Targeting FASN to eliminate metastatic breast cancer in the brain

靶向 FASN 消除脑部转移性乳腺癌

• 批准号: 10721671
• 负责人: Jian-Ting Zhang
• 金额: $ 18.06万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-08 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721671
• 关键词: Acetyl Coenzyme A; Adriamycin PFS; Binding; Biological Availability; Blood - brain barrier anatomy; Brain; Breast Cancer Cell; Breast Cancer Patient; Cell Death; Cell Line; Cell Proliferation; Central Nervous System; Clinical Trials; Computerized Medical Record; Cyclophosphamide; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Digestive System Disorders; Disease; Dose; Doxorubicin; Enzymes; FDA approved; Fatty-acid synthase; Goals; Growth; Human; Immunotherapeutic agent; Immunotherapy; In Vitro; In complete remission; Incidence; Inhibition of Cell Proliferation; Ionizing radiation; Laboratory Study; Lipids; Malignant Neoplasms; Malonyl Coenzyme A; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modeling; Molecular; Neoadjuvant Therapy; Neoplasm Metastasis; Nonhomologous DNA End Joining; Omeprazole; Organ; Outcome; Oxidative Stress; Oxidative Stress Induction; Palmitates; Pathologic; Pharmaceutical Preparations; Phase; Production; Prognosis; Proton Pump Inhibitors; Recurrence; Reporting; Research; Retrospective Studies; Serum; Supplementation; Testing; Therapeutic; Toxic effect; Trust; Up-Regulation; Xenograft procedure; blood-brain barrier permeabilization; breast cancer survival; cancer cell; cancer subtypes; cancer therapy; chemotherapy; improved; in vivo; inhibitor; malignant breast neoplasm; meter; mortality; neuroprotection; new therapeutic target; novel; novel strategies; phase II trial; prognostic; prospective; repaired; standard of care; taxane; temozolomide; therapeutic target; three dimensional cell culture; treatment strategy; triple-negative invasive breast carcinoma; tumor

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.

摘要 脑内转移性乳腺癌是一种致命的疾病，是世界上发病率第二高的肿瘤 中枢神经系统。尽管靶向和免疫疗法对癌症治疗的改进 使一些癌症可以治愈，这些新的进步和治疗方法并没有能够使乳房受益 癌症患者脑转移主要是由于血脑屏障(BBB)。最近，脂肪酸合成酶 唯一负责棕榈酸酯从头合成的胞浆酶(FASN)被证明在 乳腺癌脑转移而非其他器官转移的乳腺癌及其抑制作用 限制了乳腺癌在大脑中的生长。尽管FASN作为靶点已经建立并被抑制 靶向FASN已被确定，没有靶向FASN的疗法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。在试图改变FDA批准的药物的用途以 克服过去靶向FASN的障碍，我们最近表明，批准的质子泵抑制剂(PPI) 用于治疗消化系统疾病，有效结合和抑制FASN。他们还禁止乳腺癌细胞 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， 补充PPI，奥美拉唑，在高剂量(80毫克/天)抑制肿瘤中的FASN活性，几乎 用新佐剂AC-T(阿霉素)的护理标准将病理完全反应提高一倍 环磷酰胺-紫杉烷)化疗。同样值得注意的是，PPI已经被证明是BBB 具有通透性和神经保护作用，为将PPI开发为BCBM疗法提供了机会 目标是FASN。这项研究的长期目标是通过以下方式消除转移性乳腺癌死亡率 重新调整针对FASN的PPI。在这一探索阶段要检验的总体假设是FASN 上调DNA损伤修复活性对过度氧化应激诱导的BCBM的保护作用 脑损伤和PPI可以通过靶向FASN来诱导BCBM治疗 氧化应激导致脑部癌细胞死亡。为此，我们将实现两个具体目标：(1) 确定FASN调节DNA氧化损伤修复的分子机制 应激和(2)通过靶向FASN改变PPI治疗BCBM的目的。我们相信，这一成功的结果 探索性研究将揭示FASN如何保护大脑和乳腺癌细胞的新机制 通过改变PPI的用途，提供针对FASN的初步数据，使我们能够进行全面研究。 阳性结果还可能导致对患有脑转移的乳腺癌患者进行PPI的临床试验， 这将立即深刻地影响BCBM治疗的格局。