Metabolic Imaging of Targeted Therapies in Cancer

癌症靶向治疗的代谢成像

基本信息

批准号：
10551887
负责人：
JERRY D GLICKSON
金额：
$ 59.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-17 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551887
关键词：
Affect Aftercare Biological Biological Markers Biopsy Cancer Model Cancer Patient Cell Line Cell Transplantation Cell physiology Cells Cellular Metabolic Process Chemicals Citric Acid Cycle Clinic Clinical Clinical Trials Cytostatics Data Detection Diagnosis Disease Enzymes Evaluation Exhibits FRAP1 gene Fatty Acids Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genomics Glycolysis Goals Hexokinase 2 Hour Hyperactivity Hypoxia Image Imaging Techniques Immune system In Vitro Knowledge Lactic acid Lymphoma Lymphoma cell Malignant Neoplasms Measurement Measures Metabolic Metabolic Pathway Metabolism Methods Mission Modeling Monitor Mus Neoplasms Non-Invasive Detection Outcome Pathway interactions Patients Pentosephosphate Pathway Pharmaceutical Preparations Phosphorylation Phosphotransferases Physiologic pulse Positron-Emission Tomography Preclinical Testing Protein-Serine-Threonine Kinases Proteins Proteome Proteomics Public Health Radiation Reporting Research SDZ RAD Serine Signal Pathway Signal Transduction Sirolimus Staging Standardization Sterols System Testing Therapeutic Effect Therapeutic Intervention Tumor Markers Tumor Volume United States National Institutes of Health Work Xenograft Model Xenograft procedure biomarker selection biomarker validation cancer cell cancer therapy cancer type candidate identification candidate marker cell growth early detection biomarkers fluorodeoxyglucose positron emission tomography genome-wide imaging biomarker imaging detection imaging modality in vivo in vivo Model indexing inhibitor inhibitor therapy insight kinase inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma mTOR Inhibitor mTOR inhibition metabolic abnormality assessment metabolic imaging metabolomics mouse model neoplastic cell non-invasive imaging novel patient response personalized medicine phosphoproteomics potential biomarker pre-clinical preclinical study predicting response predictive marker protein expression research clinical testing response response biomarker small molecule targeted treatment transcriptome sequencing translational potential treatment response tumor tumor metabolism

项目摘要

Metabolic Imaging of Targeted Therapies in Cancer PROJECT SUMMARY/ABSTRACT Given the paradigm shift in cancer therapy including the ever-growing increase in the use of targeted therapies, foremost small-molecule kinase inhibitors in cancer therapy, there is an urgent need to develop reliable imaging techniques to detect and monitor the efficacy of such inhibitors in cancer patients. Because direct evaluation of cell signaling is practically not feasible and changes in tumor volume occur late after treatment initiation given the predominantly cytostatic effect of the inhibitors, we are proposing an alternative approach to monitor changes in tumor metabolism induced by kinase inhibition. This will be achieved in three stages: 1) analysis of gene expression/proteomic/phosphoproteomic to identify metabolic pathways perturbed by inhibition of the signaling pathway performed both in vitro and in vivo in the mouse xenotransplant models using patient derived cultured and primary cells (PDX), 2) metabolomic and metabolic fluxomic analysis of effect of kinase inhibition on metabolic pathways, also done in in vitro and in vivo settings, 3) analysis of biomarkers of inhibitor response validated by the above “-omics” studies by imaging techniques, preferably non-invasive, such as 1H MRS or chemical exchange saturation-transfer (CEST) with standard FDG PET imaging serving as control. In these proof-of-principle studies, we will focus on mTOR, the serine/threonine kinase hyperactive in the majority of cancer types, and employ direct and indirect inhibitors of mTOR, rapamycin/rapalog and Torin2, respectively, as index kinase/kinase inhibitor system. We will use diffuse large B-cell lymphoma (DLBCL) as experimental cancer model. In preliminary studies, we have demonstrated that rapamycin decreased concentrations of lactic acid in patient-derived lymphoma cell lines, both cultured in vitro and xenotransplanted into mice, as detected by unique 1H MRS imaging-based detection pulse sequences developed by us and our collaborators. The rapamycin-induced decrease in glycolytic metabolism correlated with and, importantly, markedly preceded inhibition of tumor cell growth, strongly supporting the notion that image-based evaluation of the key metabolic response is predictive of biological tumor cell response to the inhibition. The response also correlated with and, hence, was at least in part attributable to decreased expression of hexokinase II, other glycolytic enzymes and enzymes from other key metabolic pathways including phosphoribosyl-amidotransferase and other enzymes involved in glutaminolysis. Utilizing 13C MRS and 13C LC-MS, we have confirmed mTOR control of glycolysis and also noted decreases in fatty acid and sterol metabolism as well as inhibition of the pentose phosphate shunt and the TCA cycle. We anticipate that the proposed studies will extend our knowledge of the impact of mTOR inhibition on malignant cell metabolism and, ultimately, set the stage for future clinical evaluation of MRS or other imaging method(s) for monitoring response to inhibitors of mTOR and other cell-signaling kinases in DLBCL and other types of cancer.

癌症靶向疗法的代谢成像项目摘要/摘要鉴于癌症治疗的范式转移，包括对目标的使用不断增长疗法是癌症治疗中最重要的小分子激酶抑制剂，迫切需要发展可靠的成像技术可检测和监测此类抑制剂在癌症患者中的效率。因为细胞信号的直接评估实际上是不可行的，肿瘤体积的变化发生在很晚鉴于抑制剂的主要细胞抑制作用，我们正在提出一种替代方案监测激酶抑制引起的肿瘤代谢变化的方法。这将在三个阶段：1）分析基因表达/蛋白质组学/磷酸化蛋白质组学以识别被扰动的代谢途径通过抑制信号通路在小鼠异种移植模型中同时进行体外和体内进行使用患者衍生的培养和原代细胞（PDX），2）代谢组和代谢通量分析激酶抑制对代谢途径的影响，在体外和体内也进行了，3）分析通过成像技术验证的抑制剂反应的生物标志物，最好是非侵入性，例如1H MRS或具有标准FDG PET的化学交换安全性转移（CEST）成像用作控制。在这些原则研究中，我们将重点关注MTOR，即序列/苏氨酸在大多数癌症类型中激酶过度活跃，员工的直接和间接抑制剂MTOR，雷帕霉素/Rapalog和Torin2分别为指数激酶/激酶抑制剂系统。我们将使用大扩散 B细胞淋巴瘤（DLBCL）作为实验癌症模型。在初步研究中，我们已经证明了雷帕霉素在患者来源的淋巴瘤细胞系中形成了乳酸浓度，均在体外培养异种移植成小鼠，如唯一基于1H MRS成像的检测脉冲序列所检测到的由我们和我们的合作者开发。雷帕霉素诱导的糖酵解代谢的降低相关并且重要的是，在肿瘤细胞生长的抑制之前，很明显，强烈支持这样的观念基于图像的关键代谢反应的评估可以预测生物肿瘤细胞对抑制。响应也与至少相关，因此至少部分归因于精制己糖激酶II，其他关键代谢途径的其他糖酵解酶和酶的表达包括磷酸蛋白基 - 氨基转移酶和其他参与谷氨酰胺溶解的酶。利用13C MRS 和13C LC-MS，我们已经确认了MTOR对糖酵解的控制，并且还指出脂肪酸和固醇代谢以及抑制五磷酸五磷酸五体和TCA周期。我们预料到这一点拟议的研究将扩展我们对MTOR抑制对恶性细胞代谢的影响的了解并且，最终为MRS或其他成像方法的未来临床评估奠定了基础对DLBCL和其他类型癌症中MTOR和其他细胞信号激酶抑制剂的反应。