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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致力于开发成像选择性抑制剂的体内效应的方法。癌症中激活的信号转导通路的组成以及这些方法在癌症中的翻译诊所。实施靶向治疗的一个主要障碍是无法确定药物在肿瘤中的药效学和生物效应，定量和作为时间的函数。我们已经开发出一种方法来成像Hsp90抑制剂的药效学，这种药物可以诱导包括HER2在内的各种癌蛋白的降解。我们构建了一个F(ab‘)2片段曲妥扎马与发射正电子的同位素如68Ga发生螯合作用。这种试剂使定量的 HspQO抑制剂17-HSPQO治疗的动物移植瘤中HER2表达缺失的显像 AAG。我们现在建议使用这种试剂来测定17-AAG和其他药物的药效学效应 HspQO抑制剂正在进行临床试验，并计划在此基础上与该药物进行联合试验药效学数据。这种方法为成像其他药物的效果提供了一个平台。这将是包括识别具有胞外结构域的蛋白质，这些结构域在细胞内表达变化迅速用靶向药物治疗，产生选择性结合的抗体、多肽或其他分子与这种蛋白质紧密结合，并将结合分子与一种可成像的同位素进行螯合。我们建议对此进行测试通过尝试开发试剂来成像MEK和MEK的选择性抑制剂的效果转运蛋白。这项技术使我们能够将药物的药效学与生物目标抑制的后果。我们建议使用成像来关联，作为时间的函数，在 HER2的表达与肿瘤代谢(FDG、PET、胆碱核磁共振)的变化及DMA的抑制合成(FLT、PET)。对某些靶点的抑制可能会对细胞产生特定而深远的影响。vbl.使用传统技术，我们已经确定MEK激酶抑制剂抑制带有BRAF突变的肿瘤有选择地和有效地，而这种抑制与完全逮捕有关。我们已经对此进行了成像目前正在计划将这种方法纳入该抑制剂的第二阶段试验。这个这项工作的广泛和长期的重点是使用这项技术来探索途径的生物效应并加速它们的临床转译。