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

摘要 HER2阳性(HER2+)乳腺癌患者(约占乳腺癌患者的14%)有很高的风险 发生脑转移(34%)。新型HER2靶向剂的开发使HER2靶向药物 HER2阳性乳腺癌患者的治疗；然而，这些靶向药物的疗效非常有限 当由于血脑屏障/血肿瘤屏障(BBB/BTB)阻碍药物而导致脑部疾病时 当药物在肿瘤中累积时，大脑微环境也会产生耐药性。因此， 需要克服血脑屏障/血脑屏障和识别独特的脑特异性靶点来改善反应 乳腺癌脑转移(BCBM)，这是其他有效的治疗方法。 我们发现，脂肪合成是乳腺癌细胞在大脑中生长所需的代谢条件。这个 在乳腺癌细胞中，脂肪合成酶(FASN)的表达和活性显著增加。 与颅外部位相比，乳腺肿瘤在大脑中的数量增加。我们的初步调查结果表明 大脑中的脂质可获得性有限，使癌细胞依赖从头合成来增殖。 在这个网站上。干扰HER2+BCBM临床前模型中FASN的表达抑制肿瘤进展 小鼠有脑部损伤，但没有乳房脂肪垫或肝脏肿瘤。阻断脂质合成还可以改善 HER2信号转导抑制剂的体外疗效。根据我们的初步发现，我们假设有限的 大脑中脂质的可获得性导致依赖新的合成，并创造有针对性的新陈代谢 责任。 我们建议解开代谢适应大脑微环境的机制。 提高HER2+BCBM的治疗效果。在目标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。在目标2中，我们将通过以下方式确定特定于大脑的代谢负债 研究BCBM中的脂质代谢。最后，在目标3中，我们将确定单独针对FASN的效果， 或联合HER2轴靶向治疗，改善治疗结果。我们将使用Focus 超声(FUS)以改善对BCBM的药物输送。为了实现这些目标，我们开发了与临床相关的 动物模型，优化的FUS方案，并设计了研究体内和体外癌症代谢的方法 提供对癌症新陈代谢的分子、细胞和功能洞察。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揭示脂类代谢是如何支配的 BCBM进展，并利用这一见解来改善BCBM的治疗。

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.