使用 PET 进行代谢表型监测和预测激酶反应-猫眼课题宝

使用 PET 进行代谢表型监测和预测激酶反应

批准号：

7416817

负责人：

JOHANNES CZERNIN

金额：

$25.82万

依托单位：

UNIVERSITY OF CALIFORNIA LOS ANGELES

依托单位国家：

美国

项目类别：

财政年份：

资助国家：

美国

项目状态：

未结题

起止时间：

至

来源：

https://reporter.nih.gov/project-details/7416817

关键词：

3T3 Cells AEE 788 Affect Amino Acids Animal Cancer Model Animal Experiments Animal Model Animals Arts Basic Science Biochemical Biochemical Markers Biological Biological Process CCI-779 Cancer Patient Cancer cell line Caring Cell Death Cell Line Cell Survival Cells Chronic Myeloid Leukemia Clinic Clinical Clinical Research Clinical Trials Clinical Trials Design Collaborations Colorectal Cancer Cultured Cells Cyclotrons Data Development Doctor of Philosophy Dose EGF Signaling Pathway EGFR inhibition Effectiveness Engineering Enrollment Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Excision Experimental Designs Frequencies Funding Ganciclovir Gastrointestinal Stromal Tumors Gefitinib Gleevec Glioblastoma Glucose Goals Hour Human Image Image Analysis Imatinib In Vitro Individual Inpatients Knowledge Laboratories Luciferases MEKs Malignant Neoplasms Malignant neoplasm of lung Measurable Measures Membrane Transport Proteins Metabolic Metabolic Pathway Metabolism Metastatic Neoplasm to the Liver Modality Molecular Monitor Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Nucleosides Numbers Oncogenic Oncologist Optics PTEN gene Pathologist Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Phenotype Phosphorylation Phosphotransferases Play Positron-Emission Tomography Principal Investigator Protein Kinase Protein Kinase Inhibitors Protein-Serine-Threonine Kinases Radiochemistry Recording of previous events Recruitment Activity Recurrence Regulation Renilla Renilla Luciferases Reporter Reporter Genes Reproduction spores Research Research Personnel Resources Retroviral Vector Role SCID Mice Schedule Signal Pathway Signal Transduction Simplexvirus Solid Neoplasm Staging System T-Lymphocyte Techniques Thymidine Thymidine Kinase Time Tracer Training Translations Trastuzumab Tumor Cell Biology Tumor Cell Line Tumor Tissue U251 Week Xenograft Model Xenograft procedure base cancer therapy career cell growth regulation chemotherapy cytotoxic data acquisition day design experience fluorodeoxyglucose fluorodeoxyglucose positron emission tomography glucose metabolism human FRAP1 protein imaging probe in vivo in vivo Cellular and Molecular Imaging Centers interdisciplinary approach kinase inhibitor knock-down mTOR Inhibitor mTOR Signaling Pathway mTOR inhibition malignant breast neoplasm melanoma member molecular imaging mutant neoplastic cell novel optical imaging pre-clinical prognostic programs protein kinase inhibitor protocol development receptor research study response success translational approach treatment duration tumor tumor xenograft uptake

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英文摘要

Imaging of tumor metabolism by positron emission tomography (PET) represents an attractive approach for assessing the efficacy of kinase inhibitors in cancer patients. (1) Many signaling pathways altered in malignant tumors play a central role in the regulation of cellular metabolism (e.g. MEK/MAPK, PI3K, and mTOR). (2) Increased metabolic activity is a common feature of most malignant tumors in patients. (3) There are a number of clinically established molecular imaging probes targeting various aspects of tumor metabolism. (4) By using these probes changes in tumor metabolism can be measured clinically with high sensitivity. In contrast to gastrointestinal stromal tumor and chronic myeloid leukemia, only a small subset of patients with common solid tumors appears to benefit from targeted kinase inhibitor treatment. The molecular determinants of treatment response are currently poorly understood. Therefore, the early recognition of tumor responses by molecular imaging would offer obvious advantages to the treating clinician and to the patient, as well as to the design of clinical trials studying the effectiveness of kinase inhibitors in cancer patients. We propose a 3-aim project whereby metabolic phenotyping with PET is introduced for monitoring of cancer patients undergoing targeted kinase inhibitor treatment. Tumor metabolism will be assessed by clinically established molecular imaging probes for glucose ([18F]Flurodeoxyglucose), nucleoside ([18F]Fluorothymidine) and amino acid ([18F]Fluorodopa) utilization. Aim 1 includes both a collaborative effort with the UCLA lung cancer SPORE to monitor changes in tumor metabolism in response to Gefitinib and a collaborative effort to assess the effects of experimental mTor and EGFR kinase inhibitors on glioblastomas. In aim 2 we will elucidate, in cell cultures, the mechanisms responsible for kinase inhibitor induced changes in metabolism. In Aim 3 we use xenograft models to determine - in this preclinical setting - how to optimize the ability of PET analysis of metabolic effects in response to targeted kinase inhibitors to distinguish therapy-specific responders and nonresponders. In summary, we will expand the currently used molecular imaging approaches and will introduce "metabolic phenotyping" with PET as a technique to monitor treatment responses to targeted kinase inhibition in cancer patients.

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