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

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.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Jean-Pierre J. Issa其他文献

Targeting the cancer epigenome for therapy
针对癌症表观基因组进行治疗
  • DOI:
    10.1038/nrg.2016.93
  • 发表时间:
    2016-09-15
  • 期刊:
  • 影响因子:
    52.000
  • 作者:
    Peter A. Jones;Jean-Pierre J. Issa;Stephen Baylin
  • 通讯作者:
    Stephen Baylin
Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon
雌激素受体 CpG 岛甲基化与人类结肠衰老和肿瘤发生有关
  • DOI:
    10.1038/ng0894-536
  • 发表时间:
    1994-08-01
  • 期刊:
  • 影响因子:
    29.000
  • 作者:
    Jean-Pierre J. Issa;Yvonne L. Ottaviano;Paul Celano;Stanley R. Hamilton;Nancy E. Davidson;Stephen B. Baylin
  • 通讯作者:
    Stephen B. Baylin
DNAメチル化と正常大腸
DNA甲基化和正常结肠
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    前田修;安藤貴文;後藤秀実;Jean-Pierre J. Issa
  • 通讯作者:
    Jean-Pierre J. Issa
神経性食欲不振症の血漿アミノ酸プロファイルの解析
神经性厌食症血浆氨基酸谱分析
  • DOI:
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    前田修;安藤貴文;後藤秀実;Jean-Pierre J. Issa;安藤哲也,田村奈穂,倉尚樹,小西恵,富田吉敏,知場奈津子,本間洋州,濱田孝,石川俊男,小牧元
  • 通讯作者:
    安藤哲也,田村奈穂,倉尚樹,小西恵,富田吉敏,知場奈津子,本間洋州,濱田孝,石川俊男,小牧元
Author Correction: DNA methylation entropy as a measure of stem cell replication and aging
  • DOI:
    10.1186/s13059-023-02943-8
  • 发表时间:
    2023-04-30
  • 期刊:
  • 影响因子:
    9.400
  • 作者:
    Himani Vaidya;Hye Seon Jeong;Kelsey Keith;Shinji Maegawa;Gennaro Calendo;Jozef Madzo;Jaroslav Jelinek;Jean-Pierre J. Issa
  • 通讯作者:
    Jean-Pierre J. Issa

Jean-Pierre J. Issa的其他文献

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{{ truncateString('Jean-Pierre J. Issa', 18)}}的其他基金

Career Enhancement Program
职业提升计划
  • 批准号:
    10470369
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    10696173
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    10269647
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10269640
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10470362
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10470368
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10696172
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10696162
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
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:
    10470365
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:
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:
    10696168
  • 财政年份:
    2021
  • 资助金额:
    $ 48.22万
  • 项目类别:

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