Investigating the mechanism of SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia (AML)

研究急性髓系白血病 (AML) 中 SHP2 和 BCL2 抑制的机制

• 批准号: 10736325
• 负责人: Catherine Choy Smith
• 金额: $ 41.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736325
• 关键词: Acute Myelocytic Leukemia; Address; Adhesions; Affect; American; Apoptosis; BCL2 gene; Biochemical; Cell Survival; Cells; Clinical; Combined Modality Therapy; Development; Disease; FLT3 gene; Genes; Goals; Growth Factor; Knowledge; Leukemic Cell; MAP Kinase Gene; Mediating; Methods; Molecular; Molecular Conformation; Mutation; PTPN11 gene; Pathway interactions; Patients; Protein Tyrosine Phosphatase; Proteomics; Proto-Oncogenes; Receptor Protein-Tyrosine Kinases; Refractory; Relapse; Research; Resistance; Resistance development; Role; Signal Transduction; Time; Transcriptional Activation; Treatment Efficacy; Tyrosine Kinase Inhibitor; Work; acute myeloid leukemia cell; clinical development; efficacy testing; inhibitor; inhibitor therapy; leukemia treatment; multiple omics; mutant; novel; relapse patients; response; response biomarker; small molecule; therapeutic evaluation; treatment strategy

PROJECT SUMMARY/ABSTRACT Background: Mutations in receptor tyrosine kinase (RTK) signaling genes such as Fms-Like Tyrosine Kinase 3 (FLT3) and the KIT proto-oncogene occur in two-thirds of acute myeloid leukemia (AML) and are associated with high relapse rates. FLT3 tyrosine kinase inhibitors (TKIs) are clinically active in FLT3-mutant AML but duration of response is limited by the development of resistance due to re-activation of RAS signaling. No specific proven therapy exists for these relapsed patients or patients with other signaling mutations. Rationale: The protein tyrosine phosphatase SHP2 is a central node in RAS activation and propagation of growth factor signals. SHP2 modulates MAPK pathway activation downstream of RTKs but the full molecular mechanisms of SHP2 activity are not clear. Small molecule allosteric inhibitors of SHP2 such as RMC-4630 stabilize the closed, autoinhibited conformation of SHP2 and are in clinical development. The goal of this application is to leverage new allosteric SHP2 inhibitors (SHP2i) to elucidate the molecular role of SHP2 in RTK-mediated survival in AML and test the efficacy of SHP2i in combination with the BCL2 inhibitor (BCL2i) venetoclax. Methods: We will test the therapeutic efficacy of SHP2i in combination with BCL2i in FLT3 and KIT mutant AML. We will use single cell multiomic sequencing to discover biomarkers of response and resistance. Using biochemical and proteomic approaches, we will assess the effect of SHP2i on RTK signaling in FLT3 and KIT mutant AML cells and associated effects on apoptosis. We will isolate the role of RAS/MAPK transcriptional activation in SHP2-mediated survival and determine the role of SHP2 in adhesion-mediated survival signaling in RTK-driven AML. Expected Results: We anticipate that these studies will uncover new knowledge about the role of SHP2 in leukemic cell survival and facilitate rational development of SHP2i combination therapies, particularly in combination with BCL2i. The overall goal of this work is to develop SHP2 inhibitor therapy as a novel treatment strategy in RTK-driven AML.

项目摘要/摘要 背景：受体酪氨酸激酶（RTK）信号基因（例如FMS）的突变 酪氨酸激酶3（FLT3）和试剂盒原型癌基因出现在三分之二的急性髓样中 白血病（AML）与高复发率有关。 FLT3酪氨酸激酶抑制剂 （TKI）在FLT3突变剂AML中具有临床活性，但响应持续时间受到限制 由于RAS信号的重新激活而产生的电阻。没有特定的经过验证的治疗 这些复发的患者或患有其他信号突变的患者存在。理由： 蛋白质酪氨酸磷酸酶SHP2是RAS激活和传播的中心节点 生长因子信号。 SHP2调节RTK下游的MAPK途径激活 SHP2活性的完整分子机制尚不清楚。小分子变构抑制剂 SHP2（例如RMC-4630）稳定了封闭的自身抑制shp2的构象，并在 临床发展。该应用的目的是利用新的变构SHP2抑制剂 （SHP2I）阐明SHP2在RTK介导的AML中的生存中的分子作用并测试 SHP2I与BCL2抑制剂（BCL2I）Venetoclax结合使用的功效。方法：我们会的 测试SHP2I与BCL2I在FLT3和KIT突变体AML中结合使用的治疗功效。 我们将使用单细胞多构测序来发现反应和抗性的生物标志物。 使用生化和蛋白质组学方法，我们将评估SHP2I对RTK的影响 FLT3和试剂盒突变体AML细胞中的信号传导以及对凋亡的相关作用。我们将 隔离RAS/MAPK转录激活在SHP2介导的生存和 确定SHP2在RTK驱动的AML中粘附介导的存活信号传导中的作用。 预期结果：我们预计这些研究将发现有关角色的新知识 SHP2在白血病细胞存活中的生存，并促进SHP2I组合的合理发展 疗法，特别是与BCL2I结合使用。这项工作的总体目标是发展 SHP2抑制剂疗法是RTK驱动的AML的一种新型治疗策略。