Metabolic Imaging of Targeted Therapies in Cancer

癌症靶向治疗的代谢成像

• 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
• 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' 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

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.

肿瘤靶向治疗的代谢成像 项目总结/摘要 鉴于癌症治疗的范式转变，包括靶向化疗的使用不断增加， 作为癌症治疗中最重要的小分子激酶抑制剂，迫切需要开发 可靠的成像技术来检测和监测这种抑制剂在癌症患者中的功效。因为 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 考虑到抑制剂的主要细胞抑制作用，我们提出了一种替代方案， 一种监测激酶抑制诱导的肿瘤代谢变化的方法。这将在三个 阶段：1）基因表达/蛋白质组学/磷酸蛋白质组学分析，以确定受干扰的代谢途径 通过抑制在小鼠异种移植模型中在体外和体内进行的信号传导途径 使用患者来源的培养细胞和原代细胞（PDX），2）代谢组学和代谢通量组学分析， 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 通过成像技术的上述“组学”研究验证的抑制剂应答的生物标志物，优选 非侵入性，如1H MRS或化学交换饱和转移（CEST）与标准FDG PET 成像作为对照。在这些原理验证研究中，我们将重点关注mTOR，即丝氨酸/苏氨酸 激酶在大多数癌症类型中过度活跃，并采用mTOR的直接和间接抑制剂， 分别使用雷帕霉素/雷帕霉素和Torin 2作为索引激酶/激酶抑制剂系统。我们将使用扩散大 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， 雷帕霉素降低了体外培养的患者源性淋巴瘤细胞系中的乳酸浓度 并异种移植到小鼠中，如通过独特的基于1H MRS成像的检测脉冲序列所检测的 由我们和我们的合作者开发。雷帕霉素诱导的糖酵解代谢减少与 同时，重要的是，明显地抑制了肿瘤细胞的生长，强烈支持了这样的观点， 关键代谢反应的基于图像的评估预测生物肿瘤细胞对代谢产物的反应。 抑制作用反应也与，因此，至少部分归因于减少 己糖激酶II、其他糖酵解酶和其他关键代谢途径的酶的表达 包括磷酸核糖基-酰胺基转移酶和其它参与β-氨基糖苷分解的酶。利用13 C MRS 和13 C LC-MS，我们已经证实了mTOR对糖酵解的控制，并且还注意到脂肪酸和 固醇代谢以及抑制戊糖磷酸分流和TCA循环。我们预计 这些研究将扩展我们对mTOR抑制对恶性细胞代谢影响的认识 并最终为MRS或其他用于监测的成像方法的未来临床评价奠定基础 DLBCL和其他类型癌症中对mTOR和其他细胞信号传导激酶抑制剂的反应。