LncRNA EPIC1通过激活EZH2诱导乳腺癌免疫治疗抵抗-猫眼课题宝

LncRNA EPIC1通过激活EZH2诱导乳腺癌免疫治疗抵抗

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

项目状态：

未结题

起止时间：

2023-08-01 至 2028-07-31

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

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英文摘要

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.

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