Targeting mitochondrial complex I in acute lymphoblastic leukemia

摘要 T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液恶性肿瘤。尽管 尽管使用强化化疗成功治愈儿童T-ALL，但大多数成人T-ALL患者会复发， 死于疾病我们和其他人已经证明，在T-ALL中，氧化磷酸化（OxPhos） 通过调节产生促进生长和支持生存所必需的能量和代谢中间产物， 线粒体复合物I（CI）。这种独特的代谢和线粒体生物学使T-ALL容易受到 针对OxPhos的策略。 我们已经确定了一流的纳米级有效的OxPhos抑制剂（OxPhosi），IACS-010759， 抑制OxPhos呼吸链的CI，阻断氧消耗，并使缺氧诱导的 因子1α（HIF-1α）。我们的数据表明，这种药物在T-ALL细胞系中具有显著的生长抑制作用 和低nM浓度的原代ALL细胞，对正常BM细胞具有最小的毒性。OxPhos阻断 在体内作为单一药剂是可耐受的，但仅具有适度的治疗益处。然而，针对 OxPhos驱动的T-ALL生物学可能在正确的组合中有效。我们展示了协同效应 IACS-010759与T-ALL中使用的标准化疗药物的体外和体内T-ALL PDX 模型我们将通过IACS-010759的I/II期临床试验结合 一种改良的hyperCVAD/L-门冬酰胺酶方案治疗复发性/难治性ALL患者，使用推荐的 正在进行的AML试验中的IACS-010759 II期给药。T-ALL PDX模型的匹配临床前研究 将以人类受试者不可能的方式开发反应生物标志物。我们进一步确认了 OxPhosi与乳酸转运蛋白MCT 1抑制剂在T-ALL细胞中的合成致死组合 （AZD 3965，目前处于2期试验中），Aim 2将研究这种协同作用的机制。我们还将 使用体内双光子成像表征IACS-010759对T-ALL细胞的HIF-1α阻断作用， 通过磷光寿命显微镜进行代谢NADH和氧传感。最后，我们将进一步 使用新型高含量代谢组学药物库进行筛选，以鉴定与IACS-010759的其他组合 对T-ALL细胞有毒但对正常细胞没有毒性，用于未来的治疗应用。 我们相信，拟议中的研究将为新发现的脆弱性提供机械的见解， T-ALL至OxPhosi;鉴定IACS-010759与 化疗或MCT 1抑制剂;并为下一代OxPhosi试验开发T-ALL组合。

ABSTRACT T-cell acute lymphocytic leukemia (T-ALL) is an aggressive hematological malignancy. Despite successes in curing pediatric T-ALL with intensive chemotherapy, the majority of adult T-ALL patients will relapse and die of their disease. We and others have demonstrated that in T-ALL, oxidative phosphorylation (OxPhos) generates energy and metabolic intermediates necessary to promote growth and support survival, by regulation of mitochondrial Complex I (CI). This unique metabolic and mitochondrial biology makes T-ALL vulnerable to strategies that target OxPhos. We have identified a first-in-class nanomolar-potent inhibitor of OxPhos (OxPhosi), IACS-010759, that inhibits CI of the OxPhos respiratory chain, blocks oxygen consumption, and destabilizes Hypoxia-Inducible Factor 1α (HIF-1α). Our data demonstrated profound growth-inhibitory effects of this agent in T-ALL cell lines and primary ALL cells at low nM concentrations, with minimal toxicity against normal BM cells. OxPhos blockade in vivo was tolerable as a single agent, yet had only a modest therapeutic benefit. However, targeting the OxPhos-driven biology of T-ALL is likely to be effective in the right combinations. We have demonstrated synergy of IACS-010759 with standard chemotherapy agents used in T-ALL, both in vitro and in the in vivo T-ALL PDX models. We will translate these findings in our Aim 3, by a Phase I/II clinical trial of IACS-010759 combined with a modified hyperCVAD/L-asparaginase regimen in relapsed/refractory ALL patients, using the recommended Phase 2 dose of IACS-010759 from the ongoing AML trial. Matching pre-clinical studies on T-ALL PDX models in Aim 1 will develop biomarkers of response in ways not possible in human subjects. We have further identified a synthetically lethal combination in T-ALL cells of OxPhosi with an inhibitor of the lactate transporter MCT1 (AZD3965, now in Phase 2 trials), and in Aim 2 will investigate mechanisms of this synergy. We will also characterize the effect of HIF-1α blockade by IACS-010759 on T-ALL cells using in vivo two-photon imaging of metabolic NADH and oxygen sensing by phosphorescence lifetime microscopy. Finally, we will conduct further screening with a novel high-content metabolomic drug library to identify other combinations with IACS-010759 that are toxic to T-ALL cells but not normal cells, for future therapeutic applications. We believe that the proposed studies will provide mechanistic insights into the newfound vulnerability of T-ALL to OxPhosi; identify candidate predictive biomarkers for the combination of IACS-010759 with chemotherapy or MCT1 inhibitor; and develop combinations for the next generation of OxPhosi trials for T-ALL.