The remaining authors declare no potential conflicts of interest.The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. NNS has interest in Revolution Medicines. WCG has ownership interest in Nalo Therapeutics and Revolution Medicines. JEB is a shareholder and employee of Novartis AG. WAW has ownership interest in Auron Therapeutics, Nalo Therapeutics, and StemSynergy Therapeutics. Alex's Lemonade Stand, K08NS079485, DOD W81XWH-15-1-0166 (WCG), and the Intramural Research Programs of the National Center for Advancing Translational Sciences, National Institutes of Health.Ĭonflicts of interest: KS has funding from Novartis Institute of Biomedical Research and consults for and has stock options in Auron Therapeutics and has served as an advisor for Kronos Bio. This combination should be studied more closely in a pediatric clinical trial.įunding: This work was supported by Hyundai Hope on Wheels Scholar Award, Alex's Lemonade Stand Centers of Excellence Developmental Therapeutics Scholar Award, and NIH Texas Children's Cancer and Hematology Centers K12 Clinical Pharmacology Scholar Award (JSY). BETi+AURKAi in MYCN-amplified NBL, particularly in the context of functional TP53, provided anti-tumor benefits in preclinical models. This was most profound with TP53 restored, with marked tumor shrinkage and apoptosis induction in response to combination JQ1+Alisertib. JQ1+Alisertib combination treatment of a MYCN-amplified, TP53-null or TP53-restored genetically engineered mouse model of NBL prolonged survival better than either single agent. The combination had improved efficacy in the TP53-WT context, notably driving apoptosis in both genetic backgrounds. We treated both TP53-wild type and mutant, MYCN-amplified cell lines with the BETi JQ1 and the AURKAi Alisertib. Compared to single agents, these combinations cooperated to decrease levels of N-myc. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We previously performed a viability screen of ∼1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease.
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