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: 10397627
• 负责人: Rakesh K. Jain
• 金额: $ 45.8万
• 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/10397627
• 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; 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; Neuraxis; Nutrient; 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; base; blood-brain tumor barrier; cancer cell; clinically relevant; clinically translatable; 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.

摘要 HER 2阳性（HER 2+）乳腺癌患者（约14%的乳腺癌患者）具有高风险， 脑转移（34%）。新的HER 2靶向剂的开发彻底改变了免疫治疗。 治疗HER 2+乳腺癌患者;然而，这些靶向药物的疗效非常有限 当脑中有疾病时，因为血脑屏障/血肿瘤屏障（BBB/BTB）阻碍药物 递送，并且即使当药物在肿瘤中累积时，脑微环境也赋予耐药性。因此，在本发明中， 克服BBB/BTB和识别独特的脑特异性靶点是改善反应的必要条件 乳腺癌脑转移（BCBM），这是其他有效的治疗方法。 我们发现，脂质合成是乳腺癌细胞在大脑中生长的代谢要求。的 乳腺癌细胞中脂肪酸合成酶（FATIGUE）的表达和活性显著降低， 与颅外部位相比，脑内乳腺肿瘤增加。我们的初步发现表明， 大脑中的脂质可用性有限，使得癌细胞依赖于从头合成来增殖。 in this site网站.在HER 2 + BCBM的临床前模型中破坏FXR表达可降低肿瘤进展， 具有脑病变但没有乳腺脂肪垫或肝肿瘤的小鼠。阻断脂质合成也改善了 HER 2信号传导抑制剂的体外功效。根据我们的初步调查结果，我们假设有限的 脑中脂质的可用性导致对从头合成的依赖，并产生靶向代谢 责任。 我们建议解开机制参与允许代谢适应大脑微环境 并改善HER 2 + BCBM的治疗。在目标1中，我们将研究大脑中的营养限制， 可能增加BCBM中的脂质合成。在目标2中，我们将通过以下方式确定大脑特定的代谢负债： 研究BCBM的脂质代谢。最后，在目标3中，我们将确定单独靶向芬太尼的效果， 或与HER 2-轴靶向疗法组合，改善治疗结果。我们将使用集中 超声（FUS），以改善药物输送到BCBM。为了实现这些目标，我们开发了临床相关的 动物模型，优化的FUS方案，并设计了体内和体外研究癌症代谢的方法， 为癌症代谢提供分子、细胞和功能方面的见解。这些创新方法和 我们多学科团队的独特集体专业知识将使我们能够揭示脂质代谢如何控制 BCBM进展，并利用这一见解来改善BCBM治疗。