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LncRNA EPIC1 induces immunotherapy resistance by activating EZH2 in breast cancer

LncRNA EPIC1通过激活EZH2诱导乳腺癌免疫治疗抵抗

基本信息

批准号：
10735281
负责人：
Da Yang
金额：
$ 40.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735281
关键词：
4T1 Animal Cancer Model Antigen Presentation Antigen Presentation Pathway Antineoplastic Agents Biological Assay Biological Markers Biology Breast Cancer Patient Cells ChIP-seq Clinical Clinical Investigator Coculture Techniques Cytotoxic T-Lymphocytes DNA Methylation Data Databases EZH2 gene Epigenetic Process Epithelioid Sarcomas Exposure to FDA approved Gene Expression Gene Expression Profiling Gene Silencing Genes Genetic Goals Human IFNGR1 gene Immune Immune Evasion Immune system Immunoprecipitation Immunosuppression Immunotherapy In Situ Hybridization In Vitro Infiltration Interferon Type II Lymphocyte Activation Lymphocytic Infiltrate MHC Class I Genes Mammary Neoplasms Measures Mechanics Mediating Mutate Neoplasm Metastasis Nucleotides Outcome PD-1/PD-L1 Pathology Play Primary Neoplasm Prognosis Proteins Publications RNA RNA Binding Research Resistance Resolution Role STAT1 gene Sampling Signal Transduction Specimen T-Lymphocyte Technology Testing Therapeutic Effect Tumor Immunity Tumor Tissue Untranslated RNA antagonist anti-CTLA4 anti-PD-1 anti-PD-L1 anti-PD1 therapy anti-tumor immune response breast cancer progression cancer immunotherapy cancer therapy chromatin isolation by RNA purification sequencing design efficacy testing epigenetic silencing experience experimental study genomic profiles humanized mouse in vivo inhibitor knock-down large cell Diffuse non-Hodgkin&apos s lymphoma malignant breast neoplasm mouse model neoplastic cell novel overexpression pembrolizumab pharmacologic pre-clinical programmed cell death ligand 1 programmed cell death protein 1 promoter recruit response therapy resistant translational scientist triple-negative invasive breast carcinoma tumor tumor initiation tumor progression

项目摘要

Summary:On July 26, 2021, the FDA approved the anti-PD1 immunotherapy pembrolizumab (Keytruda®, Merck) for triple negative breast cancer (TNBC) patients. Although significant progress has been made in breast cancer immunotherapy, resistance to immunotherapy remains a major obstacle to lasting survival benefit in breast cancer patients. Targetable mechanisms to overcome therapeutic resistance are urgently needed. Emerging evidence have shown that long noncoding RNA genes (lncRNAs) play essential roles in the tumor immunity. In our recent publication, we have identified a lncRNA, EPIC1, that is specifically expressed in tumor cells and suppresses the antitumor immune response through activating EZH2 protein. Based on our preliminary data, we hypothesize that (a) EPIC1 induces immunotherapy resistance by activating EZH2 in breast cancer; and (b) EZH2 inhibitor, tazemetostat (TAZVERIK®), may enhance responses to anti-PD1 therapy for EPIC1 overexpressed breast cancer. We have designed three aims to test our hypotheses. Aim 1 will determine the association of the EPIC1-EZH2 axis with tumor immune suppression in human breast cancer samples. Aim 2 will dissect the mechanism by which the EPIC1-EZH2 axis regulates tumor immunity. Aim 3 will test the efficacy of tazemetostat, alone or combined with anti-PD1, in humanized breast cancer mouse models. We have formed a team including basic, translational and clinical investigators, who have deep experience in breast cancer pathology, RNA biology, and immunotherapy to conduct the proposed research. Our project will provide key preclinical data and biomarkers for the combination of two FDA- approved cancer drugs for breast cancer patients.

摘要：2021年7月26日，FDA批准了抗PD 1免疫疗法pembrolizumab（Keytruda®， Merck）用于三阴性乳腺癌（TNBC）患者。虽然在这方面取得了重大进展，乳腺癌免疫治疗，免疫治疗抵抗仍然是持久生存的主要障碍对乳腺癌患者有好处。迫切需要克服治疗耐药性的靶向机制。 needed.新出现的证据表明，长链非编码RNA基因（lncRNA）在细胞凋亡中起重要作用。肿瘤免疫在我们最近的出版物中，我们已经确定了一种lncRNA，EPIC 1，并通过激活EZH 2蛋白抑制抗肿瘤免疫应答。基于我们根据初步数据，我们假设（a）EPIC 1通过激活EZH 2诱导免疫治疗抗性，乳腺癌;和（B）EZH 2抑制剂tazemetostat（TAZVERIK EPIC 1过表达乳腺癌的治疗。我们设计了三个目标来验证我们的假设。要求1 将确定EPIC 1-EZH 2轴与人乳腺癌中肿瘤免疫抑制的关联癌症样本目的2将剖析EPIC 1-EZH 2轴调节肿瘤免疫的机制。目的3将测试tazemetostat单独或与抗PD 1组合在人源化乳腺癌中的功效小鼠模型。我们已经组建了一个包括基础、翻译和临床研究人员的团队，在乳腺癌病理学、RNA生物学和免疫治疗方面的丰富经验， research.我们的项目将为两种FDA- 用于乳腺癌患者的批准的癌症药物。