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身上适应良好，该小组已经建立了&gt；450 PDX，它使我们能够深入识别最适合所选药物的肿瘤亚群。 PDX在体外和体内的生长特性已被广泛表征，包括 靶向测序108个基因的体细胞突变和305的表达 与信号转导相关的蛋白质。这些模型非常适合于研究两条主要的路径， 在黑色素瘤和大多数其他癌症中持续激活：MAPK和PI3K通路。我们的整体 工作假设是，我们可以根据遗传、基因组和生物因素预测治疗反应。 肿瘤的特征。我们希望，在没有完全个性化的方法的情况下，我们可以定义 黑色素瘤将以可预测的方式对新的治疗方法和新的治疗组合产生反应。vbl.使用 通过NCI-CTEP获得的药物，我们将在第一个目标中定义最常见的黑色素瘤 对MET抑制剂和MAPK抑制剂联合使用敏感。我们还将研究多激酶 抑制剂作为单一药物，并与MAPK抑制剂联合使用。我们的工作假设是，在 黑色素瘤亚群、MET和其他受体酪氨酸激酶(PDGFR？、VEGFR、c-KIT、FGFR1) 而非受体激酶(SRC)是重要的靶点。我们希望开发出能够精确定位的生物标志物 那些最容易(或最不容易)受到激酶抑制影响的黑色素瘤。在第二个目标中，我们将定义 对MAPK和PI3K通路的联合抑制最敏感的黑色素瘤。我们的工作 假说是存在BRAF突变型黑色素瘤的一个亚群，它对 BRAF/MEK与PI3K抑制剂联合应用。根据我们的初步研究，我们将PTEN的损失作为 一个用于选择的生物标记物，但预计会有进一步的改进，特别是对于耐BRAF和 BRAF/MEK抑制剂。由于IGFR-1信号主要通过PI3K途径并被选择 黑色素瘤是获得性耐药的关键因素，我们将纳入适当的CTEP抑制剂(S)。同时 时间，我们将确定异构体特异性PI3K抑制剂是否更适合与 MAPK抑制剂。我们希望定义用于选择治疗的生物标记物--NAYVE和BRAF/MEK 具有抑制剂耐药性的肿瘤。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.