Metabolic Imaging of Targeted Therapies in Cancer

癌症靶向治疗的代谢成像

• 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
• 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' 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

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研究进展 项目摘要/摘要 鉴于癌症治疗的范式转变，包括靶向治疗的使用不断增加 治疗方法，首先是小分子激酶抑制剂在癌症的治疗中，迫切需要开发 可靠的成像技术，用于检测和监测此类抑制物在癌症患者中的疗效。因为 直接评估细胞信号实际上是不可行的，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 监测由激酶抑制引起的肿瘤代谢变化的方法。这将在三年内实现 阶段：1)分析基因表达/蛋白质组/磷蛋白质组以确定受干扰的代谢途径 通过抑制小鼠异种移植模型体内和体外的信号通路 使用患者来源的培养和原代细胞(PDX)，2)代谢组学和代谢流体学分析 同样在体外和体内环境中，抑制激酶对代谢途径的影响，3)分析 通过成像技术的上述组学研究验证的抑制剂反应的生物标记物，优选 无创，如1H MRS或标准FDG PET的化学交换饱和转移(CEST) 影像作为对照。在这些原则证明研究中，我们将重点研究mTOR，即丝氨酸/苏氨酸 在大多数癌症类型中，激酶过度活跃，并使用mTOR的直接和间接抑制剂， 分别用雷帕霉素/雷帕洛格和Torin2作为指标激酶/激酶抑制系统。我们将使用漫反射大 以B细胞淋巴瘤(DLBCL)为实验肿瘤模型。在初步研究中，我们已经证明 雷帕霉素降低体外培养的患者来源淋巴瘤细胞株的乳酸浓度 以及通过独特的基于1H MRS成像的检测脉冲序列检测到的异种移植到小鼠体内 由我们和我们的合作者开发。雷帕霉素引起的糖酵解代谢下降相关 重要的是，它明显先于抑制肿瘤细胞的生长，有力地支持了这一概念 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 抑制力。这种反应也与减少有关，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酶的表达 包括磷酸核糖-氨基转移酶等参与谷氨酰胺分解的酶。利用~(13)C-MRS 和13C LC-MS，我们证实了mTOR对糖酵解的控制，也注意到脂肪酸和 类固醇代谢以及抑制磷酸戊糖分流和三氯乙酸循环。我们预料到 拟议的研究将扩大我们对mTOR抑制对恶性细胞新陈代谢的影响的了解 并最终为将来的MRS或其他成像方法的临床评估(S)奠定了基础 DLBCL和其他类型癌症对mTOR和其他细胞信号通路抑制剂的反应。