Novel drug to treat poor prognosis AML

治疗预后不良的 AML 的新药

• 批准号: 10443887
• 负责人: Reuben Kapur
• 金额: $ 18.03万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443887
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adult; Biological; Biological Assay; Biology; Cell Culture Techniques; Cells; Clinic; Clinical Trials; Complex; Cyclic GMP; Data; Disease remission; Drug resistance; FLT3 gene; Gatekeeping; Goals; Growth; Hematopoietic stem cells; High Prevalence; In Vitro; Incidence; Karyotype; Leukemic Cell; Membrane; Modeling; Mus; Mutate; Mutation; Myeloproliferative disease; Naphthyridines; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Point Mutation; Positioning Attribute; Prognosis; Prognostic Marker; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recurrent disease; Refractory; Relapse; Reporting; Resistance; Resistance development; Series; Small Business Innovation Research Grant; Structure-Activity Relationship; Therapeutic; Translating; United States Food and Drug Administration; acute myeloid leukemia cell; analog; antileukemic activity; base; cell transformation; clinically significant; hematopoietic stem cell self-renewal; high risk; in vivo; inhibitor; leukemia treatment; mouse model; mutant; nanomolar; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; prognostic of survival; resistance mechanism; response; standard of care; targeted treatment

PROJECT SUMMARY/ABSTRACT The incidence of acute myeloid leukemia (AML) has been on the rise. Activating mutations in the fms like tyrosine kinase 3 (FLT3) are present in 25-30% of AML, ~10% of myelodysplastic (MDS) and 5-6% of acute lymphoblastic leukemia (ALL) patients. The common mutations include missense point mutations in the kinase domain, in frame deletions and internal tandem duplications (ITD) in the juxta membrane domain leading to constitutive activation of the receptor tyrosine kinase (RTK) activity. FLT3-ITD is present in ~25% AML patients with normal karyotype and is considered an independent prognostic marker. Patients with FLT3-ITD mutation are at a higher risk of disease relapse and reduced overall 5-year survival. Activating mutations of FLT3 contribute to deregulated proliferation of hematopoietic progenitor cells leading to myeloproliferative neoplasm (MPN). We and others have shown that co-occurrence of mutations that enhance the self-renewal of hematopoietic stem cells (HSC) can transform these cells into AML.However, despite the high prevalence rate and the clinical significance of FLT3 mutations in the pathogenesis of AML, there are limited options for targeted therapy. In 2017, Midostaurin (Rydapt), a multi-kinase inhibitor became the first targeted therapy to be approved by food and drug administration (FDA) for the treatment of AML, followed by Gilteritinib (Xospata), a FLT3 and AXL1 specific inhibitor in 2018. Additional experimental drugs specific for mutant FLT3 in various stages of clinical trials including Quizartinib and Crenolanib have also been described, although they are known to develop both intrinsic and acquired resistance in response to FLT3 targeted therapy the intrinsic resistance in AML to therapy with FLT3 directed inhibitors depends on the presence of co-occurring mutations acquired resistance is due to activation of parallel survival pathways and/or acquisition of secondary mutations in FLT3-ITD. More recently, emergence of RAS mutations has been reported in AML patients treated with Gilteritinib. Thus, there is a critical unmet need to identify and develop potent and selective inhibitor(s) for mutant FLT3 to provide additional therapeutic options for treating AML patients with these mutations. To this end, we have recently identified a novel class of naphthyridine based FLT3 inhibitors that not only selectively target FLT3-ITD at sub-nanomolar concentrations but are also effective against the drug resistance conferring secondary mutations acquired in response to targeted therapy. Based on our preliminary data, we hypothesize that in comparison to recently FDA approved FLT3 inhibitors, including Gilteritinib, we have identified novel and potent drugs with inhibitory activity against FLT3-ITD as well as gatekeeper mutations of FLT3 for a more robust and durable AML treatment. We will utilize two of these inhibitors (KRX-101 & KRX-107; also defined as HSN608 & HSN748, respectively) to further characterize its biological impact on primary de novo AMLs, drug resistant AMLs as well as relapsed/refractory AMLs bearing FLT3 mutations along with other co-occurring mutations.

项目总结/文摘

项目成果

Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells.

• DOI: 10.1016/j.ymthe.2022.04.009
• 发表时间: 2022-07-06
• 期刊: MOLECULAR THERAPY
• 影响因子: 12.4
• 作者: Ramdas, Baskar;Yuen, Lisa Deng;Palam, Lakshmi Reddy;Patel, Roshini;Pasupuleti, Santhosh Kumar;Jideonwo, Victoria;Zhang, Ji;Maguire, Callista;Wong, Eric;Kanumuri, Rahul;Zhang, Chujing;Sandusky, George;Chan, Rebecca J.;Zhang, Chi;Stieglitz, Elliot;Haneline, Laura;Kapur, Reuben
• 通讯作者: Kapur, Reuben