BioCentury
ARTICLE | Distillery Therapeutics

Cancer

July 10, 2018 9:40 PM UTC

Cell culture and mouse studies suggest combining Mekinist trametinib with IGF1R inhibitors could help treat PAX3-PAX7 fusion-negative rhabdomyosarcoma. Screening of a panel of 1,912 approved or tool compound small molecule inhibitors in a viability assay in fusion-positive and five fusion-negative rhabdomyosarcoma cell lines, identified 35 compounds, including the dual MAP2K1/MAP2K2 inhibitor Mekinist, as selective inhibitors of the fusion-negative cells. Screening of combinations of the 35 hits and an unspecified number of additional inhibitors in fusion-negative rhabdomyosarcoma cell lines identified Mekinist plus the IGF1R inhibitor BMS-754807 as the combination that most potently inhibited cell viability. In a xenograft mouse model of PAX3-PAX7 fusion-negative rhabdomyosarcoma, the combination decreased tumor growth and increased survival compared with vehicle. Next steps include testing Mekinist and BMS-754807 in additional mouse models of PAX3-PAX7 fusion-negative rhabdomyosarcoma.

Japan Tobacco Inc. and Novartis AG market Mekinist for melanoma and non-small cell lung cancer (NSCLC), and have the compound in Phase II testing for pancreatic and other cancers, Phase I/II testing for colorectal cancer and solid tumors and preclinical studies for acute lymphoblastic leukemia (ALL)...