Exploiting metabolic vulnerabilities of breast cancer brain metastases for therapy

利用乳腺癌脑转移的代谢脆弱性进行治疗

• 批准号: 10589771
• 负责人: Keene Abbott
• 金额: $ 4.77万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589771
• 关键词: Affect; Award; Biology; Biomass; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast Cancer Cell; Breast Cancer Treatment; CD36 Antigens; CD36 gene; CRISPR/Cas technology; Cells; Cephalic; Clinical; Clinical Research; Dependence; Disease; Distant; Drug Delivery Systems; Drug Targeting; Encapsulated; Environment; Enzymes; Epidermal Growth Factor Receptor; FASN gene; Fatty acid glycerol esters; Formulation; Future; Genes; Goals; Growth; Human; Impairment; Implant; In Vitro; Intercellular Fluid; Knock-out; Laboratories; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metastatic malignant neoplasm to brain; Null Lymphocytes; Nutrient; Nutrient availability; Oncogenic; Pathway interactions; Patients; Penetrance; Permeability; Pharmaceutical Preparations; Physiological; Proliferating; Proteins; Research; Resources; Scientist; Site; Survival Rate; Systemic disease; Testing; Tissues; Training; Tumor Burden; Up-Regulation; cancer cell; career; disorder control; improved; ineffective therapies; inhibitor; insight; malignant breast neoplasm; mammary; mind control; nanoparticle; new therapeutic target; novel therapeutics; prevent; skills; synergism; tumor; tumor growth; tumor metabolism; uptake

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.

尽管有新的靶向治疗方法，但乳腺癌细胞向大脑的转移性扩散通常是致命的。 乳腺癌的致癌驱动因素可以有效控制全身性疾病，但这些药物无法治疗 乳腺癌脑部肿瘤难以治疗的两个重要原因是： 跨血脑屏障输送药物具有挑战性，并且大脑微环境会影响 乳腺癌细胞的生物学特性使治疗即使充分递送至脑肿瘤也无效。 因此，改善脑转移肿瘤的药物输送并了解乳腺癌细胞如何适应 改善脑环境对于改善乳腺癌脑转移的治疗十分必要。 为了使癌细胞增殖，它们必须通过获得大分子来复制其生物量 来自周围环境的前体物质，以及细胞的生物合成能力， 影响其定植独特组织环境和生长的能力。 大脑中的细胞可以获取营养物质，并对癌细胞在该部位的生长产生独特的挑战。 具体来说，我们发现植入大脑而不是颅外部位的乳腺癌细胞需要 涉及生长和存活的 FASN 酶的新型脂质合成发生这种情况是因为脂质可以。 乳腺癌细胞在大脑环境中所利用的水平比在其他组织中的水平要低。 结果，用脑渗透性 FASN 抑制剂治疗乳腺癌肿瘤可适度减少 我认为大脑特定的营养微环境施加了独特的肿瘤负担。 癌细胞代谢的限制可以有针对性地改善乳腺癌脑部的治疗 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。 在目标 2 中，我将通过脂质转运蛋白 CD36 介导的脂质摄取上调来调节环境。 基于 CRISPR/Cas9 的筛选，针对乳腺癌细胞中的非必需代谢物合成途径 为了确定大脑中生长的乳腺癌细胞的其他代谢依赖性，我将在目标 3 中进行研究。 通过配制纳米颗粒改善药物代谢靶向依赖性向大脑的输送 我预计封装相关抑制剂并评估它们对乳腺癌脑肿瘤生长的影响。 这项研究的结果将直接为未来改善乳腺癌治疗的临床研究提供信息 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 Vander Heiden 实验室可利用癌症的代谢脆弱性来开发新疗法。 麻省理工学院的生物系为我提供了丰富的训练环境和近乎无限的资源 我很幸运能够利用这些机会来发展我进一步发展我所需的技能 作为一名独立研究科学家的职业生涯。