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Investigating the Impact of ABL Kinase Signaling on Epigenetic Reprogramming in Metastatic Triple Negative Breast Cancer

研究 ABL 激酶信号转导对转移性三阴性乳腺癌表观遗传重编程的影响

基本信息

批准号：
10614415
负责人：
Ashley Colemon
金额：
$ 3.99万
依托单位：
DUKE UNIVERSITY
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：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614415
关键词：
ATAC-seq Address Antitumor Response Brain Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast cancer metastasis CRISPR screen Cancer Etiology Cell Death Cell Line Cell Survival Cessation of life Chromatin Chromatin Remodeling Factor Clinical Trials Combined Modality Therapy Data Drug Targeting Enzymes Epigenetic Process Family Genetic Transcription Goals Growth Factor Receptors Hormones Human Impairment In Vitro Invaded Knowledge Link Malignant Neoplasms Metastatic Neoplasm to the Bone Modification Molecular Mus Neoplasm Metastasis Pathway interactions Patients Pharmacotherapy Phenotype Phosphotransferases Protein Tyrosine Kinase Relapse Research Signal Transduction Site Therapeutic Woman bone cancer cell efficacy testing epigenetic drug epigenome experience experimental study genetic regulatory protein improved in vitro Assay in vivo inhibitor loss of function migration mouse model novel therapeutic intervention novel therapeutics response standard of care synergism therapeutically effective transcriptome transcriptomics triple-negative invasive breast carcinoma tumor tumor progression tumor xenograft

项目摘要

Because of its highly metastatic potential and limited treatment options, triple-negative breast cancer (TNBC) remains a leading cause of cancer associated deaths in women. Recent studies have shown that distinct chromatin landscapes correspond to metastatic relapse. Our lab has shown that the Abelson (ABL) family of non-receptor tyrosine kinases promote metastasis of breast cancer cells through activation of downstream transcriptional changes. However, how these changes exist in the greater context of global chromatin dynamics has yet to be explored. My preliminary data suggest that simultaneously targeting the epigenome and the ABL kinase- regulated transcriptome might be a promising new therapeutic strategy for treating metastatic triple negative breast cancer. The overall hypothesis of the proposal is that inhibition of ABL kinases leads to distinct changes in the chromatin landscape that sensitizes TNBC cells to treatment with drugs targeting epigenetic regulatory proteins leading to TNBC cell death. The aims of the proposal are to elucidate the epigenetic landscape associated with ABL kinase signaling to promote metastatic progression, and to understand how these dynamic changes might be exploited to elicit therapeutic benefit in metastatic TNBC models. Approaches used to address these objectives will include CRISPR/Cas9 screens, ATAC-seq, and in vitro and in vivo drug treatment experiments using cell lines and mice respectively.

由于其高度转移的可能性和有限的治疗选择，三阴性乳腺癌