Cancer

Patient sample and cell culture studies suggest inhibiting MGMT or its downstream mediator USP17L2 alone or in combination with HDAC inhibitors could help treat ovarian cancer. In patients, high tumor expression of MGMT and USP17L2 was associated with chemoresistance and high tumor expression of USP17L2 was associated with poor survival. In two human ovarian cancer cell lines, an shRNA targeting USP17L2 or a tool compound MGMT inhibitor decreased viability compared with non-targeting shRNA or vehicle, respectively. In one of those cell lines and a third cell line, the HDAC inhibitors entinostat, abexinostat or mocetinostat in combination with the MGMT inhibitor decreased growth compared with any agent alone. Next steps include testing undisclosed MGMT and USP17L2 inhibitors alone or in combination with HDAC inhibitors in patient-derived xenograft (PDX) and organoid models of ovarian cancer.

Bayer AG, EOC Pharma Group, Kyowa Hakko Kirin Co. Ltd., NovaMedica LLC and Syndax Pharmaceuticals Inc. have entinostat in Phase III testing for breast cancer, Phase II testing for acute myelogenous leukemia (AML) and Phase I/II testing for ovarian and renal cancers. The companies and Merck & Co. Inc. also have the product in Phase II testing for lung cancer and Phase I/II testing for colorectal cancer and melanoma...