Therapeutics: BRCA1-associated protein 1 (BAP1); enhancer of zeste homolog 2 (EZH2)

In vitro and mouse studies suggest inhibiting EZH2 could help treat BAP1-mutant cancers and myeloproliferative disorder. In human BAP1-mutant mesothelioma cell lines, EZH2 knockdown or a small molecule inhibitor of EZH2 increased apoptosis compared with normal EZH2 expression or vehicle, respectively. In a BAP1-knockout mouse model of myeloproliferative disorder, EZH2 knockout decreased expansion of myeloid progenitor cells and other disease markers compared with normal EZH2 expression. In a xenograft mouse model of BAP1-mutant mesothelioma, the EZH2 inhibitor decreased tumor growth and lung metastasis compared with vehicle. Next steps could include testing EZH2 inhibitors in additional models of BAP1-mutant diseases.

Epizyme Inc. and Eisai Co. Ltd. have the EZH2 inhibitor EPZ-6438 in Phase I/II testing to treat non-Hodgkin's lymphoma (NHL) and lymphoma, and have submitted an IND for the compound to treat sarcoma...