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Therapeutic targeting of orphan NR in ER-negative breast cancer

ER 阴性乳腺癌孤儿 NR 的治疗靶向

基本信息

批准号：
10527316
负责人：
Hongwu Chen
金额：
$ 41.1万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527316
关键词：
Adjuvant Chemotherapy Agonist Biochemical Breast Cancer Cell Breast Cancer Patient Cancer Etiology Cessation of life ChIP-seq Chemoresistance Chemosensitization Cholesterol Cholesterol Homeostasis Chromatin Complex Development Disease Dose Ectopic Expression Epigenetic Process Estrogen receptor negative Family Gene Expression Gene Silencing Genes Genetic Genomic approach Genomics Growth Human In complete remission Link Lipids Malignant Neoplasms Mammary Neoplasms Mediating Mesenchymal Metabolic Modeling Molecular Mus Neoadjuvant Therapy Neoplasm Metastasis Nuclear Receptors Orphan Outcome PIK3CA gene PTEN gene Pathologic Pathway interactions Patient-derived xenograft models of breast cancer Pharmaceutical Preparations Prevention Recurrent tumor Safety Testing Therapeutic Time Toxic effect Woman antagonist brca gene breast cancer progression chemotherapy data mining epigenetic silencing experimental study functional genomics gene synthesis genomic data histone methyltransferase inhibitor innovation insight malignant breast neoplasm member metabolomics mevalonate neoplastic cell new therapeutic target novel orphan nuclear receptor ROR-gamma overexpression pharmacologic programs receptor response small molecule inhibitor stem synergism targeted treatment therapeutic target therapeutically effective therapy resistant transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

ABSTRACT Triple-negative breast cancers (TNBC) still lack effective targeted therapy, despite the fact that TNBC often presents as invasive diseases with poor outcome. Subtypes of TNBC show rare or low pathological complete response (pCR) rates to neoadjuvant chemotherapies. Despite the newly acquired tumor genomics data, readily actionable, therapy-effective targets are yet to be revealed or established. Our recent data mining and other tumor analysis revealed that RORC/RORγ, an orphan member of the nuclear receptor family of transcription factors, is amplified or overexpressed in over 30% of TNBC and that its overexpression is significantly associated with poor outcomes. Our functional studies revealed that it is required for growth and survival of TNBC cells, and that its inhibitors, developed recently by us, are highly effective in killing TNBC cells selectively and stopping tumor growth and metastasis at relatively low doses, without overt toxicity. With other preliminary studies, we hypothesize that overexpression and/or hyperactivation of RORγ drives TNBC progression through a novel cholesteromic feed-forward loop and that targeting RORγ with a potent tumor-selective, small-molecule inhibitor, either alone or in combination with chemotherapy, can be a novel and effective therapeutic strategy for TNBC. The hypothesis will be tested in 3 specific aims: Aim 1 will establish that overexpressed RORγ drives tumor growth and therapeutic resistance through its function in reprogramming lipid/cholesterol metabolism; Aim 2 will establish that induction of an epigenetic switch underlies the superior anti-TNBC potency of the RORγ inhibitor, and Aim 3 will thoroughly examine the anti-tumor efficacy of the optimized inhibitor using PDX and other tumor models. Successful completion of the proposed studies should, for the first time, establish RORγ as a new, major driver of TNBC and effective therapeutic target.

摘要