HSC-1535 Pharmacological EZH2 inhibition enhances cancer cell sensitivity to genotoxic insults through suppressing DNA damage repair
Kexin Xu: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Myles Brown: Center for Functional Cancer Epigenetics and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Chen-Hao Chen and Xiaole Shirley Liu: Department of Data Sciences, Dana-Farber Cancer Institute and Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
THE PROBLEM Lymphoma and Leukemia cancer cells lack of therapeutic sensitivity
Value Proposition
Unmet needs
Therapeutic molecules and radiological treatments that are less toxic to the patients.
Advantages of the new therapy
The methyltransferase EZH2 is a well-known anticancer drug target with several highly selective inhibitors readily available. They are mainly tested in cancers that carry the gain-of-function mutations of EZH2, such as lymphoma or leukemia. However, efficacies of EZH2 inhibitors on solid tumors with no significant genetic alterations remain unclear, despite of the accumulating evidence suggesting that EZH2 drives the malignant features of solid tumors.
Our study revealed a previously unappreciated mechanism of EZH2 inhibitors, and expanded the clinical applications of these compounds. We found that EZH2 inhibitors enhance sensitivity of cancer cells to DNA repair targeted therapies, such as ionizing radiation and olaparib. Therefore, our new idea is to combine EZH2 inhibitors with radiotherapy or PARP inhibitor olaparib to treat a wide range of advanced cancer. In addition, we found a group of DNA repair genes, whose expression well predicts sensitivities of cancer cells to EZH2 inhibitors, even more robustly than the presence of mutational status of EZH2. In summary, our work indicated a novel combination cancer therapy and identified a potential biomarker to forecast the benefit of this therapy in cancer patients.
Stage of Development
Dr. Kexin Xu, A CPRIT Scholar is further refining the invention described above at UT Health San Antonio.
Patent Status
Provisional patent application filed 06/26/2019 Serial # 62/867,109