PDF(Pubmed)
Abstract：
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 amplified MYCN, 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 amplified MYCN was 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. Amplified MYCN does 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.
摘要：
神经母细胞瘤(NB),婴儿最常见的癌症和儿童脑外最常见的实体瘤，积极生长，对目前的治疗反应不佳。我们已经确定了一种新药(opaganib，也称为ABC294640），通过通过鞘氨醇激酶2抑制鞘氨醇1-磷酸（S1P）的合成并通过抑制二氢神经酰胺去饱和酶来提高二氢神经酰胺来调节鞘脂代谢。本研究试图确定opaganib在NB的细胞培养和异种移植模型中的潜在治疗活性。细胞毒性试验表明，NB细胞，包括扩增的MYCN细胞，被奥帕加尼布的浓度有效杀死，远低于体内肿瘤中积累的浓度。Opaganib被证明会导致Neuro-2a细胞中S1P和己糖神经酰胺水平的剂量依赖性降低，同时提高二氢神经酰胺的水平。和其他肿瘤细胞一样，opaganib降低了Neuro-2a细胞中的c-Myc和Mcl-1蛋白水平，也降低了N-Myc蛋白的表达。通过以小鼠良好耐受的剂量口服opaganib，可以抑制具有扩增的MYCN的人SK-N-（BE）2细胞的异种移植物的体内生长。opaganib与替莫唑胺加伊立替康合用，被认为是治疗复发性或难治性NB的骨干，与替莫唑胺加伊立替康或奥帕加尼单独使用相比，体内抗肿瘤活性增加。当奥帕加尼与替莫唑胺加伊立替康合用时，小鼠没有失去额外的体重，表明该组合耐受性良好。当与检查点抑制剂抗CTLA-4抗体组合时，Opaganib对Neuro-2a肿瘤具有附加的抗肿瘤活性;然而，与单独使用opaganib相比,opaganib与抗PD-1或抗PD-L1抗体的组合没有增加抗肿瘤活性.总的来说,数据表明，opaganib可调节NB细胞中的鞘脂代谢和细胞内信号传导，并单独或与其他抗癌药物联合抑制NB肿瘤生长。扩增的MYCN不赋予对opaganib的抗性，and,事实上,该药物减弱c-Myc和N-Myc的表达。opaganib的安全性已经在成人晚期癌症或严重COVID-19的临床试验中得到证实，因此opaganib在治疗NB患者方面具有极好的潜力，特别是与替莫唑胺和伊立替康或抗CTLA-4抗体组合。
