# Cyclin Dependent Kinases as Epigenetic Therapy Targets

> **NIH NIH P50** · CORIELL INSTITUTE FOR MEDICAL RESEARCH · 2021 · $482,163

## Abstract

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 epigeneti...

## Key facts

- **NIH application ID:** 10269643
- **Project number:** 1P50CA254897-01A1
- **Recipient organization:** CORIELL INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Jean-Pierre J. Issa
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $482,163
- **Award type:** 1
- **Project period:** 2021-08-16 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10269643

## Citation

> US National Institutes of Health, RePORTER application 10269643, Cyclin Dependent Kinases as Epigenetic Therapy Targets (1P50CA254897-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10269643. Licensed CC0.

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