Targeting FL3 and SRC kinases for AML therapy

靶向 FL3 和 SRC 激酶进行 AML 治疗

• 批准号: 10658259
• 负责人: E Premkumar Reddy
• 金额: $ 23.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658259
• 关键词: Acute Myelocytic Leukemia; Address; Animal Model; Animals; Aspartate; Attention; Binding; Biological Assay; Biological Availability; Biological Models; Bone Marrow; Cell Line; Cell Survival; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Cytarabine; Dasatinib; Daunorubicin; Differentiation and Growth; Disease Progression; Disease remission; Exhibits; FDA approved; FLT3 gene; Genes; Genetic Engineering; Goals; Hematopoietic stem cells; In Vitro; In complete remission; Induction of Apoptosis; MAP Kinase Gene; Malignant - descriptor; Measures; Medical; Methods; Modeling; Molecular Conformation; Mus; Mutagenesis; Mutation; Myeloid Cells; Nature; Nude Mice; Oral; PI3K/AKT; PKC412; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Placebos; Population; Process; Protein Kinase C; Protein Kinase C Inhibitor; Protocols documentation; Receptor Protein-Tyrosine Kinases; Recurrent disease; Relapse; Remission Induction; Resistance; Risk; Route; Signal Pathway; Stat5 protein; Survival Rate; System; Testing; Therapeutic; Work; Xenograft procedure; acute myeloid leukemia cell; chemotherapy; clinically relevant; comparative efficacy; compare effectiveness; drug testing; efficacy evaluation; experimental study; inhibitor; kinase inhibitor; leukemia; leukemia treatment; mutant; neoplastic cell; overexpression; patient derived xenograft model; patient response; pharmacologic; placebo group; relapse patients; resistance mechanism; response; small molecule; small molecule inhibitor; src-Family Kinases; theories; tumor

Abstract Approximately one third of patients suffering from acute myeloid leukemia (AML) harbor an internal tandem duplication in the FLT3 gene (FLT3-ITD), which is clinically associated with an increased rate of relapse in response to standard therapies. As a result, targeted small molecules such as quizartinib, a type 2 FLT3 inhibitor that induces differentiation of AML cells, have garnered attention as a means by which relapsed FLT3-ITD+ AML can be effectively treated. Unfortunately, the median duration response of these patients to quizartinib was found to be 12.1 weeks due to the acquisition of secondary mutations at the D835 locus in the FLT3 gene. A second type 1 inhibitor of FLT3-ITD, midostaurin, was developed by Novartis, which, as a single agent failed to induce complete remission (CR) and when bone marrow was analyzed, there was no significant difference seen between the midostaurin-treated and placebo groups. However, in combination with chemotherapy, the CR rate was 59% compared to 54% CR induced by chemotherapy alone. Midostaurin, in combination with daunorubicin and cytarabine, decreased the risk of AML-related death by 22% compared with placebo and was approved by the FDA for the treatment of AML. To explain the lack of efficacy of midostaurin as a single agent, it has been proposed that AML cells often overexpress SRC family kinases and their elevated expression may provide a survival advantage. This theory was further supported by studies which showed that combination of midostaurin and dasatinib (a SRC inhibitor) were more effective in killing FLT3-ITD+ cell lines (in vitro) than single agent therapy. These observations suggest that there is a need to develop additional FLT3 inhibitors which can induce complete remission in AML patients harboring mutant FLT3. To address this medical need, we developed a compound that inhibits both FLT3 and SRC family kinases (150030). 150030 is a Type I inhibitor that inhibits the FLT3-ITD as well as the D835 mutant forms. Cell viability assays showed that 150030 induced apoptosis of FLT3-mutant AML cells while sparing AMLs with WT-FLT3. 150030 is orally bioavailable, exhibited excellent pharmacological profile and induced complete regression of tumors in nude mouse xenograft assays. The studies proposed are aimed at further evaluating the mechanism of action and therapeutic potential of 150030 in an effort to advance this compound to clinical trials. The aims are: (1) To compare the effects of midostaurin and 150030 on the growth and differentiation of murine myeloid cell line, 32Dcl3, co-expressing FLT3-ITD and SRC family kinases and determine the effects of these two compounds on leukemia progression in syngeneic animal models; (2) To compare the efficacy of 150030 and midostaurin in clinically relevant PDX models of AML to develop protocols for a single agent and combination therapy; and (3) To determine the resistance mechanisms associated with 150030.

抽象的 患有急性髓样白血病（AML）的患者中约有三分之一具有内部 FLT3基因（FLT3-ITD）中的串联重复 响应标准疗法的复发。结果，有针对性的小分子，例如quizartinib，a 诱导AML细胞分化的2型FLT3抑制剂已引起人们的注意作为一种手段 可以有效治疗复发的FLT3-ITD+ AML。不幸的是，中位持续时间响应 在这些患者中，由于获得了二次突变，发现Quizartinib为12.1周 在FLT3基因的D835基因座。开发了第二种类型的1型FLT3-ITD抑制剂Midostaurin 由诺华，作为单个代理商未能诱导完全缓解（CR）和骨髓何时 被分析了，在米德斯托森治疗和安慰剂之间没有显着差异 组。但是，与化学疗法结合使用，CR速率为59％，而CR则为54％ 仅由化学疗法诱导。 Midostaurin，与Daunorubicin和Cytarabine结合使用， 与安慰剂相比，与AML相关死亡的风险降低了22％，并获得了FDA批准 用于治疗AML。为了解释Midostaurin作为单一代理的缺乏疗效，它一直是 提出AML细胞经常过表达SRC家族激酶及其表达升高可能 提供生存优势。研究进一步支持了这一理论，该研究表明 Midostaurin和Dasatinib（SRC抑制剂）的组合更有效地杀死FLT3-ITD+ 细胞系（体外）比单药治疗。这些观察表明，有必要发展 其他可以诱导携带突变体的AML患者完全缓解的FLT3抑制剂 flt3。为了满足这种医疗需求，我们开发了一种抑制FLT3和SRC家族的化合物 激酶（150030）。 150030是I型抑制剂，抑制FLT3-ITD以及D835突变体形式。 细胞活力测定表明，150030诱导FLT3突变剂AML细胞的凋亡 与WT-FLT3的AML。 150030是口服生物利用的，表现出极好的药理特征和 诱导的裸鼠异种移植分析中肿瘤的完全消退。提出的研究针对 进一步评估150030的作用和治疗潜力的机理，以促进 这是临床试验的化合物。目的是：（1）比较Midostaurin和150030对 鼠髓样细胞系的生长和分化32DCL3，共表达FLT3-ITD和SRC 家族激酶并确定这两种化合物对白血病进展的影响 动物模型； （2）比较150030和Midostaurin在临床相关的PDX模型中的功效 AML开发单个药物和联合疗法方案； （3）确定 与150030相关的电阻机制。