Overcoming Resistance to KIT/PDGFRA Inhibition in GIST

克服 GIST 中对 KIT/PDGFRA 抑制的耐药性

基本信息

  • 批准号:
    8485721
  • 负责人:
  • 金额:
    $ 19.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
这项建议寻求有效的联合疗法,通过同时靶向生物学上关键的MEK/MAPK途径,最大化GIST对KIT/PDGFRA抑制的反应。大多数GIST表达突变的、成分激活的KIT或PDGFRA,我们已经证明,这些以前无法治疗的癌症可以通过口服甲磺酸伊马替尼单药治疗在80%的患者中得到缓解。然而,对伊马替尼有反应的患者有持续的可测量的疾病,通常在开始治疗的两年内产生耐药性。因此,迫切需要更有效、更广谱的治疗方法。值得注意的是,我们的初步研究表明,KIT/PDGFRA伊马替尼的耐药机制因患者而异,在给定患者的转移灶之间也不同,但统一依赖MEK/MAPK信号来支持细胞增殖。在目标1中,通过研究MEK/MAPK信号和反应机制,我们将开发与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耐药的机制,因为这样的研究很可能确定MEK/MAPK通路中的生物关键调控节点,这些节点--就像在AIM 1中发现的那些一样--将成为GIST临床试验中的生物分子和治疗靶点。AIMS 1-2中的集体研究,通过揭示MEK/MAPK信号在GIST中的范围,将提供设计更有效和毒性更低的临床试验所需的理解。在目标3中,我们评估了伊马替尼和Meki的联合治疗,作为一种策略,以抑制每个伊马替尼耐药患者不同功能增益KIT突变的下游信号,同时保持对不进展的GIST亚克隆的伊马替尼抑制。这将通过肌动蛋白激酶抑制剂MEKI62与伊马替尼联合进行的L/II期临床试验来实现,试验对象是服用伊马替尼或舒尼替尼出现转移性胃肠间质瘤进展的患者。通过这些研究,我们将把这一孢子提出的基础科学转化为临床应用。

项目成果

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JONATHAN Alfred FLETCHER其他文献

JONATHAN Alfred FLETCHER的其他文献

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{{ truncateString('JONATHAN Alfred FLETCHER', 18)}}的其他基金

Career Enhancement Program
职业提升计划
  • 批准号:
    10493635
  • 财政年份:
    2022
  • 资助金额:
    $ 19.28万
  • 项目类别:
PROJECT 1: Genomic Vulnerabilities in Leiomyosarcoma (LMS)
项目 1:平滑肌肉瘤 (LMS) 的基因组漏洞
  • 批准号:
    10705729
  • 财政年份:
    2022
  • 资助金额:
    $ 19.28万
  • 项目类别:
Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment
平滑肌肉瘤 (LMS) 的遗传学和基因组学:增进对癌症生物学和诊断和治疗新方法的了解
  • 批准号:
    10705677
  • 财政年份:
    2022
  • 资助金额:
    $ 19.28万
  • 项目类别:
PROJECT 1: Genomic Vulnerabilities in Leiomyosarcoma (LMS)
项目 1:平滑肌肉瘤 (LMS) 的基因组漏洞
  • 批准号:
    10493629
  • 财政年份:
    2022
  • 资助金额:
    $ 19.28万
  • 项目类别:
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
  • 财政年份:
    2007
  • 资助金额:
    $ 19.28万
  • 项目类别:
TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA
干细胞白血病/淋巴瘤中 8-13 的易位
  • 批准号:
    2769908
  • 财政年份:
    1997
  • 资助金额:
    $ 19.28万
  • 项目类别:
TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA
干细胞白血病/淋巴瘤中 8-13 的易位
  • 批准号:
    2388744
  • 财政年份:
    1997
  • 资助金额:
    $ 19.28万
  • 项目类别:
TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA
干细胞白血病/淋巴瘤中 8-13 的易位
  • 批准号:
    2895778
  • 财政年份:
    1997
  • 资助金额:
    $ 19.28万
  • 项目类别:
TUMOR SUPPRESSOR LOCI IN MESOTHELIOMA
间皮瘤中的肿瘤抑制基因座
  • 批准号:
    2390897
  • 财政年份:
    1996
  • 资助金额:
    $ 19.28万
  • 项目类别:
TUMOR SUPPRESSOR LOCI IN MESOTHELIOMA
间皮瘤中的肿瘤抑制基因座
  • 批准号:
    2683616
  • 财政年份:
    1996
  • 资助金额:
    $ 19.28万
  • 项目类别:

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