Cyclin Dependent Kinases as Epigenetic Therapy Targets

细胞周期蛋白依赖性激酶作为表观遗传治疗靶点

基本信息

批准号：
10696168
负责人：
Jean-Pierre J. Issa
金额：
$ 49.82万
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/10696168
关键词：
AML/MDS ATAC-seq Achievement Address Affect Antigen Presentation Applications Grants CDC2 gene CDK4 gene CDK5 gene Cancer Model Cell Cycle Cells Cellular Assay ChIP-seq Clinic Clinical Clinical Drug Development Clinical Trials Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinase Inhibitor 2A Cyclin-Dependent Kinases DNA Modification Methylases DNA methyltransferase inhibition Data Dendritic Cells Development Dominant-Negative Mutation Dose Double-Stranded RNA Drug Screening Drug Targeting Engineering Enzymes Epigenetic Process Gene Activation Gene Expression Gene Silencing Genetic Transcription Heart Heterochromatin Immune checkpoint inhibitor Immune response Immune system Immunotherapy Interferon Type II Interferons Malignant Neoplasms Modeling Myeloid Leukemia Oncogenes PD-1/PD-L1 Patients Pharmaceutical Preparations Phosphorylation Proteins Regulation Reporter Repression Resistance Signal Transduction System T cell infiltration T cell response Testing Therapeutic Effect Toxicology Tumor Immunity Tumor Suppressor Proteins Up-Regulation antitumor effect cancer cell cancer therapy checkpoint inhibition design efficacy study epigenetic drug epigenetic profiling epigenetic silencing epigenetic therapy epigenome expectation falls immunoregulation improved inhibitor interest leukemia malignant breast neoplasm mouse model neoplastic cell novel strategies novel therapeutic intervention novel therapeutics pre-clinical preclinical study programs promoter response targeted treatment transcriptome sequencing trial comparing tumor tumorigenesis

项目摘要

PROJECT SUMMARY Epigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect. To date, DNA methyltransferase (DNMT) inhibition (DNMTi) is the most effective form of epigenetic therapy, being particularly active in myeloid leukemias. Using a live cell assay to screen for drugs that achieve the same degree of epigenetic reprogramming as DNMTi, we discovered a new class of epigenetic drugs that activate silenced expression through inhibition of CDK9. Cyclin Dependent Kinases (CDKs) are of considerable clinical interest in cancer therapy and fall into two classes – cell cycle regulatory (e.g. CDK1,2,4,6 etc.) and transcriptional regulators (e.g. CDK7,9,12 etc.). Our new data place CDK9 at the heart of a node that regulates both gene silencing and activation. Targeting CDK9 has pleotropic effects on gene expression that appear ideal from an anti-tumor perspective: One observes simultaneous gene activation (of tumor suppressors), repression (of oncogenes), and induction of an interferon immune signature, which may be immunosensitizing for cancer therapy. This latter effect is of particular interest given the phenomenal recent development of immune based therapies, and our preliminary data suggest that CDK9 targeting may be a useful new approach to immunosensitization. Interestingly, CDK9 may not be the only CDK involved in immune regulation. Inhibition of CDK4/6 and of CDK5 have been shown to induce an IFN response and/or to be immunosensitizing in cancer therapy. Moreover, other transcriptional CDKs (e.g. CDK7) share phosphorylation targets with CDK9, raising the possibility that they also similarly affect gene silencing. Given that drugs that target CDK4 and/or 6 are in clinical use in breast cancer, and drugs targeting CDK7 and/or 9 are in clinical trials, it becomes important to know whether other CDKs are also immunosensitizing epigenetic regulators. Epigenetic effects may lead to different strategies for clinical development of these drugs (e.g. low doses rather than MTD, expectation of slow responses that take multiple cycles to occur, etc.) and for the design of combination strategies (combined epigenetic therapy, combinations with immune checkpoint inhibitors etc.). This project therefore aims to test the hypothesis that targeting CDKs leads to immunosensitizing epigenetic effects. We will confirm this hypothesis and test mechanisms and clinical/translational implications for cancer therapy in three aims: (i) Immunosensitization by CDK9 inhibition, in which we will study mechanisms and potential ways to enhance the effects; (ii) Epigenetic effects of CDKs, in which we will ask whether targeting CDK4,5,6 and 7 has similar epigenetic and immunosensitizing effects as targeting CDK9; and (iii) Preclinical studies and a clinical trial of combined CDK9 inhibition, DNMT inhibition and Immune checkpoint inhibition in AML and MDS, in which we will complete the necessary studies to bring CDK targeting as epigenetic therapy into the clinic, in combination with DNMT targeting and immune checkpoint inhibition. Successful achievement of these aims will introduce a new form of epigenetic therapy for cancer and leukemias.

项目概要表观遗传疗法旨在重新编程癌细胞中的基因表达以达到治疗效果。 DNA 甲基转移酶 (DNMT) 抑制 (DNMTi) 是表观遗传治疗最有效的形式，使用活细胞筛选达到相同检测水平的药物尤其活跃。 DNMTi 等表观遗传重编程研究中，我们发现了一类新的表观遗传药物，可以激活沉默的表观遗传药物通过抑制 CDK9 的表达具有相当大的临床意义。癌症治疗分为两类——细胞周期调节（例如CDK1、2、4、6等）和转录我们的新数据将 CDK9 置于调节这两个基因的节点的核心。沉默和激活 CDK9 对基因表达具有多效性，这看起来很理想。抗肿瘤观点：观察到同时基因激活（肿瘤抑制因子）、抑制（肿瘤抑制因子）癌基因），以及诱导干扰素免疫特征，这可能对癌症具有免疫增敏作用鉴于最近基于免疫的显着发展，后一种效应特别令人感兴趣疗法，我们的初步数据表明 CDK9 靶向可能是一种有用的新方法提示，CDK9可能不是唯一参与免疫调节的CDK。 CDK4/6 和 CDK5 已被证明可诱导 IFN 反应和/或在癌症中具有免疫增敏作用此外，其他转录 CDK（例如 CDK7）与 CDK9 共享磷酸化靶点，从而提高了治疗效果。鉴于针对 CDK4 和/或 6 的药物已进入临床，它们也可能同样影响基因沉默。用于乳腺癌，并且针对 CDK7 和/或 9 的药物正在进行临床试验，了解这一点变得很重要其他CDK是否也具有免疫增敏表观遗传调节作用，可能会导致不同的表观遗传效应。这些药物的临床开发策略（例如低剂量而不是 MTD、预期反应缓慢需要多个周期才能发生等）以及组合策略的设计（组合表观遗传因此，该项目旨在检验该假设。靶向 CDK 会导致免疫增敏表观遗传效应，我们将证实这一假设并进行测试。癌症治疗的三个目标的机制和临床/转化意义：（i）免疫增敏 CDK9 抑制，我们将研究增强效应的机制和潜在方法 (ii) 表观遗传； CDK 的影响，其中我们将询问靶向 CDK4、5、6 和 7 是否具有相似的表观遗传和靶向 CDK9 的免疫增敏作用；以及 (iii) 联合 CDK9 的临床前研究和临床试验 AML和MDS中的抑制、DNMT抑制和免疫检查点抑制，其中我们将完成将 CDK 靶向作为表观遗传疗法与 DNMT 结合引入临床进行必要的研究靶向和免疫检查点抑制的成功实现将引入一种新形式。癌症和白血病的表观遗传学治疗。