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.

项目概要急性髓系白血病 (AML) 是一种异质性疾病，其特征是快速积累具有分化缺陷的骨髓系增殖性肿瘤细胞。白血病细胞的特征 AML 中的改变包括细胞存活率的提高，以及细胞代谢和线粒体功能的改变。在尽管关于 AML 和有利预后因素的识别有大量已知信息，但很大一部分患者复发并死于疾病。肿瘤间和肿瘤内的异质性 AML 使得确定这种疾病的治疗靶点变得尤其具有挑战性。因此，有迫切需要确定可以针对 AML 作为复合疾病的多靶点药物。烟酰胺磷酸核糖基转移酶 (NAMPT) 是一种参与肿瘤细胞中 NAD+ 生成的蛋白质。白血病原始细胞显示出比正常细胞更高的 NAD+ 周转率，表明 NAD+ 生物合成可能至关重要血液系统恶性肿瘤所需，因此针对 NAD+ 的再生提供了一个有吸引力的选择 AML 中的替代策略。与许多只能针对一种基因/分子的靶向疗法不同 AML 亚型，通过 NAMPT 抑制靶向 NAD+ 再生，可能与更广泛的群体相关基于肿瘤细胞和正常细胞之间的代谢差异。虽然两种针对 NAMPT 的药物已经过 I 期临床试验，剂量限制性毒性包括血小板减少症和胃肠道毒性毒性导致其临床终止。需要具有改善的耐受性的新型化合物。我们的研究利用由 Karyopharm Therapeutics 开发的新型 NAMPT 抑制剂 KPT-9274，我们的数据在体外和体内证明对 AML 细胞系和原代 AML 母细胞具有有效的细胞毒性作用。初步的毒理学数据显示 KPT-9274 具有可接受的特性，这将其与之前检查的其他产品区分开来 NAMPT 抑制剂。 KPT-9274 目前正在实体瘤患者的 1 期研究中进行检查。我们的初步数据表明，使用 KPT-9274 抑制 NAMPT 会导致细胞凋亡增加，减少 AML 细胞系和原代 AML 细胞的增殖，对正常造血系统的毒性最小细胞。 KPT-9274 还能够延长体内疾病进展时间并提高总体生存率 AML细胞系传播的异种移植小鼠模型。通过此提案，我们的目标是 1) 确定 NAMPT 如何影响 AML 未成熟骨髓细胞及其正常对应细胞的代谢和自我更新，同时检查可能对此类药物极其敏感的 AML 不同亚型； 2）测试理性联合疗法以及利用 NAMPT 抑制剂识别新型合成致死伙伴； 3) 启动使用 KPT-9274 作为单一药物启动，然后与地西他滨联合进行的 Ib/II 期试验，包括对复发性和难治性 AML 患者进行详细的药效学评估。完成此操作后项目预计提出的方法将导致新的治疗策略，其中包括 KPT-9274 对 AML 患者的 NAMPT 抑制作用。