Targeting NAMPT in Acute Myeloid Leukemia

靶向 NAMPT 治疗急性髓系白血病

基本信息

批准号：
10006058
负责人：
Rosa Lapalombella
金额：
$ 47.09万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-02 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006058
关键词：
AML1-ETO fusion protein Acute Myelocytic Leukemia Affect Age Allogenic Anabolism Apoptosis BRCA1 gene Base Excision Repairs Biological Cardiac Cell Line Cell Survival Cell physiology Cells Cellular Metabolic Process Chronic Lymphocytic Leukemia Clinical Clinical Data Combined Modality Therapy Complex Cytogenetics DNA Damage DNA Repair DNA Sequence Alteration Data Decitabine Defect Development Diagnosis Disease Disease Progression Disease-Free Survival Dose Dose-Limiting Drug Combinations Enzymes Epigenetic Process Exhibits Generations Genes Genome Stability Glycolysis Hematologic Neoplasms Hematopoietic Impairment In Vitro Karyotype Knowledge Leukemic Cell Mediating Metabolic Metabolism Methods Mitochondria Modeling Molecular Genetics Mutation Myelogenous Myeloid Cells Natural regeneration Niacinamide Nicotinamide adenine dinucleotide Nonhomologous DNA End Joining Normal Cell Outcome Outcome Study Oxidative Phosphorylation Oxygen Consumption Pathogenesis Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacodynamics Phase I Clinical Trials Phase Ib/II Trial Phenotype Poly(ADP-ribose) Polymerases Polymerase Population Process Proliferating Property Proteins Refractory Relapse Retina Role Signal Transduction Solid Neoplasm Stem cell transplant Testing Therapeutic Therapeutic Agents Thrombocytopenia Time Toxic effect Toxicology Xenograft procedure acute myeloid leukemia cell base cytotoxic disease heterogeneity disease natural history gastrointestinal high risk population homologous recombination improved in vivo inhibitor/antagonist leukemia leukemia initiating cell molecular subtypes mouse model neoplastic cell nicotinamide phosphoribosyltransferase novel novel strategies novel therapeutics outcome forecast overexpression phase 1 study phase 1 testing pre-clinical preclinical toxicity preservation relapse patients repaired response self-renewal success targeted agent targeted treatment therapeutic target treatment strategy tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY Acute Myeloid Leukemia (AML) is a heterogeneous disease characterized by an accumulation of rapidly proliferating neoplastic cells of the myeloid lineage with differentiation defects. The hallmarks of leukemic cells in AML include increased cell survival, as well as altered cellular metabolism and mitochondrial functionality. In spite of the vast amount of information known about AML and the identification of favorable prognosis factors, a very large proportion of patients relapse and die from their disease. The inter- and intra-tumor heterogeneity of AML makes the identification of therapeutic targets for this disease particularly challenging. Therefore, there is an urgent need to identify multi-targeted agents that could target AML as a composite disease. Nicotinamide phosphoribosyltransferase (NAMPT) is a protein involved in the generation of NAD+ in tumor cells. Leukemic blasts show a higher NAD+ turnover rate than normal cells, suggesting that NAD+ biosynthesis could be critically required in hematologic malignancies and therefore targeting the regeneration of NAD+ offers an attractive alternative strategy in AML. Unlike many targeted therapies that can only be directed at one genetic/molecular subtype of AML, targeting regeneration of NAD+ via NAMPT inhibition could be relevant to a much broader group based upon the metabolic differences between tumor and normal cells. While two agents targeting NAMPT have been tested in Phase I clinical trials, dose-limiting toxicities including thrombocytopenia and gastrointestinal toxicities led to their clinical discontinuation. Novel compounds with improved tolerability are needed. Our studies utilize a novel NAMPT inhibitor, KPT-9274, developed by Karyopharm Therapeutics for which our data demonstrate potent cytotoxic effects in AML cell lines and primary AML blasts in vitro and in vivo. Preliminary toxicology data shows acceptable properties of KPT-9274, which differentiate it from other previously examined NAMPT inhibitors. KPT-9274 is currently being examined in a phase 1 study for solid tumor patients. Our preliminary data demonstrates that inhibition of NAMPT using KPT-9274, leads to increased apoptosis and decreased proliferation of AML cell lines and primary AML cells with minimal toxicity in normal hematopoietic cells. KPT-9274 was also able to prolong the time to disease progression in vivo and improve overall survival in an AML cell line-disseminated xenograft mouse model. With this proposal we aim to 1) to determine how NAMPT affects metabolism and self-renewal in AML immature myeloid cells and their normal counterparts while examining for distinct subtypes of AML that might be exquisitely sensitive to this class of drugs; 2) test rational combination therapies as well as identify novel synthetic lethal partners with NAMPT inhibitors; and 3) to initiate a Phase Ib/II trial with KPT-9274 as single agent priming followed by combination with decitabine that includes detailed pharmacodynamic assessment in patients with relapsed and refractory AML. At completion of this project it is anticipated that the approaches brought forward will lead to new treatment strategies involving NAMPT inhibition with KPT-9274 in patients with AML.

项目摘要急性髓样白血病（AML）是一种异质疾病，其特征是迅速积累髓样谱系的增殖肿瘤细胞具有分化缺陷。白血病细胞的标志在AML中包括增加的细胞存活以及细胞代谢和线粒体功能的改变。在有大量有关AML的信息以及有利的预后因素的识别，A 很大一部分患者复发并死于疾病。肿瘤内和肿瘤内异质性 AML鉴定了该疾病的治疗靶标，特别具有挑战性。因此，有迫切需要确定可以将AML作为复合疾病的多靶向药物。烟酰胺磷酸贝糖基转移酶（NAMPT）是一种参与肿瘤细胞中NAD+产生的蛋白质。白血病爆炸显示出比正常细胞更高的NAD+周转率，这表明NAD+生物合成可能是至关重要的血液学恶性肿瘤中需要，因此针对NAD+的再生提供了一种吸引力的 AML中的替代策略。与许多只能针对一个遗传/分子的靶向疗法不同 AML的亚型，针对NAD+通过NAMPT抑制的再生可能与更广泛的群体有关基于肿瘤和正常细胞之间的代谢差异。而两个针对nampt的代理有在I期临床试验中进行了测试，包括血小板减少症和胃肠道的剂量限制性毒性毒性导致了他们的临床中断。需要具有提高耐受性的新型化合物。我们的研究利用一种新型的NAMPT抑制剂KPT-9274，由Karyopharm Therapeutics开发在体外和体内证明了在AML细胞系和原代AML爆炸中的有效细胞毒性作用。初步的毒理学数据显示了KPT-9274的可接受特性，该特性与其他先前检查的 NAMPT抑制剂。目前，正在针对实体瘤患者的1期研究中检查KPT-9274。我们的初步数据表明，使用KPT-9274抑制NAMPT，导致凋亡增加和在正常造血的毒性中，AML细胞系和原代AML细胞的增殖减少细胞。 KPT-9274还能够延长体内疾病进展的时间，并提高整体生存率 AML细胞线 - 触发异种移植小鼠模型。通过此建议，我们的目标是1）确定份额如何影响AML未成熟髓样细胞及其正常对应物的新陈代谢和自我更新检查可能对这类药物非常敏感的AML的不同亚型； 2）测试理性组合疗法以及与NAMPT抑制剂一起鉴定新的合成致死伙伴； 3）发起与KPT-9274的IB/II期试验作为单剂启动复发和难治性AML患者的详细药效学评估。完成此完成预计所带来的方法将导致涉及的新治疗策略 AML患者对KPT-9274的NAMPT抑制。