Overcoming Resistance to KIT/PDGFRA Inhibition in GIST

该提案寻求有效的联合治疗，通过同时靶向生物学关键的MEK/MAPK通路，使GIST对KIT/PDGFRA抑制的反应最大化。大多数GIST表达突变的、组成性激活形式的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具有持续的可测量的疾病，并且通常在开始治疗的两年内产生耐药性。因此，迫切需要更有效和更广谱的治疗方法。值得注意的是，我们的初步研究表明，KIT/PDGFRA伊马替尼耐药机制因患者而异，并且在给定患者的转移性病变之间也不同，但一致地依赖于MEK/MAPK信号传导来支持细胞增殖。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中可能具有更大的特异性。在目标2中，我们将描述MEKi抗性的机制，因为这样的研究很可能识别MEK/MAPK通路中的生物学必需的调控节点，这些节点-像目标1中发现的那些-将成为GIST临床试验中的生物标志物和治疗靶点的候选者。目的1-2中的集体研究通过揭示GIST中MEK/MAPK信号传导的范围，将提供设计更有效和毒性更小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，作为抑制每个伊马替尼耐药患者不同功能获得性KIT突变的下游信号的策略，同时维持伊马替尼对非进展性GIST亚克隆的抑制。这将通过MEK抑制剂MEKI 62与伊马替尼联合在伊马替尼或舒尼替尼治疗显示转移性GIST进展的患者中进行的I/II期临床试验来实现。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。

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.