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

• 批准号: 10269643
• 负责人: Jean-Pierre J. Issa
• 金额: $ 48.22万
• 依托单位: CORIELL INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 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/10269643
• 关键词: AML/MDS; ATAC-seq; Achievement; Address; Affect; Antigens; Applications Grants; CDC2 gene; CDK4 gene; CDK5 gene; Cancer Model; Cell Cycle; Cells; Cellular Assay; ChIP-seq; Clinic; Clinical; Clinical Data; 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; 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; Lead; Malignant Neoplasms; Modeling; Myeloid Leukemia; Oncogenes; PD-1/PD-L1; Patients; Pharmaceutical Preparations; Phosphorylation; Proteins; RNA; Regulation; Reporter; Repression; Resistance; Signal Transduction; System; T cell response; T-Lymphocyte; Testing; Therapeutic Effect; Toxicology; Tumor Immunity; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Up-Regulation; antitumor effect; base; cancer cell; cancer therapy; checkpoint inhibition; design; efficacy study; epigenetic drug; epigenetic profiling; epigenetic silencing; epigenetic therapy; epigenome; expectation; falls; immunoregulation; improved; inhibitor/antagonist; 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

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.

项目摘要 表观遗传疗法旨在重新编程癌细胞中的基因表达，以达到治疗作用。迄今为止， DNA甲基转移酶（DNMT）抑制（DNMTI）是表观遗传疗法的最有效形式，是 在髓样白血病中特别活跃。使用活细胞测定法筛选获得相同程度的药物 表观遗传重编程为DNMTI，我们发现了一种新的表观遗传药物，它们激活了沉默 通过抑制CDK9的表达。细胞周期蛋白依赖性激酶（CDKS）在考虑临床方面具有临床意义 癌症治疗并分为两类 - 细胞周期调节（例如CDK1,2,4,6等）和转录 调节器（例如CDK7,9,12等）。我们的新数据将CDK9放置在调节两个基因的节点的核心 沉默和激活。靶向CDK9对基因表达具有多重作用，这似乎是理想的 抗肿瘤的观点：一个人观察（肿瘤补充剂）的同时基因激活，表达（ 致癌基因）和干扰素免疫识别的诱导，这可能是对癌症的免疫敏感性的 治疗。鉴于现象的最新发展，后来的效果特别令人感兴趣 疗法和我们的初步数据表明，CDK9靶向可能是一种有用的新方法 免疫敏化。有趣的是，CDK9可能不是唯一参与免疫测量的CDK。抑制 CDK4/6和CDK5已显示出诱导IFN反应和/或在癌症中进行免疫敏感性 治疗。此外，其他转录CDK（例如CDK7）与CDK9共享磷酸化靶标，从而提高 它们也可能会影响基因沉默。鉴于靶向CDK4和/或6的药物在临床上 用于乳腺癌和靶向CDK7和/或9的药物在临床试验中，重要的是要知道 其他CDK是否也是免疫敏感的表观遗传调节剂。表观遗传效应可能导致不同 这些药物的临床开发策略（例如低剂量而不是MTD，对缓慢反应的期望 这需要多个循环发生等），并为组合策略设计（结合表观遗传学 治疗，与免疫检查点抑制剂的组合等）。因此，该项目旨在检验假设 靶向CDK会导致免疫敏化表观遗传效应。我们将确认这一假设和检验 三个目的的机制和临床/转化对癌症治疗的影响：（i）通过 CDK9抑制作用，我们将研究增强影响的机制和潜在方法； （ii）表观遗传学 CDK的影响，我们将询问靶向CDK4,5,6和7是否具有相似的表观遗传和 免疫敏化作用作为靶向CDK9； （iii）临床前研究和联合CDK9的临床试验 AML和MDS中的DNMT抑制和免疫检查点抑制作用，我们将完成 将CDK靶向表观遗传疗法的必要研究与DNMT结合 靶向和免疫检查点抑制。这些目标的成功实现将引入一种新的形式 癌症和白血病的表观遗传疗法。