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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）是一种最具侵袭性和转移性的乳腺癌亚型