Venetoclax-based rational combinations are effective in models of MYCN-amplified neuroblastoma.

摘要: Venetoclax is a small molecule inhibitor of the pro-survival protein BCL-2 that has gained market approval in dependent hematological cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma (NB) heterogenous pediatric cancer with five-year survival rate less than 50% for high-risk patients, which include nearly all cases amplified MYCN. We previously demonstrated venetoclax active MYCN-amplified NB but limited single-agent activity most models, presumably result other family expression or insufficient pro-death mobilization. As relative tolerability makes it amenable to co-dosing therapies, we evaluated sensitivity models rational combinations agents have both mechanistic complementarity clinical programs. First, MDM2 NVP-CGM097 increases BH3-only NOXA sensitize p53-wild-type, NBs venetoclax. Second, MCL-1 S63845 sensitizes through neutralization MCL-1, inducing synergistic cell killing when combined Lastly, standard care drug cocktail cyclophosphamide topotecan reduces apoptotic threshold NB, thus setting stage robust combination efficacy In cases, these translated vivo tumor regressions PDX models. currently being patients clinic, neuroblastoma (NCT03236857). While establishment safety still ongoing, data disclosed herein indicate clinically actionable strategies could potentiate patients.