Epigenetic Therapies - New Approaches

表观遗传疗法 - 新方法

基本信息

批准号：
10470361
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/10470361
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 Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases DNA Repair 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 Institutes Interferons Isocitrate Dehydrogenase Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Mentors Modification Molecular Mus Nature Neoadjuvant Therapy Pathology Patients Pattern Pharmaceutical Preparations Phase I Clinical Trials Phase I/II Trial Phenotype 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 drug action drug testing epigenetic drug epigenetic regulation epigenetic silencing epigenetic therapy improved inhibitor inhibitor therapy malignant breast neoplasm next generation novel novel therapeutic intervention pharmacodynamic biomarker preclinical study programs response response biomarker synergism targeted treatment therapy design 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基因表达模式重塑，并参与了细胞身份和虚假转录的抑制，包括重复性元素。在过去的20年中，在此应用中，调查人员的一部分工作中，表观遗传的变化是被认为是癌症形成，进展和对治疗抗性的重要驱动因素。这个认可，以及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作用。这个领域，哪个从DNA甲基转移酶（DNMT）抑制剂开始，已经生长到十几个表观遗传靶标，超过30个临床试验中的药物。四个目标已经获得了US-FDA批准（DNMT，组蛋白脱乙酰基酶（HDACS）， EZH2和异急塞脱氢酶）和成千上万的癌症患者每年受益。随着新靶标的鉴定以及表观遗传学与敏感性和抗性有关的认识对于化学疗法和免疫疗法，在认真。从缺乏强大的活动生物标志物到出现，仍然存在着根本的挑战抗性，以及血液学恶性肿瘤和实体瘤之间反应的无法解释的鸿沟。该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癌症表观遗传学和表观遗传疗法领域的先驱，并探讨了新的表观遗传靶标和结合策略以及强大的生物标志物分析管道，以识别可能反应和反应的患者反应的药效学标记。该团队利用强大的临床和转化管道建造通过Van Andel Institute站起来参加癌症表观遗传学梦想团队，该团队进行了14 在过去的几年中，表观遗传疗法临床试验，并完全致力于此处提出的临床试验应用。这种表观遗传疗法孢子包括四个主要主题：（i）开发和测试药物针对新的表观遗传靶标（项目1，2），（ii）免疫敏化的机械和翻译研究通过表观遗传疗法（项目1-3），（iii）对药物组合的研究，增强了已知的疗效表观遗传药物（项目1-3）；（iv）生物标志物研究以定义对表观遗传的敏感性和抗性诊所的治疗（所有项目）。这些主题将通过3个项目解决：（i）依赖细胞周期蛋白激酶作为表观遗传疗法靶标；（ii）DNMT和EZH1/2抑制剂之间的表观遗传协同作用；（iii）将炎性体信号的表观遗传学诱导与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，基因组学）的支持，关键目标也将是指导下一代表观遗传疗法研究者，并通过职业增强和发展研究计划。