Targeting mitochondrial complex I in acute lymphoblastic leukemia

靶向急性淋巴细胞白血病中的线粒体复合物 I

• 批准号: 9815737
• 负责人: Marina Y Konopleva
• 金额: $ 58.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815737
• 关键词: 3-Dimensional; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute T Cell Leukemia; Adult; Adult Precursor T Lymphoblastic Leukemia; Advanced Malignant Neoplasm; Affect; Bioenergetics; Biological Assay; Biology; Bone Marrow; Bone Marrow Cells; Cancer Science; Cell Line; Childhood Precursor T Lymphoblastic Leukemia; Citric Acid Cycle; Clinical Trials; Coculture Techniques; Combination Drug Therapy; Complex; Cytometry; Data; Development; Disease; Doctor of Medicine; Dose; Drug Kinetics; Drug Screening; Future; Gene Expression Profile; Genetic; Genus Hippocampus; Glycolysis; Growth; Hematologic Neoplasms; Homeostasis; Hypoxia; Hypoxia Inducible Factor; Impairment; In Vitro; Induction of Apoptosis; Infiltration; Institutes; Laboratories; Lactate Transporter; Libraries; Lymphoma; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Metabolic; Metabolic stress; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Mus; NADH; Oncogenic; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Pathway interactions; Patients; Pegaspargase; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation Inhibition; Property; Proteomics; Refractory; Regimen; Regulation; Relapse; Reporting; Respiration; Respiratory Chain; Role; Safety; Schedule; Stromal Cells; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toxic effect; Translating; Work; Xenograft Model; Xenograft procedure; acute T-cell lymphoblastic leukemia cell; acute lymphoblastic leukemia cell; asparaginase; biomarker evaluation; candidate marker; chemotherapy; first-in-human; high throughput screening; human subject; in vivo; in vivo imaging; in vivo two-photon imaging; inhibitor/antagonist; insight; leukemia; leukemia initiating cell; lymphoblast; metabolic imaging; metabolomics; mouse model; nanomolar; next generation; novel; peripheral blood; phosphorescence; preclinical study; predictive marker; resistance mechanism; response; response biomarker; screening; success; synergism; transcriptome sequencing; tumor; tumor hypoxia; tumor metabolism; two-photon

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.

抽象的 T细胞急性淋巴细胞性白血病（T-ALL）是一种侵略性的血液恶性肿瘤。尽管 大多数成人T-ALL患者将成功地固化小儿T-All用深度化疗，将会中继 并死于他们的疾病。我们和其他人已经证明，在T-All中，氧化磷酸化（OXPHOS） 通过调节产生能量和代谢中间体，以促进生长和支持生存 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容易受到影响 针对Oxphos的策略。 我们已经确定了Oxphos（Oxphosi），IACS-010759的一流的纳摩尔功能抑制剂 抑制OXPHOS呼吸链的CI，阻止氧气消耗，并破坏缺氧诱导的稳定 因子1α（HIF-1α）。我们的数据表明，该药物在T-ALL细胞系中的生长抑制作用深远 主要的所有细胞在低NM浓度下，对正常BM细胞的毒性最少。 Oxphos块 体内可以忍受为单一药物，但只有适度的治疗益处。但是，针对 T-All的Oxphos驱动的生物学可能在正确的组合中有效。我们已经证明了协同作用 IAC-010759的体外和体内T-ALL PDX中使用的标准化学疗法剂 型号。我们将通过IACS-010759的I/II期临床试验将这些发现转换为AIM 3中 使用建议 从正在进行的AML试验中的IACS-010759剂量2剂量。匹配T-ALL PDX模型的临床前研究 在AIM 1中，将以人类受试者不可能的方式发展反应的生物标志物。我们进一步确定了 Oxphosi的T-All细胞中的合成作用组合与鞋底转运蛋白MCT1的抑制剂 （AZD3965，现在正在第2阶段试验中），在AIM 2中将研究这种协同作用的机制。我们也会 用IACS-010759的HIF-1α阻断对T-ALL细胞的影响使用体内两光子成像的影响 代谢NADH和氧气通过磷光寿命显微镜进行感测。最后，我们将进一步进行 使用新型的高含有代谢组药库进行筛选，以识别IACS-010759的其他组合 对于将来的治疗应用，对T-ALL细胞而不是正常细胞有毒。 我们认为，拟议的研究将为新发现的脆弱性提供机械见解 T-All到Oxphosi；确定候选人预测生物标志物，以组合IACS-010759与 化学疗法或MCT1抑制剂；和下一代Oxphosi试验的开发组合。