Targeting mitochondrial complex I in acute lymphoblastic leukemia

摘要 T细胞急性淋巴细胞白血病(T-ALL)是一种侵袭性血液系统恶性肿瘤。尽管 强化化疗治愈儿童T-ALL成功多数成人T-ALL患者将复发 然后死于他们的疾病。我们和其他人已经证明了在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需的能量和代谢中间体 线粒体复合体I(CI)。这种独特的代谢和线粒体生物学使T-ALL容易患上 针对OxPhos的策略。 我们已经确定了一种一流的氧化膦(OxPhosi)纳米分子有效抑制剂IacS-010759，它 抑制OxPhos呼吸链的CI，阻断氧气消耗，破坏缺氧诱导的稳定性 因子1α(HIF-1α)。我们的数据显示，这种药物对T-ALL细胞株有明显的生长抑制作用 和原代ALL细胞在低NM浓度下，对正常BM细胞毒性最小。OXPHOS封锁 作为单一药物，在体内是可以耐受的，但只有轻微的治疗益处。然而，目标是 OXPHOS驱动的T-ALL生物学在正确的组合中可能是有效的。我们已经展示了协同效应 在T-ALL体外和体内T-ALL PDX中使用标准化疗药物的Iacs-010759 模特们。我们将把这些发现转化为我们的目标3，通过IACS-010759的I/II期临床试验结合 改良的高CVAD/L-天冬酰胺酶方案治疗复发/难治性急性淋巴细胞白血病 正在进行的急性髓细胞白血病试验中的IacS-010759第二阶段剂量。T-ALL PDX模型的临床前配对研究 在目标1中，将以人类受试者不可能实现的方式开发生物反应标记物。我们进一步确定了 OxPhosi与乳酸转运蛋白MCT1抑制剂在T-ALL细胞中的合成致死组合 (AZD3965，现处于第二阶段试验)，目标2将研究这种协同作用的机制。我们还将 用体内双光子成像法研究IacS-010759阻断缺氧诱导因子-1α对T-ALL细胞的影响 磷光寿命显微镜下的代谢nadh和氧传感。最后，我们将进一步进行 用一种新的高含量代谢药物文库进行筛选以鉴定与IACS-010759的其他结合 对T-ALL细胞有毒性，但对正常细胞没有毒性，用于未来的治疗应用。 我们相信，拟议的研究将提供对新发现的 T-ALL到OxPhosi；确定IacS-010759与OxPhosi结合的候选预测生物标志物 化疗或MCT1抑制剂；并为T-ALL的下一代OxPhosi试验开发组合。

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.