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

通过靶向脂质代谢改善 HER2 乳腺癌脑转移的治疗

• 批准号: 10620649
• 负责人: Rakesh K. Jain
• 金额: $ 45.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620649
• 关键词: Animal Model; Biology; Biomass; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; CRISPR/Cas technology; Cells; Central Nervous System; Cephalic; Clinic; Clinical; Clinical Trials; Data; Dependence; Development; Disease; Disseminated Malignant Neoplasm; Dose; Drug Delivery Systems; Drug Targeting; Drug resistance; Drug usage; ERBB2 gene; Enzymes; Epidermal Growth Factor Receptor; Exhibits; Family; Fatty Acids; Fatty acid glycerol esters; Fatty-acid synthase; Focused Ultrasound; Future; Genes; Genetic Transcription; Growth; Human; Implant; In Vitro; Intercellular Fluid; Lesion; Lipids; Liver; Liver X Receptor; Liver neoplasms; Malignant Neoplasms; Mammary Neoplasms; Metabolic; Metastatic malignant neoplasm to brain; Methods; Molecular; Mus; Neoplasm Metastasis; Nutrient; Nutrient availability; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Proliferating; Protocols documentation; Refractory; Refractory Disease; Signal Transduction; Site; Technology; Therapeutic; Therapeutic Index; Tissues; Treatment Efficacy; Treatment outcome; barrier to care; blood-brain tumor barrier; cancer cell; clinical translation; clinically relevant; design; disorder control; effective therapy; environmental change; high risk; improved; in vivo; inhibitor; innovation; insight; lipid biosynthesis; lipid metabolism; lymph nodes; malignant breast neoplasm; mammary; mortality; multidisciplinary; new therapeutic target; novel; novel strategies; patient prognosis; response; targeted agent; targeted treatment; translatable strategy; treatment response; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; uptake

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.

抽象的 HER2阳性（HER2+）乳腺癌（约14％的乳腺癌患者）患者的风险很高。 发展脑转移（34％）。新颖的HER2靶向代理的发展彻底改变了 治疗HER2+乳腺癌患者；但是，这些靶向药物的功效非常有限 当大脑中有疾病时，由于血脑屏障/血肿瘤屏障（BBB/BTB）阻碍药物 递送，大脑微环境即使在肿瘤中产生药物也赋予了耐药性。因此， 需要克服BBB/BTB并确定独特的大脑特异性目标以改善响应 乳腺癌脑转移（BCBM），这是有效的疗法。 我们发现脂质合成是乳腺癌细胞在大脑中生长的代谢需求。这 脂肪酸合酶（FASN）的表达和活性，一种脂肪酶，在乳腺癌细胞中显着 与颅外部位相比，大脑乳腺肿瘤的增加。我们的初步发现表明 大脑的脂质可利用率有限，使癌细胞依赖于从头合成以增殖 在这个网站中。在HER2+ BCBM的临床前模型中破坏FASN的表达降低了肿瘤的进展 患有脑病变的小鼠，但没有乳腺脂肪垫或肝肿瘤。阻断脂质合成也改善了 HER2信号抑制剂在体外的功效。根据我们的初步发现，我们假设有限 大脑中脂质的可用性可导致依赖性依赖性综合并创建一个可靶向的代谢 责任。 我们建议阐明允许代谢适应大脑微环境的机制 并改善HER2+ BCBM的处理。在AIM 1中，我们将检查大脑中的营养限制 可能会增加BCBM中的脂质合成。在AIM 2中，我们将通过 研究BCBM中的脂质代谢。最后，在AIM 3中，我们将确定单独靶向FASN的影响 或与HER2轴靶向疗法结合使用，以改善治疗结果。我们将使用专注的 超声（FUS）以改善向BCBM的药物递送。为了实现这些目标，我们已经开发了临床相关的 动物模型，优化的FUS方案以及研究体内癌症代谢的设计方法 为癌症代谢提供分子，细胞和功能见解。这些创新的方法和 我们多学科团队的独特集体专业知识将使我们能够发现脂质代谢如何管理 BCBM进展，并利用这种见解来改善BCBM治疗。

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