Research Project 1 - Targeting the MAPK and PI3K pathways in melanoma PDX

项目摘要-项目1 黑色素瘤细胞移植到免疫缺陷小鼠后适应良好，该组已建立>450 PDX，它使我们能够深入识别最适合选定药物的肿瘤亚组。 PDX已被广泛表征其体外和体内生长特性，包括 转移形成，通过靶向测序在108个基因中的体细胞突变，以及305个 与信号转导相关的蛋白质。这些模型非常适合研究两种主要的途径， 在黑色素瘤和大多数其他癌症中始终被激活：MAPK和PI 3 K通路。我们的整体 工作假设是，我们可以预测治疗反应的基础上，遗传，基因组和生物 肿瘤的特征我们希望，我们可以定义，一个完整的个性化的方法， 黑色素瘤将以可预测的方式对新疗法和新疗法组合作出反应。使用 通过NCI-CTEP可获得的药物，我们将在第一个目标中定义那些最常见的黑色素瘤。 对MET抑制剂与MAPK抑制剂的组合敏感。我们还将研究多激酶 抑制剂作为单一药剂以及与MAPK抑制剂组合。我们的工作假设是， 黑色素瘤亚组、MET以及其他受体酪氨酸激酶（PDGFR β、VEGFR、c-KIT、FGFR 1） 和非受体激酶（SRC）是重要的靶点。我们希望开发出生物标记物， 那些对激酶抑制最敏感（或最不敏感）的黑素瘤。在第二个目标中，我们将定义 对MAPK和PI 3 K途径的联合抑制最敏感的黑色素瘤。我们的工作 一种假设是，存在BRAF突变型黑色素瘤的亚组，其高度易感于 BRAF/MEK与PI 3 K抑制剂的组合。基于我们的初步研究，我们将使用PTEN的缺失作为 一种用于选择的生物标志物，但期望进一步改进，特别是对于BRAF耐药的肿瘤， BRAF/MEK抑制剂。由于IGFR-1主要通过PI 3 K途径进行信号传导， 由于黑色素瘤是获得性耐药的关键因素，我们将包括适当的CTEP抑制剂。在同一 时间，我们将确定是否亚型特异性PI 3 K抑制剂更适合与 MAPK抑制剂。我们期望定义用于选择初治和BRAF/MEK的生物标志物 耐药肿瘤。我们的研究应该为启动临床试验提供强有力的理由。

Project Summary – Project 1 Melanoma cells adapt well when transplanted to immune-deficient mice and the group has established >450 PDX, which allow us to identify in-depth those subgroups of tumors that are most suitable for selected drugs. The PDX have been extensively characterized for their growth properties in vitro and in vivo including metastasis formation, somatic mutations in 108 genes through targeted sequencing, and expression of 305 proteins related to signal transduction. The models are superbly suited to investigate two major pathways that are consistently activated in melanoma and in most other cancers: MAPK and PI3K pathways. Our overall working hypothesis is that we can predict therapy responses based on the genetic, genomic, and biologic signatures of tumors. We expect that we can define, short of a complete personalized approach, subgroups of melanomas that will respond to new therapies and new combinations of therapies in a predictable way. Using drugs that are available through NCI-CTEP, we will define in the first aim those melanomas that are most sensitive to inhibitors of MET in combination with MAPK inhibitors. We will also investigate multi-kinase inhibitors as single agents and in combination with MAPK inhibitors. Our working hypothesis is that in subgroups of melanomas, MET as well as other receptor tyrosine kinases (PDGFRß, VEGFR, c-KIT, FGFR1) and non-receptor kinases (SRC) are important targets. We expect to develop biomarkers that will pinpoint those melanomas that are most (or least) susceptible to kinase inhibition. In the second aim, we will define melanomas that are most sensitive to combined inhibition of the MAPK and PI3K pathways. Our working hypothesis is that a subgroup of BRAF-mutant melanomas exists, which is highly susceptible to the combination of BRAF/MEK with PI3K inhibitors. Based on our preliminary studies we will use loss of PTEN as one biomarker for selection but expect further refinements, especially for tumors resistant to BRAF and BRAF/MEK inhibitors. Since IGFR-1 signals predominantly through the PI3K pathway and is in selected melanomas a key player in acquired resistance, we will include the appropriate CTEP inhibitor(s). At the same time, we will determine whether isoform specific PI3K inhibitors are more appropriate in combination with MAPK inhibitors. We expect to define biomarkers for the selection of both treatment-naïve and BRAF/MEK inhibitor-resistant tumors. Our studies should provide a strong rationale for initiating clinical trials.