供了一个丰富的培训环境， 和机会，我很幸运，能够借鉴，以发展我所需要的技能，以进一步发展我的 作为一名独立的研究科学家。

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.