Overcoming Resistance to KIT/PDGFRA Inhibition in GIST

克服 GIST 中对 KIT/PDGFRA 抑制的耐药性

• 批准号: 8933243
• 负责人: JONATHAN Alfred FLETCHER
• 金额: $ 24.03万
• 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/8933243
• 关键词: Basic Science; Biochemical; Biological Assay; Biological Markers; Biopsy; Cell Proliferation; Cells; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complement; Dana-Farber Cancer Institute; Drug resistance; Event; Exhibits; Exposure to; Extinction (Psychology); Failure; Gene Expression Profile; Gene Mutation; Genes; Genetic; Goals; Human; Imatinib; Imatinib mesylate; Intervention; MAP Kinase Gene; MEK inhibition; MEKs; Malignant Neoplasms; Measurable Disease; Metastatic Lesion; Molecular; Mutation; Oncogenic; Oral; PDGFRA gene; PDGFRB gene; Pathway interactions; Patients; Phase; Phosphoproteins; Phosphotransferases; Property; Receptor Protein-Tyrosine Kinases; Regimen; Research; Resistance; Resistance development; Signal Pathway; Signal Transduction; Specificity; Supporting Cell; Testing; Therapeutic; Translating; Translations; Treatment Efficacy; Validation; Work; Xenograft procedure; anticancer activity; bench to bedside; clinical application; clinically relevant; design; exome sequencing; functional genomics; gain of function; inhibitor/antagonist; insight; kinase inhibitor; mutant; novel; pre-clinical; preclinical study; research clinical testing; resistance mechanism; response; small hairpin RNA; success; therapeutic target; therapy development; tumor

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/ll clinical trial of the MEK inhibitor, MEK162, 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.

该提案寻求有效的联合疗法，通过同时靶向生物学上关键的 MEK/MAPK 通路，最大限度地提高 GIST 对 KIT/PDGFRA 抑制的反应。大多数 GIST 表达突变型、组成型激活形式的 KIT 或 PDGFRA，我们已经证明，80% 的患者可以通过口服甲磺酸伊马替尼单药治疗来缓解这些以前无法治疗的癌症。然而，对伊马替尼有反应的患者具有持续的可测量疾病，并且通常在开始治疗后两年内出现耐药性。因此，更有效、更广谱的治疗方法是 急需。值得注意的是，我们的初步研究表明 KIT/PDGFRA 伊马替尼耐药机制 不同患者之间以及特定患者的转移灶之间也存在差异，但统一依赖于 MEK/MAPK 信号传导支持细胞增殖。在目标 1 中，通过研究 MEK/MAPK 信号传导和 反应机制，我们将开发临床相关的生物标志物，最重要的是，我们将 确定替代的 MEK 依赖性治疗靶点，与 MEK 相比，这些靶点在 GIST 中可能具有更高的特异性。在目标 2 中，我们将描述 MEKi 耐药机制，因为此类研究可能会识别 MEK/MAPK 通路中生物学上必需的调节节点，这些节点与目标 1 中发现的节点一样，将成为 GIST 临床试验中生物制造者和治疗靶点的候选者。目标 1-2 中的集体研究通过揭示 GIST 中 MEK/MAPK 信号传导的范围，将提供 需要了解设计更有效和毒性更低的临床试验。在目标 3 中，我们评估 伊马替尼和 MEKi 的联合疗法，作为抑制各种下游信号的策略 每个伊马替尼耐药患者的功能获得性 KIT 突变，同时维持伊马替尼对非进展的抑制 GIST 亚克隆。这将通过 MEK 抑制剂 MEK162 与伊马替尼联合进行的 I/II 期临床试验来实现，试验对象是接受伊马替尼或舒尼替尼治疗后出现转移性 GIST 进展的患者。通过这些研究，我们将把本 SPORE 中提出的基础科学转化为临床应用。