RRC ID 65484
Author Dalton KM, Krytska K, Lochmann TL, Sano R, Casey C, D'Aulerio A, Khan QA, Stein Crowther G, Coon C, Cai J, Jacob S, Kurupi R, Hu B, Dozmorov M, Greninger P, Souers AJ, Benes CH, Mossé YP, Faber AC.
Title Venetoclax-based rational combinations are effective in models of MYCN-amplified neuroblastoma.
Journal Mol Cancer Ther
Abstract Venetoclax is a small molecule inhibitor of the pro-survival protein BCL-2 that has gained market approval in BCL-2 dependent hematological cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma (NB) is a heterogenous pediatric cancer with a five-year survival rate of less than 50% for high-risk patients, which include nearly all cases with amplified MYCN. We previously demonstrated that venetoclax is active in MYCN-amplified NB but has limited single-agent activity in most models, presumably the result of other pro-survival BCL-2 family protein expression or insufficient pro-death protein mobilization. As the relative tolerability of venetoclax makes it amenable to co-dosing with other therapies, we evaluated the sensitivity of MYCN-amplified NB models to rational combinations of venetoclax with agents that have both mechanistic complementarity and active clinical programs. First, MDM2 inhibitor NVP-CGM097 increases the pro-death BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified NBs to venetoclax. Second, the MCL-1 inhibitor S63845 sensitizes MYCN-amplified NB through neutralization of MCL-1, inducing synergistic cell killing when combined with venetoclax. Lastly, the standard of care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of NB, thus setting the stage for robust combination efficacy with venetoclax. In all cases, these rational combinations translated to in vivo tumor regressions in MYCN-amplified PDX models. Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). While establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in MYCN-amplified NB patients.
Published 2021-6-4
DOI 10.1158/1535-7163.MCT-20-0710
PII 1535-7163.MCT-20-0710
PMID 34088831
Human and Animal Cells HCE-T(RCB2280)