Neuroblastoma (NB), the most common cancer in infants and the most common solid tumor outside the brain in children, grows aggressively and responds poorly to current therapies. We have identified a new drug (opaganib, also known as ABC294640) that modulates sphingolipid metabolism by inhibiting the synthesis of sphingosine 1-phosphate (S1P) by sphingosine kinase-2 and elevating dihydroceramides by inhibition of dihydroceramide desaturase. The present studies sought to determine the potential therapeutic activity of opaganib in cell culture and xenograft models of NB. Cytotoxicity assays demonstrated that NB cells, including cells with amplifiedMYCN, are effectively killed by opaganib concentrations well below those that accumulate in tumors in vivo. Opaganib was shown to cause dose-dependent decreases in S1P and hexosylceramide levels in Neuro-2a cells, while concurrently elevating levels of dihydroceramides. As with other tumor cells, opaganib reduced c-Myc and Mcl-1 protein levels in Neuro-2a cells, and also reduced the expression of the N-Myc protein. The in vivo growth of xenografts of human SK-N-(BE)2 cells with amplifiedMYCNwas suppressed by oral administration of opaganib at doses that are well tolerated in mice. Combining opaganib with temozolomide plus irinotecan, considered the backbone for therapy of relapsed or refractory NB, resulted in increased antitumor activity in vivo compared with temozolomide plus irinotecan or opaganib alone. Mice did not lose additional weight when opaganib was combined with temozolomide plus irinotecan, indicating that the combination is well tolerated. Opaganib has additive antitumor activity toward Neuro-2a tumors when combined with the checkpoint inhibitor anti-CTLA-4 antibody; however, the combination of opaganib with anti-PD-1 or anti-PD-L1 antibodies did not provide increased antitumor activity over that seen with opaganib alone. Overall, the data demonstrate that opaganib modulates sphingolipid metabolism and intracellular signaling in NB cells and inhibits NB tumor growth alone and in combination with other anticancer drugs. AmplifiedMYCNdoes not confer resistance to opaganib, and, in fact, the drug attenuates the expression of both c-Myc and N-Myc. The safety of opaganib has been established in clinical trials with adults with advanced cancer or severe COVID-19, and so opaganib has excellent potential for treating patients with NB, particularly in combination with temozolomide and irinotecan or anti-CTLA-4 antibody.
神经母细胞瘤（NB）是婴幼儿最常见的恶性肿瘤，也是儿童除脑部外最常见的实体肿瘤，其生长侵袭性强且对现有疗法反应不佳。我们鉴定出一种新型药物opaganib（亦称ABC294640），该药物通过抑制鞘氨醇激酶-2介导的1-磷酸鞘氨醇合成，并抑制二氢神经酰胺去饱和酶以提升二氢神经酰胺水平，从而调控鞘脂代谢。本研究旨在探究opaganib在NB细胞培养及异种移植模型中的潜在治疗活性。细胞毒性实验表明，包括MYCN扩增型细胞在内的NB细胞可被远低于体内肿瘤蓄积浓度的opaganib有效杀伤。在Neuro-2a细胞中，opaganib能剂量依赖性降低S1P与己糖基神经酰胺水平，同时提升二氢神经酰胺含量。与其他肿瘤细胞类似，opaganib可降低Neuro-2a细胞中c-Myc和Mcl-1蛋白水平，并抑制N-Myc蛋白表达。口服耐受性良好的opaganib剂量能显著抑制MYCN扩增型人源SK-N-(BE)2细胞异种移植瘤的体内生长。与目前复发/难治性NB基础疗法替莫唑胺联合伊立替康方案相比，opaganib与该联合方案联用可产生更强的体内抗肿瘤活性。联合用药未导致小鼠体重额外下降，表明该方案耐受性良好。当opaganib与检查点抑制剂抗CTLA-4抗体联用时，对Neuro-2a肿瘤产生叠加抗肿瘤效应；但与抗PD-1或抗PD-L1抗体联用未显示出优于单药opaganib的疗效。总体而言，本研究表明opaganib能调控NB细胞鞘脂代谢及胞内信号传导，单药或联合其他抗癌药物均可抑制NB肿瘤生长。MYCN扩增不导致对opaganib的耐药性，且该药物能同时抑制c-Myc与N-Myc表达。opaganib在晚期癌症及重症COVID-19成人患者的临床试验中已证实其安全性，因此该药物在治疗NB患者方面，特别是与替莫唑胺、伊立替康或抗CTLA-4抗体联合应用时，展现出卓越的临床潜力。
肿瘤(癌症)患者之家