# Target MDM2/MDMX for reducing normal tissue toxicity induced by chemotherapy

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2021 · $364,856

## Abstract

Summary
 Although targeted therapies have transformed medical oncology, traditional
cytotoxic chemotherapeutics remain one of the primary cancer treatments. Toxicity to
normal tissues, the renewable tissue in particular continues to represent major challenge
in the clinic. Effective strategies of normal tissue protection are in great need for
reducing the side effects and thus improving cancer patient’s quality of life. We recently
uncovered a novel mechanism by which p53-regulated MDM2 functions together with
MDMX to govern DNA damage sensitivity by targeting EZH2 for degradation. As a
histone methyltransferase, EZH2 promotes H3K27me3 and therefore chromatin
compaction to protect DNA. We showed that interference of the association between
MDM2 and MDMX could stabilize EZH2, resulting in protection of renewable tissues
from DNA damage agents-induced acute injury. Based on these findings, we propose to
test the hypothesis that the MDM2/MDMX complex can be targeted for EZH2
stabilization and thereby for normal tissue chemotherapy protection. The deliverable of
this proposal is to establish a novel strategy of targeting MDM2/MDMX-regulated EZH2
to selectively protect normal cells. Additionally, the proposal will develop the
pharmacological approach and has already identified lead compounds. Therefore the
success of our proposed studies would pave the way of targeting MDM2/MDMX-
regulated EZH2 for chemotherapy protection to the clinic, promising a great potential to
enhance the efficacy of chemotherapy and to improve patient quality of life.

## Key facts

- **NIH application ID:** 10200710
- **Project number:** 5R01CA233558-03
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** ZHI-MIN YUAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,856
- **Award type:** 5
- **Project period:** 2019-05-10 → 2023-04-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200710

## Citation

> US National Institutes of Health, RePORTER application 10200710, Target MDM2/MDMX for reducing normal tissue toxicity induced by chemotherapy (5R01CA233558-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10200710. Licensed CC0.

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