Overcoming Resistance to KIT/PDGFRA Inhibition in GIST

克服 GIST 中对 KIT/PDGFRA 抑制的耐药性

• 批准号: 8485721
• 负责人: JONATHAN Alfred FLETCHER
• 金额: $ 19.28万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-31 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485721
• 关键词: Basic Science; Biological Markers; Cell Proliferation; Clinical; Clinical Trials; Combined Modality Therapy; Dana-Farber Cancer Institute; Human; Imatinib; Imatinib mesylate; MAP Kinase Gene; MEKs; Malignant Neoplasms; Measurable Disease; Metastatic Lesion; Mutation; Oncogenic; Oral; PDGFRA gene; Pathway interactions; Patients; Phase; Phosphotransferases; Research; Resistance; Resistance development; Signal Transduction; Specificity; Supporting Cell; Translating; clinical application; clinically relevant; design; gain of function; inhibitor/antagonist; mutant; resistance mechanism; response; therapeutic target; therapy development

This proposal seeks effective combination therapies that maximize GIST response to KIT/PDGFRA inhibition by concurrently targeting the biologically key MEK/MAPK pathway. Most GISTs express mutant, constitutively activated forms of the KIT or PDGFRA, and we have shown that these formerly untreatable cancers can be palliated in 80% of patients by oral single-agent therapy with imatinib mesylate. However, patients responding to imatinib have persistent measurable disease and generally develop resistance within two years of starting treatment. Therefore, more effective and broader-spectrum therapies are urgently needed. Notably, our preliminary studies show that KIT/PDGFRA imatinib resistance mechanisms vary from patient to patient, and also between metastatic lesions in a given patient, but uniformly rely upon MEK/MAPK signaling to support cell proliferation. In Aim 1, by studying MEK/MAPK signaling and response mechanisms, we will develop clinically-relevant biomarkers and - most importantly - we will identify alternate MEK-dependent therapeutic targets which might have greater specificity, in GIST, compared to MEK. In Aim 2, we will characterize mechanisms of MEKi resistance, since such studies are likely to identify biologically essential regulatory nodes in MEK/MAPK-pathways, which - like those found in Aim 1 - will be candidates as biomakers and therapeutic targets in GIST clinical trials. The collective studies in Aims 1-2, by revealing the scope of MEK/MAPK signaling in GIST, will provide the understanding needed to design more effective and less toxic clinical trials. In Aim 3 we evaluate combination therapies with imatinib and MEKi, as a strategy to inhibit downstream signals from the varied gain-of-function KIT mutations each imatinib-resistant patient, while maintaining imatinib inhibition of nonprogressing GIST subclones. This will be accomplished through a phase l/II clinical trial of the MEK inhibitor, MEKI62, combined with imatinib, in patients showing progression of metastatic GIST on imatinib or sunitinib. Through these studies, we will translate the basic science proposed in this SPORE through to clinical application.

该提案寻求有效的组合疗法，通过同时靶向生物学关键的MEK/MAPK途径，从而最大程度地提高了对套件/PDGFRA抑制的反应。大多数GIST表示试剂盒或PDGFRA的组成型激活形式，我们已经表明，这些以前不可治疗的癌症可以通过伊马替尼的口服单药疗法在80％的患者中抑制80％的患者。但是，对伊马替尼反应的患者患有可衡量的疾病，通常在开始治疗的两年内发展抗药性。因此，迫切需要更有效和更广泛的疗法。值得注意的是，我们的初步研究表明，试剂盒/PDGFRA伊马替尼的耐药机制因患者而异，并且在给定患者的转移性病变之间，但均匀地依赖MEK/MAPK信号来支持细胞增殖。在AIM 1中，通过研究MEK/MAPK信号传导和响应机制，我们将开发与临床上相关的生物标志物，并且 - 最重要的是 - 我们将确定与MEK相比，GIST可能具有更大特异性的MEK依赖性治疗靶标。在AIM 2中，我们将表征MEKI耐药性的机制，因为此类研究很可能会在MEK/MAPK -Pathways中识别生物学上必不可少的调节节点，就像在AIM 1中发现的那样 - 在AIM 1中发现的是候选者作为生物制造商和GOIS临床试验中的治疗靶标的候选者。 AIMS 1-2中的集体研究通过揭示要点中MEK/MAPK信号的范围，将提供设计更有效和毒性较小的临床试验所需的理解。在AIM 3中，我们评估了与伊马替尼和MEKI的组合疗法，作为一种抑制各种功能收益试剂盒突变的策略，同时维持伊马替尼对非促进性GIST子球的抑制作用。这将通过MEK抑制剂MEKI62的L/II期临床试验与伊马替尼相结合，在伊马替尼或苏尼替尼的转移性要点进展中。通过这些研究，我们将把孢子中提出的基础科学转换为临床应用。