# Project 1: New epigenetic therapy targets

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $269,820

## Abstract

Abstract 
Epigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect. To date, 
DNMT inhibition is the most effective form of epigenetic therapy in myeloid leukemias. We have developed and 
validated a live cell assay to screen for drugs that achieve the same degree of epigenetic reprogramming as 
DNMT inhibition. Using this screen, we discovered a new class of epigenetic drugs that activate silenced 
expression through inhibition of CDK9. CDK9 is a transcriptional regulator previously linked to gene activation 
through the pTEFb complex that phosphorylates RNAPII and promotes transcriptional elongation. Our new data 
now place CDK9 at the heart of a node that regulates both gene silencing and activation in proliferating cells. As 
such, 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 immune-sensitizing. Known CDK9 inhibitors 
(flavopiridol, SNS-032) have activity in leukemias but are marred by serious chemotherapy-like toxicities. 
Examining published data, we find that doses of these drugs in use clinically are at least an order of magnitude 
higher than what is needed to inhibit CDK9, and we speculate that the toxicity observed is typical of cross-target 
inhibition of other CDKs (e.g. CDK1/2). Thus, we hypothesize that low doses of CDK9-selective drugs may 
preserve activity through epigenetic effects of CDK9 inhibition, while reducing toxicity by avoiding other 
CDKs. In this grant, we will elucidate mechanisms of epigenetic effects of CDK9, determine the downstream 
effects of CDK9 inhibition on cellular function and immune responses, and conduct a clinical trial of a new CDK9- 
selective drug in myeloid leukemias. Successful completion of these aims will introduce a new form of epigenetic 
therapy in the treatment of leukemias.

## Key facts

- **NIH application ID:** 10247502
- **Project number:** 5P50CA100632-19
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jean-Pierre J. Issa
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $269,820
- **Award type:** 5
- **Project period:** 2003-08-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247502

## Citation

> US National Institutes of Health, RePORTER application 10247502, Project 1: New epigenetic therapy targets (5P50CA100632-19). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247502. Licensed CC0.

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