A New Small Molecule Targeted Therapeutic for Acute Myeloid Leukemia

急性髓系白血病小分子靶向治疗新药

• 批准号: 9046515
• 负责人: Xueyan Mu
• 金额: $ 27.8万
• 依托单位: TEAMEDON INTERNATIONAL, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046515
• 关键词: 1 year old; Acute Myelocytic Leukemia; Address; Adult; Affect; Anabolism; Biological Assay; Blood; Bone Marrow; CD34 gene; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Clinical; Complement; Development; Diagnosis; Disease remission; Dose; Elderly; Engraftment; Glycolysis; Goals; Hematopoietic stem cells; Human; In Vitro; Incidence; Leukemic Cell; Longevity; MLL-AF9; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Medical; Metabolic; Monitor; Mus; Outcome; Oxidative Phosphorylation; Oxidative Stress; Patients; Phase; Population; Process; Production; Protein Isoforms; Pyruvate Kinase; Reactive Oxygen Species; Recurrent disease; Relapse; Research; Resistance; Safety; Sampling; Small Business Innovation Research Grant; Toxic effect; Transgenic Organisms; Transplantation; Xenograft Model; Xenograft procedure; aerobic glycolysis; base; cancer cell; chemotherapy; dimer; killings; leukemia; leukemia treatment; leukemic stem cell; mouse model; new therapeutic target; novel therapeutics; older patient; patient population; pre-clinical; public health relevance; relapse patients; small molecule; small molecule therapeutics; targeted treatment; tumor; tumor growth

 DESCRIPTION (provided by applicant): We propose to develop ML265, a small molecule PKM2 (M2 isoform of pyruvate kinase) activator, into a new targeted therapeutic for Acute Myeloid Leukemia (AML). The majority (91%) of AML cases is diagnosed in adults, and incidence increases significantly among elderly population. The outcomes for adults with AML are poor. Although chemotherapy results in high rates of remission, the majority of patients relapse, with an overall 5 year survival only 40-50% for younger patients and a median overall survival less than 1 year for older patients. The persistence of leukemia stem cells (LSCs) following chemotherapy is a major factor contributing to clinical relapse. Therefore, there is an urgent need to develop novel therapeutics that specifically target LSCs in AML patients. Pyruvate kinase catalyzes the last step of glycolysis. Its M2 isoform, PKM2, is highly expressed in tumors of all kinds, including AML cells, but with low pyruvate kinase activity. PKM2 occurs in tetramer (active) and dimer (inactive) forms; a high tetramer-to-dimer ratio leads to energy production, while a low ratio channels metabolites into synthetic processes. ML265 potently activates human PKM2 in vitro, induces PKM2 tetramer formation, and significantly reduces aerobic glycolysis in cancer cells. In addition, ML265 also increases reactive oxygen species (ROS) concentrations and induces oxidative stress in cancer cells. PKM2 is abundantly expressed (up to 11.3x of control) in many AML cell lines and primary AML patient samples suggesting all subtypes of AML could benefit from ML265 treatment. ROS is important for the maintenance of malignant LSCs in AML. Significantly lower ROS level is observed in LSCs-like CD34+ cells compared to more mature CD34- cells. In human primary AML samples, ML265 increases ROS level and significantly reduces the colony formation of LSCs. In AML transgenic (MLL-AF9) mouse model, deletion of PKM2 with expression of PKM1 (a situation similar to ML265 treatment) reduces the levels of metabolic intermediates important for biosynthesis and impairs leukemic cells in blood and bone marrow without perturbing normal hematopoietic stem cells (HSCs). ML265 is well tolerated in repeat dose toxicity studies in mice suggesting a greater than 5X margin of safety based on an in vitro efficacious concentration in human primary AML samples. Our SBIR Phase I goal is to establish the pre-clinical proof-of-concept and demonstrate that ML265 selectively targets LSCs and complements standard therapy in AML patient derived xenograft (PDX) mouse. The specific aims proposed in this proposal include: (1) Determine the optimal concentration of ML265 via in vitro viability assays. At this concentration, ML265 not only strongly reduces the survival of phenotypically described LSCs, but is also well tolerated by normal HSCs. (2) We will investigate whether ML265 could selectively target LSCs using AML PDX model. We will treat the AML PDX mice with ML265 for 4 weeks, followed by a secondary serial transplantation to validate killing of LSCs. (3) Using AML PDX mouse, we will further determine whether ML265 could complement current standard induction chemotherapy and extend the life span of chemotherapy-treated AML mouse. We will treat the AML PDX mice with ML265, induction chemotherapy, or ML265 in combination with induction chemotherapy. The dosing of ML265 will last for 8 weeks, mice will be monitored for survival and signs of leukemia. Demonstrating that ML265 selectively targets LSCs and complements standard therapy in AML will justify Phase II research and open development of a new way to attack one of world's most deadly cancers.

 描述（由适用提供）：我们建议开发ML265，这是一种小分子PKM2（丙酮酸激酶的M2同工型）活化剂，成为一种新的针对急性骨髓性白血病（AML）的靶向疗法。在成年人中诊断出大多数AML病例（91％），而老年人口的发病率显着增加。 AML成年人的结果很差。尽管化学疗法导致高缓解率很高，但大多数患者中继，年轻患者的总生存期仅为40-50％，而老年患者的总体生存率仅为1岁。化疗后白血病干细胞（LSC）的持久性是导致临床缓解的主要因素。因此，迫切需要开发新的疗法，该疗法专门针对AML患者的LSC。丙酮酸激酶催化糖酵解的最后一步。 M2同工型PKM2在包括AML细胞在内的各种肿瘤中高度表达，但丙酮酸激酶活性低。 PKM2发生在四聚体（活动）和二聚体（非活动）形式中。高四聚体比例的比例可导致能量产生，而低比率通道将代谢产物分为合成过程。 ML265可能在体外激活人PKM2，诱导PKM2四聚体形成，并显着降低癌细胞中的有氧糖酵解。此外，ML265还增加了活性氧（ROS）浓度，并诱导癌细胞中的氧化应激。在许多AML细胞系中，PKM2基本上表达（最多为11.3倍），主要AML患者样品表明AML的所有亚型都可以从ML265治疗中受益。 ROS对于维持AML中的恶性LSC很重要。与更成熟的CD34-细胞相比，在LSCS样CD34+细胞中观察到ROS水平明显降低。在人类初级AML样品中，ML265增加了ROS水平，并显着降低了LSC的落形成。在AML转基因（MLL-AF9）小鼠模型中，PKM2的缺失（类似于ML265治疗的情况）降低了对生物合成重要的代谢中间体的水平，对生物合成很重要，并损害血液中的白血病细胞，而无需扰动正常血肿的血肿细胞（HSCSS）。在小鼠的重复剂量毒性研究中，ML265的耐受性良好，表明基于人类原代AML样品的体外有效浓度，其安全性大于5倍。我们的SBIR I期目标是建立临床前的概念验证，并证明ML265有选择地靶向LSC并完成AML患者衍生的Xenographic（PDX）小鼠的标准治疗。该提案中提出的具体目的包括：（1）通过体外生存能力评估确定ML265的最佳浓度。在此浓度下，ML265不仅强烈降低了表型描述的LSC的存活，而且还可以通过正常的HSC耐受。 （2）我们将研究ML265是否可以使用AML PDX模型有选择地靶向LSC。我们将用ML265治疗AML PDX小鼠4周，然后进行继发序列移植以验证LSC的杀戮。 （3）使用AML PDX小鼠，我们将进一步确定ML265是否可以完成当前的标准诱导化疗并延长化学疗法处理的AML小鼠的寿命。我们将用ML265，诱导化疗或ML265与诱导化疗一起治疗AML PDX小鼠。 ML265的剂量将持续8周，将监测小鼠的生存和白血病迹象。证明ML265在AML中有选择地靶向LSC和完成标准疗法，将证明II期研究合理性并开发了一种攻击世界上最致命的癌症之一的新方法。