Imaging the Effects of Inhibition of Oncogene Signaling on Tumor Growth and....

研究项目3(RP3)的中心主题是使用选择性靶向抑制剂进行生物发现 人类癌症中最常被激活的两条信号转导通路：RAS/RAF/ERK 和PI3K/AKT/MT0R。目前正在开发多种RAF、MEK、P13K、AKT和mTOR的抑制剂，用于 这些肿瘤的治疗。在这份提案中。PET和MRI的分子成像(ML)可作为一种 了解靶抑制和优化这些治疗方案的指南。这项工作是基于 本课题组最近在通路调节和功能方面的基础研究；抑制剂对 这些途径的组成部分；用于成像途径抑制和肿瘤的ML模式的发展 临床前模型和患者的反应。RAF抑制剂PLX4032近期临床试验 有突变BRAF的黑色素瘤在很大程度上是基于我们的基本发现，并导致85%的临床 应答率，并作为靶向这些通路的效用的原则证明(NEJM 2010年；363：809-19)。ERK信号驱动肿瘤的增殖，在这种情况下它被激活，我们有 结果表明，利用Flt/PET(癌症研究)可以有效地对该途径的抑制进行成像。 67：11463-9)，相比之下，PI3K/AKT/mTOR信号调节葡萄糖稳态和FDG摄取 对mTOR抑制剂非常敏感。这些数据表明，m1既是一种衡量 药效学途径抑制和肿瘤反应，以及肿瘤生物学的其他变化。为 例如，在最近的试验中，我们发现抑制ERK通路可以诱导碘转运体和碘 突变BFIAF对肿瘤亲和力的影响RPS研究计划由休耕的具体目标组成。 选择性抑制P13K信号转导通路在肿瘤中的作用 路径。SA2：成像选择性抑制ERK信号通路在突变BRAF肿瘤中的作用。 SA3：成像使用P13K或ERK信号通路抑制剂的联合治疗的效果。少校 该项目的目标是开发成像作为一种工具，用于测量 靶向药物在抑制通路、肿瘤生物学和肿瘤生长方面的作用。我们正在使用的抑制剂都是 或即将进入试验，其主要限制是无法评估途径抑制或 理性地选择组合，所以我们希望这个项目中的发现能得到快速翻译，并 有重大的临床影响。

The central theme of Research Project 3 {RP3) is biologic discovery with selective targeted inhibitors of the two signal transduction pathways that are activated most frequently in human cancer: RAS/RAF/ERK and PI3K/AKT/MT0R. Multiple inhibitors of RAF, MEK, P13K, AKT, and mTor are now being developed for the treatment of these tumors. In this proposal. Molecular Imaging (Ml) with PET and MRI w/ill be used as a guide for understanding target inhibition and optimizing these therapeutic regimens. This work is based on recent fundamental studies from our group on pathway regulation and function; effects of inhibitors on components of these pathway; development of Ml modalities for imaging pathway inhibition and tumor response in preclinical models and patients. The recent clinical trial of the RAF inhibitor PLX4032 in melanomas with mutant BRAF was based in large part on our basic findings and resulted in an 85% clinical response rate and serves as proof of principle for the utility of targeting these pathways (NEJM 2010;363:809-19). ERK signaling drives the proliferation of tumors in which it is activated and we have shown that inhibition of the pathway can be imaged effectively with by FLT/PET (Cancer Res. 2007;67:11463-9), In contrast, PI3K/AKT/mTor signaling regulates glucose homeostasis and FDG uptake is very sensitive to mTor inhibitors. These data suggest a role for Ml both as a measure of pharmacodynamic pathway inhibition and tumor response, as well as other changes in tumor biology. For instance, in recent trials, we showed that ERK pathway inhibition induces the iodide transporter and iodine avidity of tumors with mutant BFIAF. The RPS research plan is comprised of the fallowing specific aims. SAl; .Imaging the effects of selective inhibition of P13K signaling in tumors with mutational activation of the pathway. SA2: Imaging the effects of selective inhibition of ERK signaling in tumors with mutant BRAF. SA3: Imaging the effects of combination therapy utilizing inhibitors of P13K or ERK signaling. The major goal of the project is to develop imaging as a tool for measuring the quantitative and temporal effects of targeted drugs on pathway inhibition, tumor biology and tumor growth. The inhibitors we are using are all in or about to enter trials, the major limitations of which are the inability to assess pathway inhibition or to rationally choose combinations, so we expect the findings in this project to be rapidly translated and to have a major clinical impact.