Targeting FASN to eliminate metastatic breast cancer in the brain

总结 脑转移性乳腺癌是一种致命的疾病，是世界上第二大肿瘤发病率。 中枢神经系统尽管靶向和免疫疗法的癌症治疗的改善已经 虽然一些癌症可以治愈，但这些新的进步和治疗方法并不能使乳腺癌受益。 主要由于血脑屏障（BBB）引起的脑转移的癌症患者。最近，脂肪酸合成酶 （FABR 4），负责棕榈酸从头合成的唯一胞质酶，被证明在哺乳动物中上调。 乳腺癌脑转移（BCBM），但不能转移到其他器官的乳腺癌及其抑制 限制乳腺癌在大脑中的生长。尽管已经确立了作为靶点的Festival， 尽管已经鉴定了靶向FXR的药物，但是还没有靶向FXR的治疗剂被批准用于癌症治疗 由于各种原因，包括毒性和生物利用度。在试图重新利用FDA批准的药物， 为了克服过去在靶向质子泵抑制剂方面的障碍，我们最近发现， 用于治疗消化系统疾病，有效地结合并抑制FSH。他们还禁止乳腺癌细胞 在实验室研究中的扩散。在一项针对三阴性乳腺癌（TNBC）患者的II期试验中， 高剂量（80 mg/天）的PPI奥美拉唑补充剂抑制了肿瘤中的FGFAP活性， 用标准新辅助治疗AC-T（阿霉素）使病理完全反应加倍 环磷酰胺-紫杉烷）化疗。同样值得注意的是，PPI已被证明是BBB 具有渗透性和神经保护作用，为开发PPI作为BCBM治疗剂提供了机会 目标是法布雷加斯这项研究的长期目标是通过以下方法消除转移性乳腺癌的死亡率： 重新利用PPI来针对FRENTERS。在这个探索阶段要检验的总体假设是， 通过上调DNA损伤修复活性来保护BCBM免受过度氧化应激诱导的DNA损伤 在脑损伤和PPI可以开发为BCBM治疗剂，通过靶向FXR， 氧化应激诱导的脑中癌细胞死亡。为此，我们将实现两个具体目标：（1） 确定FXR在调节氧化损伤诱导的DNA损伤修复中的分子机制， 压力和（2）重新利用PPI通过靶向FXR治疗BCBM。我们相信， 探索性研究将揭示一种新的机制，即FXR如何保护大脑中的乳腺癌细胞， 提供通过重新利用PPI来靶向FRESINS的初步数据，使我们能够进行全面研究。 积极的结果也可能导致临床试验测试PPI对乳腺癌患者脑转移， 这将立即和深刻地影响BCBM治疗前景。

Summary Metastatic breast cancer in the brain is a deadly disease and the second most tumor incidence in the central nervous system. Although improvement of cancer treatments with targeted and immunotherapies have made some cancer curable, these new advancements and therapeutics have not been able to benefit breast cancer patients with brain metastasis primarily due to blood brain barrier (BBB). Recently, fatty acid synthase (FASN), the sole cytosolic enzyme responsible for de-novo synthesis of palmitate, was shown to upregulate in breast cancer brain metastasis (BCBM) but not in metastatic breast cancer in other organs and its inhibition limited breast cancer growth in the brain. Although FASN as a target has been established and inhibitors targeting FASN have been identified, no therapeutics targeting FASN have been approved for cancer treatments due to various reasons including toxicity and bioavailability. In attempting to repurpose FDA-approved drugs to overcome the past hurdles in targeting FASN, we recently showed that proton pump inhibitors (PPIs), approved for treating digestive disorders, effectively bind to and inhibit FASN. They also prohibit breast cancer cell proliferation in a laboratory study. In a phase II trial of triple negative breast cancer (TNBC) patients, supplementation of a PPI, omeprazole, at high dose (80 mg/day) inhibited FASN activity in the tumors and nearly doubled the pathological complete response with the standard of care neoadjuvant AC-T (Adriamycin cyclophosphamide-taxane) chemotherapy. It is also noteworthy that PPIs have been shown to be BBB permeable and have neuroprotective effects, providing an opportunity to develop PPIs as BCBM therapeutics targeting FASN. The long-term goal of this line of research is to eliminate metastatic breast cancer mortality by repurposing PPIs targeting FASN. The overall hypotheses to be tested in this explorative phase are that FASN protects BCBM by up-regulating DNA damage repair activity against excessive oxidative stress-induced DNA damage in the brain and that PPIs could be developed as BCBM therapeutics by targeting FASN to elicit oxidative stress-induced cancer cell death in the brain. To this end, we will accomplish two specific aims to (1) determine the molecular mechanism of FASN function in regulating repair of DNA damages induced by oxidative stress and (2) repurpose PPIs to treat BCBM by targeting FASN. We trust that the successful outcome of this explorative study will reveal a novel mechanism on how FASN protects breast cancer cells in the brain and provide preliminary data on targeting FASN by repurposing PPIs that will enable us to conduct a full-scale study. The positive outcome may also lead to a clinical trial testing PPIs on breast cancer patients with brain metastasis, which will immediately and profoundly impact the BCBM treatment landscape.