Targeting FASN to eliminate metastatic breast cancer in the brain

靶向 FASN 消除脑部转移性乳腺癌

基本信息

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
项目类别：
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

项目摘要

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.

概括大脑中的转移性乳腺癌是一种致命的疾病，是肿瘤的第二大疾病中枢神经系统。尽管对靶向和免疫疗法的癌症治疗的改善具有使一些癌症可以治愈，这些新的进步和治疗剂无法使乳房受益脑转移的癌症患者主要是由于血脑屏障（BBB）。最近，脂肪酸合酶（FASN），唯一负责棕榈酸酯合成的唯一的胞质酶，已显示出上调乳腺癌脑转移（BCBM），但在其他器官的转移性乳腺癌及其抑制大脑乳腺癌的生长有限。尽管已经建立了FASN作为目标并抑制剂已经确定了靶向FASN，尚未批准针对FASN的治疗剂进行癌症治疗由于各种原因，包括毒性和生物利用度。试图将FDA批准的药物重新利用为克服了靶向FASN的过去障碍，我们最近表明质子泵抑制剂（PPI）已批准用于治疗消化系统疾病，有效地结合并抑制FASN。他们还禁止乳腺癌细胞实验室研究中的扩散。在三重阴性乳腺癌（TNBC）患者的II期试验中，在高剂量（80 mg/day）下补充PPI，奥美拉唑，抑制了肿瘤中的FASN活性，几乎用新辅助AC-T（adriamycin）将病理完全反应加倍环磷酰胺 - taxane）化学疗法。还值得注意的是，PPI已被证明为BBB 可渗透并具有神经保护作用，提供了开发PPI为BCBM治疗剂的机会定位FASN。这一研究的长期目标是消除通过重新利用靶向FASN的PPI。在这个探索阶段要测试的总体假设是FASN 通过上调DNA损伤修复活性来保护BCBM，以防止过度氧化应激诱导的DNA 大脑的损害和PPI可以通过靶向FASN来形成BCBM治疗剂氧化应激诱导的大脑癌细胞死亡。为此，我们将实现两个具体目标（1）确定FASN功能在调节氧化诱导的DNA损伤修复中的分子机制应力和（2）通过靶向FASN来治疗BCBM的PPI。我们相信成功的结果探索性研究将揭示一种有关FASN如何保护大脑乳腺癌细胞和通过重新利用PPI来提供有关靶向FASN的初步数据，这将使我们能够进行全面的研究。积极的结果还可能导致对脑部转移乳腺癌患者的PPI进行临床试验测试，这将立即影响BCBM治疗局势。