Exploiting metabolic vulnerabilities of breast cancer brain metastases for therapy

乳腺癌细胞向大脑的转移性扩散普遍是致命的。尽管有新的靶向治疗 乳腺癌的致癌驱动因素在控制全身疾病方面有效，但这些药物无法治疗 乳腺癌是大脑中的肿瘤。脑转移瘤难以治疗的两个重要原因是 具有挑战性的跨血脑屏障给药，以及大脑微环境影响 乳腺癌细胞的生物学使治疗无效，即使在充分输送到脑瘤。 因此，改善对脑转移瘤的药物输送并了解乳腺癌细胞如何适应 对脑环境的改善对提高乳腺癌脑转移的治疗是必要的。 为了使癌细胞增殖，它们必须通过获取大分子来复制它们的生物量。 来自周围环境的前驱物质。营养的局部可获得性，以及细胞的生物合成能力， 影响其在独特的组织环境中定居和生长的能力。血脑屏障限制了 大脑中的细胞可以获得营养物质，这给癌细胞在这个部位的生长带来了独特的挑战。 具体地说，我们发现植入大脑的乳腺癌细胞，而不是颅外部位的乳腺癌细胞，需要 新的脂肪合成，涉及生长和生存的FASN酶。这是因为脂类可以 与其他组织相比，乳腺癌细胞在脑环境中的水平较低。作为一名 结果，使用脑透性FASN抑制剂治疗乳腺癌肿瘤的人数适度减少 脑部的肿瘤负担。我假设大脑特定的营养微环境施加了独特的 抑制癌细胞代谢，可靶向改善乳腺癌脑治疗 转移瘤。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 通过脂类转运体CD36介导的脂类摄取上调环境。在《目标2》中，我将表演 基于CRISPR/Cas9靶向乳腺癌细胞非必需代谢物合成途径的筛选 以确定在大脑中生长的乳腺癌细胞的额外代谢依赖性。在《目标3》中，我会 通过形成纳米粒来改善针对代谢依赖的药物向大脑的输送 包埋相关抑制物并评价其对乳腺癌脑瘤生长的影响。我期待着 这项研究的结果将直接指导未来的临床研究，以改进乳腺癌的治疗 脑转移瘤。 我获得F31训练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被利用来开发新的治疗方法。范德海登实验室 麻省理工学院的生物系为我提供了丰富的培训环境和几乎无限的资源 和机会，我有幸能够从中吸取发展我所需的技能，以进一步发展我的 独立研究科学家的职业生涯。

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.