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

体内成像方法的开发和新型 Inhi 的效果

基本信息

批准号：
7729470
负责人：
NEAL ROSEN
金额：
$ 12.25万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729470
关键词：
17-(Allylamino)-17-demethoxygeldanamycin 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin Allosteric Site Androgen Receptor Animal Model Animals Antibodies Antitumor Response BRAF gene Binding Binding Proteins Biochemical Biological Assay Biological Factors Biology CCI-779 Cancer Biology Cells Choline Clinic Clinical Clinical Research Clinical Trials Collaborations Combined Modality Therapy Complex Cultured Cells Cyclin D1 DNA biosynthesis DNA chemical synthesis Daily Data Development Diffuse Dose Drug Delivery Systems Drug effect disorder ERBB2 gene Epidermal Growth Factor Receptor Evaluation Extracellular Domain Family Functional Imaging G1 Phase Gallium Geldanamycin Goals Grant HRAS gene Half-Life Histone Deacetylase Hour Human Image Imaging technology Immunoglobulin Fragments Immunohistochemistry Insulin-Like-Growth Factor I Receptor Invasive Isotopes Kinetics Knowledge Light MEK inhibition MEKKs MEKs Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Mediating Membrane Memorial Sloan-Kettering Cancer Center Metabolism Methodology Methods Mitogen-Activated Protein Kinases Modality Modeling Molecular Chaperones Mus Mutate Mutation Neoplasm Metastasis Oncogene Proteins PTEN gene Pathway interactions Patients Peptide antibodies Pharmaceutical Preparations Pharmacodynamics Phase Phase II Clinical Trials Phosphotransferases Positron Positron-Emission Tomography Property Protein Kinase Protein Tyrosine Kinase Proteins Proteomics Proto-Oncogene Proteins c-akt Ras/Raf Reagent Reporter Resistance Roche brand of trastuzumab Schedule Signal Pathway Signal Transduction Signal Transduction Inhibitor Signal Transduction Pathway Staining method Stains System Techniques Technology Testing Thymidine Time Tissues Translating Translations Trastuzumab Tumor Biology Tumor Tissue Work Xenograft procedure base concept fluorodeoxyglucose positron emission tomography human FRAP1 protein human MAP3K1 protein human study in vivo in vivo Cellular and Molecular Imaging Centers inhibitor/antagonist interest kinase inhibitor malignant breast neoplasm melanoma member method development multicatalytic endopeptidase complex mutant novel pre-clinical preclinical study response small molecule tissue culture tumor tumor xenograft uptake

项目摘要

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.

项目4致力于开发用于成像选择性抑制剂体内影响的方法癌症中激活信号转导途径的组成部分以及将这些方法转换为诊所。实施目标治疗的主要障碍是无法确定该药物在肿瘤中的药效学和生物学作用，定量和随时间的函数。我们已经开发了一种用于成像HSP90抑制剂的药效学的方法，诱导的药物包括HER2在内的各种癌蛋白的降解。我们构建了一个f（ab'）2 trastuzamab螯合到正电子同位素（例如68GA）。该试剂允许定量在用HSPQO抑制剂17-治疗的动物中HER2表达丧失的肿瘤异种移植物中的成像 AAG。现在，我们建议使用该试剂来确定17-AAG和其他其他的药效学作用基于这些药物药效数据。该方法为成像其他药物的影响提供了一个平台。这会包括鉴定蛋白质具有细胞外域的蛋白质，其表达在细胞中迅速变化用靶向药物处理，开发有选择性结合的抗体，肽或其他分子紧密地与该蛋白质并将结合分子螯合到可成像的同位素上。我们建议对此进行测试通过尝试开发试剂来成像MEK和MEK选择性抑制剂的影响的概念 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。我们建议使用成像将随着时间的函数相关联 HER2表达随肿瘤代谢的变化（FDG PET，胆碱NMR）和DMA抑制合成（FLT PET）。对某些靶标的抑制可能具有特定的，深刻的细胞作用。使用传统技术，我们已经确定MEK激酶抑制剂抑制了BRAF突变的肿瘤有选择地和有效的，这种抑制与完整的逮捕有关。我们已经成像了对FLT PET的效果，现在正计划将此方法纳入抑制剂的第二阶段试验中。这工作的长期重点是使用该技术探测途径的生物学效应抑制剂并加速其临床翻译。