Development of Methodologies for the In Vivo Imaging og the Effects of Novel Inhi

项目4致力于开发用于成像选择性抑制剂的体内作用的方法， 癌症中激活的信号转导途径的组成部分以及这些方法的翻译 诊所实施靶向治疗的一个主要障碍是无法确定靶向治疗的靶向剂量。 药物在肿瘤中的药效学和生物学效应，定量地和作为时间的函数。我们 已经开发了一种方法，用于成像热休克蛋白90抑制剂的药效学，药物诱导 包括HER 2在内的各种癌蛋白的降解。我们构建了一个F（ab '）2片段， 与正电子发射同位素如68 Ga螯合的曲妥珠单抗。该试剂允许定量 在用HspQO抑制剂17治疗的动物中HER 2表达丧失的肿瘤异种移植物中成像， AAG。我们现在建议使用该试剂来确定17-AAG和其他药物的药效学作用。 HspQO抑制剂的临床试验，并计划与这种药物的组合试验基于这些 药效学数据。这种方法为其他药物的作用成像提供了一个平台。这将 包括鉴定具有细胞外结构域的蛋白质，所述蛋白质的表达在细胞中迅速变化， 用靶向药物治疗，开发选择性结合的抗体、肽或其他分子， 并将结合分子与可成像同位素螯合。我们打算测试一下 通过尝试开发用于成像MEK的选择性抑制剂的作用的试剂， mTOR激酶。这项技术使我们能够将药物的药效学与生物学相关联， 目标抑制的后果。我们建议使用成像来关联作为时间函数的 HER 2表达与肿瘤代谢变化（FDG PET，胆碱NMR）和DMA抑制 合成（FLT PET）。对某些靶点的抑制可能具有特定的、深刻的细胞效应。使用 传统技术，我们已经确定MEK激酶抑制剂抑制BRAF突变的肿瘤 选择性地和有效地，抑制与完全逮捕有关。我们想象了一下 FLT PET的效果，现在正计划将这种方法纳入抑制剂的2期试验。的 这项工作的一个广泛的、长期的重点是使用这项技术来探测途径的生物学效应。 抑制剂并加速其临床转化。

Project 4 is dedicated to the development of methods for imaging the in vivo effects of selective inhibitors of components of activated signal transduction pathways in cancer and the translation of these methods to the clinic. A major obstacle to the implementation of targeted therapy is the inability to determine the pharmacodynamics and biologic effects of the drug in the tumor, quantitatively and as a function of time. We have developed a method for the imaging of the pharmacodynamics of Hsp90 inhibitors, drugs that induce the degradation of various oncoproteins including HER2. We constructed an F(ab')2 fragment of trastuzamab chelated to positron emitting isotopes such as 68Ga. This reagent allowed the quantitative imaging in tumor xenografts of the loss of HER2 expression in animals treated with the HspQO inhibitor 17- AAG. We now propose to use this reagent to determine the pharmacodynamic effects of 17-AAG and other HspQO inhibitors in clinical trials and to plan combination trials with this drug based on these pharmacodynamic data. This method provides a platform for imaging the effects of other drugs. This will comprise identifying proteins with extracellular domains, the expression of which changes rapidly in cells treated with the targeted drug, developing an antibody, peptide or other molecule that binds selectively and tightly to this protein and chelating the binding molecule to an imageable isotope. We propose to test this concept by attempting to develop reagents for imaging the effects of selective inhibitors of the MEK and mTOR kinases. This technology allows us to correlate the pharmacodynamics of the drug with the biologic consequences of target inhibition. We propose to use imaging to correlate, as a function of time, changes in HER2 expression with changes in tumor metabolism (FDG PET, choline NMR) and inhibition of DMA synthesis (FLT PET). Inhibition of certain targets may have specific, profound cellular effects. Using traditional techniques, we have determined that MEK kinase inhibitors inhibit tumors with BRAF mutation selectively and potently and that inhibition is associated with completed arrest. We have imaged this effect with FLT PET and are now planning to incorporate this method into Phase 2 trials of the inhibitor. The broad, long-term focus of the work is the use of this technology to probe the biologic effects of pathway inhibitors and to accelerate their clinical translation.