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：
10391657
负责人：
JERRY D GLICKSON
金额：
$ 62.55万
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/10391657
关键词：
Affect Aftercare BCL2 gene Biological Biological Markers Biopsy Cancer Model Cancer Patient Cell Line 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 Gene Proteins 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 Cancer Detection Outcome Pathway interactions Patients Pentosephosphate Pathway Pharmaceutical Preparations Phosphorylation Phosphotransferases Physiologic pulse Positron-Emission Tomography Preclinical Testing Protein-Serine-Threonine Kinases Proteome Proteomics Public Health Radiation Reporting Research SDZ RAD Signal Pathway Signal Transduction Sirolimus Staging Standardization Sterols System Testing Therapeutic Effect Therapeutic Intervention Translations Transplantation Tumor Markers Tumor Volume United States National Institutes of Health Work Xenograft Model base biomarker validation cancer cell cancer therapy cancer type candidate marker cell growth fluorodeoxyglucose positron emission tomography genome-wide imaging biomarker imaging detection imaging modality imaging study 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 predictive marker protein expression research clinical testing response response biomarker small molecule targeted treatment transcriptome sequencing 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.

癌症靶向治疗的代谢成像项目概要/摘要鉴于癌症治疗的范式转变，包括靶向药物的使用不断增加疗法，尤其是癌症治疗中最重要的小分子激酶抑制剂，迫切需要开发成像技术来检测和监测此类抑制剂对癌症患者的可靠疗效。直接评估细胞信号传导实际上是不可行的，并且肿瘤体积的变化发生在晚期鉴于抑制剂的主要细胞抑制作用，我们提出了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方面实现。阶段：1) 分析基因表达/蛋白质组/磷酸蛋白质组，以确定受到干扰的代谢途径通过抑制小鼠异种移植模型中体外和体内的信号通路使用患者来源的培养细胞和原代细胞 (PDX)，2) 代谢组学和代谢流组学分析激酶抑制对代谢途径的影响，也在体外和体内环境中进行，3) 分析优选地，通过上述“组学”研究通过成像技术验证的抑制剂反应的生物标志物非侵入性，例如 1H MRS 或使用标准 FDG PET 的化学交换饱和转移 (CEST) 在这些原理验证研究中，我们将重点关注 mTOR（丝氨酸/苏氨酸）。大多数癌症类型中激酶过度活跃，并采用 mTOR 的直接和间接抑制剂，雷帕霉素/雷帕洛格和Torin2分别作为指标激酶/激酶抑制剂系统，我们将使用弥散大。 B 细胞淋巴瘤（DLBCL）作为实验性癌症模型，在初步研究中，我们已经证明了这一点。雷帕霉素降低了体外培养的患者来源的淋巴瘤细胞系中的乳酸浓度和异种移植到小鼠体内，通过独特的基于 1H MRS 成像的检测脉冲序列进行检测由我们和我们的合作者开发的雷帕霉素诱导的糖酵解代谢减少相关。重要的是，明显先于肿瘤细胞生长的抑制，强烈支持这样的观点：对关键代谢反应的基于图像的评估可以预测生物肿瘤细胞对代谢反应的反应该反应也与抑制相关，因此至少部分归因于抑制。己糖激酶 II、其他糖酵解酶和其他关键代谢途径酶的表达包括磷酸核糖酰胺转移酶和其他参与谷氨酰胺分解的酶。利用 13C MRS。和 13C LC-MS，我们证实了 mTOR 对糖酵解的控制，并且还注意到脂肪酸和我们预计，甾醇代谢以及戊糖磷酸分流和 TCA 循环的抑制。拟议的研究将扩展我们对 mTOR 抑制对恶性细胞代谢影响的认识并最终为 MRS 或其他监测成像方法的未来临床评估奠定基础 DLBCL 和其他类型癌症中对 mTOR 和其他细胞信号激酶抑制剂的反应。