Regulation of Tumor Oxygenation by BACH1 in Breast Cancer

BACH1 在乳腺癌中对肿瘤氧合的调节

基本信息

批准号：
10693966
负责人：
MARSHA R ROSNER
金额：
$ 39.83万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693966
关键词：
Angiogenic Factor Antioxidants BACH1 gene Blood flow Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis Cancer Etiology Cancer Patient Catabolism Cell Hypoxia Cessation of life Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytotoxic Chemotherapy Data Disease Drug Delivery Systems ERBB2 gene Endothelial Cells Epigenetic Process FDA approved Gene Expression Genes Genetic Transcription Goals Heme Hemin Hormone Receptor Hypoxia Hypoxia Inducible Factor Immunotherapy Localized Malignant Neoplasm Mediating Metabolic Mus Oxygen Oxygen Therapy Care Patients Pharmaceutical Preparations Phenotype Play Production Publishing Radiation Radiation therapy Refractory Regulation Resistance Role Scheme Signal Transduction Specificity Stress Survival Rate Testing Therapeutic Transcriptional Regulation Treatment Efficacy Tumor Oxygenation Ubiquitin Woman Work Xenograft procedure aggressive breast cancer angiogenesis biological adaptation to stress cancer cell cancer subtypes chemotherapy cytotoxic gene repression improved inhibitor malignant breast neoplasm migration mortality mouse model multicatalytic endopeptidase complex mutant neoplastic cell novel novel therapeutic intervention overexpression oxidation prognostic programs public health relevance radiation resistance response small hairpin RNA standard of care transcription factor treatment strategy triple-negative invasive breast carcinoma tumor tumor hypoxia tumor microenvironment

项目摘要

Triple negative breast cancer (TNBC), the most aggressive and metastatic subtype of breast cancer, is one of the major causes of cancer death in women. TNBC also has lower survival rates for primarily local cancers. Loss of hormone receptors and the lack of HER2 overexpression in TNBC limit treatments to cytotoxic therapies such as radiation, a key clinical strategy for 10-15% of breast cancer patients. Hypoxia is a major cause of resistance to radiotherapy, chemotherapy and even immunotherapy. Thus, identifying mechanisms to suppress the hypoxia stress response and increase the sensitivity of TNBC tumors to therapy remains a top clinical priority. Upon hypoxic stress, cancer cells initiate a transcriptional program that enables them to survive and migrate from an inhospitable microenvironment. While hypoxia-inducible factors (HIFs) are generally considered the main effectors, growing evidence suggests the hypoxia cellular response is much more complex and requires coordinated signaling with other stress response factors. One promising candidate is BACH1, a transcription factor that is induced by hypoxia and represses transcription of genes involved in heme oxidation and anti-oxidant production. Based on preliminary results, we now hypothesize that BACH1 is stabilized by hypoxia and functions as a key inducer of the cellular hypoxia response in TNBC cells leading to abnormal leaky vasculature that contributes to intratumoral hypoxia and radiation resistance. Specifically, we plan to: 1. Determine whether BACH1 is regulated by oxygen and induces a transcriptional hypoxic stress response in TNBC cells; 2. Determine whether BACH1 promotes angiogenesis, leaky vasculature and hypoxia in TNBC tumors; and 3. Determine whether BACH1 depletion sensitizes TNBC tumors to radiation. We propose that targeting BACH1 represents a unique strategy for increasing tumor oxygenation to improve the efficacy of cytotoxic, standard-of-care therapies such as radiation. Normalizing vasculature to suppress leakiness should also facilitate drug delivery to tumors. Since BACH1 can be targeted by an FDA approved drug either alone or in combination with HIF inhibitors, the proposed work could lead to a clinical trial in breast cancer and other cancer patients whose treatment involves radiation therapy.

三阴性乳腺癌 (TNBC) 是乳腺癌中最具侵袭性和转移性的亚型之一女性癌症死亡的主要原因。 TNBC 的生存率也较低，主要是本地人癌症。 TNBC 中激素受体的丧失和 HER2 过度表达的缺乏限制了治疗细胞毒性疗法（例如放射疗法）是 10-15% 乳腺癌患者的关键临床策略。缺氧是对放疗、化疗甚至免疫治疗产生耐药性的主要原因。因此，识别抑制缺氧应激反应并增加 TNBC 肿瘤敏感性的机制治疗仍然是临床的首要任务。在缺氧应激下，癌细胞启动转录程序使它们能够在恶劣的微环境中生存并迁移。而缺氧诱导因素（HIF）通常被认为是主要效应器，越来越多的证据表明缺氧细胞反应是更为复杂，需要与其他应激反应因素协调信号传导。一位有前途的候选者是 BACH1，一种由缺氧诱导并抑制基因转录的转录因子参与血红素氧化和抗氧化剂的产生。根据初步结果，我们现在假设 BACH1 通过缺氧而稳定，并作为 TNBC 细胞缺氧反应的关键诱导物发挥作用细胞导致脉管系统异常渗漏，导致瘤内缺氧和辐射反抗。具体来说，我们计划： 1.确定BACH1是否受到氧气调节并诱导 TNBC 细胞的转录缺氧应激反应； 2.确定BACH1是否促进血管生成， TNBC 肿瘤中的脉管系统渗漏和缺氧； 3. 确定 BACH1 耗尽是否会使 TNBC 敏感肿瘤对辐射的影响。我们认为，靶向 BACH1 是一种增加肿瘤生长的独特策略。氧合以提高细胞毒性、标准护理疗法（例如放射疗法）的疗效。正火化抑制渗漏的脉管系统也应有利于药物向肿瘤的输送。由于 BACH1 可以作为目标通过 FDA 批准的药物单独或与 HIF 抑制剂联合使用，拟议的工作可能会导致在乳腺癌和其他涉及放射治疗的癌症患者中进行的临床试验。