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Epigenetic Therapies - New Approaches

表观遗传疗法 - 新方法

基本信息

批准号：
10696160
负责人：
STEPHEN B. BAYLIN
金额：
$ 234.54万
依托单位：
CORIELL INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696160
关键词：
Address Biochemical Biological Markers Cancer Patient Cells Clinic Clinical Clinical Research Clinical Trials Combination immunotherapy Combined Modality Therapy Cultured Cells Cyclin-Dependent Kinases DNA Damage DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases DNA methyltransferase inhibition Development Dreams Drug Combinations EZH2 gene Ensure Enzymes Epigenetic Process Funding Gene Expression Gene Expression Profile Generations Genetic Transcription Genomics Goals Hematologic Neoplasms Histone Deacetylase Immune Immune checkpoint inhibitor Immunocompetent Immunologic Monitoring Immunotherapy Inflammasome Interferons Isocitrate Dehydrogenase Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Mentors Modification Molecular Mus Nature Pathology Patients Pattern Pharmaceutical Preparations Phase I Clinical Trials Phase I/II Trial Phenotype Poly(ADP-ribose) Polymerase Inhibitor Regulation Repetitive Sequence Repression Research Research Personnel Research Project Grants Resistance Running Science Signal Transduction Solid Neoplasm Testing Therapeutic Therapeutic Effect Therapy Clinical Trials Tissues Translational Research Work analysis pipeline cancer cell cancer therapy cancer type career chemotherapy chromatin remodeling clinical application design drug action drug testing epigenetic drug epigenetic regulation epigenetic silencing epigenetic therapy immune modulating agents improved inhibitor inhibitor therapy malignant breast neoplasm next generation novel novel therapeutic intervention pharmacodynamic biomarker preclinical study programs repaired response response biomarker synergism targeted treatment therapy resistant translational pipeline translational study tumor tumor growth

项目摘要

ABSTRACT (Overall) Epigenetics refers to stable gene expression patterns mediated by DNA methylation and/or chromatin remodeling and is involved in cellular identity and repression of spurious transcription, including from repetitive elements. Over the past 20 years, in work led in part by investigators in this application, epigenetic changes were recognized as important drivers of cancer formation, progression and resistance to therapy. This recognition, along with the reversible nature of the biochemical modifications required for epigenetics led to the field of Epigenetic Therapy, which aims to reprogram gene expression to achieve a therapeutic effect. This field, which started with DNA methyltransferase (DNMT) inhibitors, has grown to a dozen epigenetic targets and over 30 drugs in clinical trials. Four targets have made it to US-FDA approval (DNMTs, Histone Deacetylases (HDACs), EZH2 and Isocitrate Dehydrogenases) and tens of thousands of cancer patients benefit from this every year. With the identification of new targets and the recognition that epigenetics is involved in sensitivity and resistance to chemotherapy and immunotherapy, the clinical potential of epigenetic therapy has begun to be explored in earnest. There remain fundamental challenges, from the lack of robust biomarkers of activity, to the emergence of resistance, and to the unexplained divide in responses between hematologic malignancies and solid tumors. This SPORE application will address all of these challenges. The SPORE team consists of investigators who are pioneers in the fields of cancer epigenetics and epigenetic therapy and explores new epigenetic targets and combination strategies along with a robust biomarker analysis pipeline to identify patients likely to respond and pharmacodynamic markers of response. The team leverages a strong clinical and translational pipeline built through the Van Andel Institute Stand Up To Cancer Epigenetics Dream Team, which has conducted 14 epigenetic therapy clinical trials in the past few years, and is fully committed to the clinical trials proposed in this application. This Epigenetic Therapy SPORE encompasses four major themes: (i) Develop and test drugs against new epigenetic targets (Projects 1, 2), (ii) Mechanistic and translational studies of immunosensitization by epigenetic therapy (projects 1-3), (iii) Studies of drug combinations that enhance the efficacy of known epigenetic drugs (projects 1-3); and (iv) Biomarker studies to define sensitivity and resistance to epigenetic therapy in the clinic (all Projects). These themes will be addressed through 3 projects: (i) Cyclin Dependent Kinases as Epigenetic Therapy Targets; (ii) Epigenetic synergy between DNMT and EZH1/2 inhibitors; (iii) Linking epigenetic-therapy induction of inflammasome signaling to generation of a BRCAness phenotype. These projects will be supported by three cores (administrative, pathology, genomics) and a key goal will also be to mentor the next generation of Epigenetic Therapy investigators and support cutting-edge science through the Career Enhancement and Developmental Research Programs.

摘要(总体) 表观遗传学是指由DNA甲基化和/或染色质介导的稳定的基因表达模式重塑，并参与细胞识别和抑制虚假转录，包括来自重复的元素。在过去的20年里，在部分由这一应用的研究人员领导的工作中，表观遗传变化是被认为是癌症形成、进展和抗拒治疗的重要驱动因素。这种认可，随着表观遗传学所需的生化修饰的可逆性，导致了表观遗传疗法，旨在重新编程基因表达以达到治疗效果。此字段，即从DNA甲基转移酶(DNMT)抑制剂开始，已经发展到12个表观遗传靶点和30多个临床试验中的药物。已有四个靶点获得了美国-FDA的批准(DNMT，组蛋白脱乙酰酶(HDAC)， EZH2和异柠檬酸脱氢酶)，每年有成千上万的癌症患者从中受益。随着新靶点的识别和对表观遗传学与敏感性和耐药性的认识除了化疗和免疫治疗外，表观遗传治疗的临床潜力已经开始在#年探索。诚挚的。仍然存在根本性的挑战，从缺乏强有力的活动生物标志物到出现耐药，以及血液系统恶性肿瘤和实体肿瘤之间无法解释的反应差异。这一孢子应用程序将解决所有这些挑战。孢子团队由调查人员组成，他们癌症表观遗传学和表观遗传学治疗领域的先驱，并探索新的表观遗传学靶点和与强大的生物标志物分析管道相结合的策略，以识别可能有反应的患者和反应的药效学标志物。该团队利用建立的强大的临床和翻译渠道通过Van Andel研究所对抗癌症表观遗传学梦想团队，该团队已经进行了14次表观遗传疗法在过去几年的临床试验，并全力致力于本报告中提出的临床试验申请。这种表观遗传疗法孢子包含四个主要主题：(I)开发和测试药物针对新的表观遗传靶点(项目1、2)，(2)免疫增敏的机制和翻译研究通过表观遗传疗法(项目1-3)，(3)加强已知药物疗效的药物组合研究表观遗传药物(项目1-3)；和(4)确定表观遗传敏感性和耐药性的生物标记物研究临床治疗(所有项目)。这些主题将通过3个项目加以解决：(I)依赖自行车作为表观遗传治疗靶点的激酶；(Ii)DNMT和EZH1/2抑制剂之间的表观遗传协同作用；(Iii) 将表观遗传疗法诱导炎症体信号与BRCAness表型的产生联系起来。这些项目将得到三个核心(行政、病理学、基因组学)的支持，一个关键目标也将是指导下一代表观遗传疗法研究人员，并通过职业提升和发展研究计划。