Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma.
Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma.
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DOI：
10.1158/1535-7163.mct-20-0710
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发表时间：
2021-08
影响因子：
5.7
通讯作者：
Faber, Anthony C.
中科院分区：
文献类型：
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作者：
Dalton, Krista M.;Krytska, Kateryna;Lochmann, Timothy L.;Sano, Renata;Casey, Colleen;D'Aulerio, Alessia;Khan, Qasim A.;Crowther, Giovanna Stein;Coon, Colin;Cai, Jinyang;Jacob, Sheeba;Kurupi, Richard;Hu, Bin;Dozmorov, Mikhail;Greninger, Patricia;Souers, Andrew J.;Benes, Cyril H.;Mosse, Yael P.;Faber, Anthony C.
维奈托克是一种促生存蛋白BCL-2的小分子抑制剂，已获得BCL-2依赖性血液学癌症（如慢性淋巴细胞白血病（CLL）和急性髓性白血病（AML））的市场批准。神经母细胞瘤（NB）是一种异质性儿科癌症，高危患者的五年生存率低于50%，其中包括几乎所有扩增MYCN的病例。我们之前已经证明，维奈托克在MYCN扩增的NB中具有活性，但在大多数模型中具有有限的单药活性，推测是其他促生存BCL-2家族蛋白表达或促死亡蛋白动员不足的结果。由于维奈托克的相对耐受性使其适合与其他疗法共同给药，我们评估了MYCN扩增的NB模型对维奈托克与具有机制互补性以及积极临床计划的药物合理组合的敏感性。首先，MDM 2抑制剂NVP-CGM 097诱导仅促死亡BH 3蛋白NOXA的增加，以使p53野生型、MYCN扩增的NB对维奈托克敏感。第二，MCL 1抑制剂S63845通过直接中和MCL-1使MYCN扩增的NB敏感，当与BCL-2抑制剂组合时，其诱导显著的协同细胞杀伤。最后，护理药物鸡尾酒环磷酰胺和托泊替康的标准降低NB的凋亡阈值，从而为与维奈托克的稳健组合功效奠定基础。在所有情况下，这些合理的组合在MYCN扩增的PDX模型中转化为体内肿瘤消退。维奈托克目前正在临床儿科患者中进行评价，包括神经母细胞瘤患者（NCT 03236857）。虽然在该人群中安全性的建立仍在进行中，但本文公开的数据表明可以增强维奈托克在MYCN扩增的NB患者中的活性的合理且临床上可行的组合策略。
Venetoclax is a small molecule inhibitor of the pro-survival protein BCL-2 that has gained market approval in BCL-2 dependent hematological cancers such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). 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 have 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 as well as active clinical programs. First, MDM2 inhibitor NVP-CGM097 induces an increase in the pro-death BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified NBs to venetoclax. Second, the MCL1 inhibitor S63845 sensitizes MYCN-amplified NB through direct neutralization of MCL-1, which induces marked synergistic cell killing when combined with BCL-2 inhibition. 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 those with neuroblastoma (NCT03236857). While establishment of safety is still ongoing in this population, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in MYCN-amplified NB patients.