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.

项目总结