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.

Public Health Relevance

We aim in this proposal to address a major issue of normal tissue toxicity of chemotherapy. We propose to develop a novel strategy by targeting MDM2/MDMX-regulated EZH2 for protection of normal tissues. Information derived from this work would not only advance our understanding of the mechanism of normal tissue sensitivity to DNA damage but also pave a way to clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA233558-01A1
Application #
9814796
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Venkatachalam, Sundaresan
Project Start
2019-05-10
Project End
2024-04-30
Budget Start
2019-05-10
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115