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Targeting FL3 and SRC kinases for AML therapy

靶向 FL3 和 SRC 激酶进行 AML 治疗

基本信息

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
项目类别：
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

项目摘要

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.

摘要