Metabolic Phenotyping with PET to Monitor and Predict Response to Kinase

用正电子发射断层扫描(PET)对肿瘤代谢进行成像是一种有吸引力的方法，可用于评估激酶抑制剂在癌症患者中的疗效。(1)许多在恶性肿瘤中改变的信号通路在调节细胞代谢方面起着中心作用(如MEK/MAPK、PI3K和mTOR)。(2)代谢活动增强是大多数恶性肿瘤患者的共同特征。(3)临床上已建立了许多针对肿瘤代谢各个方面的分子成像探针。(4)使用这些探针可以高灵敏度地在临床上测量肿瘤代谢的变化。与胃肠道间质瘤和慢性髓系白血病相比，只有一小部分常见实体肿瘤患者似乎受益于靶向激酶抑制剂治疗。目前对治疗反应的分子决定因素知之甚少。因此，肿瘤的早期识别 通过分子成像的反应将为治疗的临床医生和患者提供明显的优势，以及对研究激酶抑制剂在癌症患者中的有效性的临床试验的设计。我们提出了一个3个目标的项目，在这个项目中，我们引入了代谢表型与正电子发射计算机断层扫描，以监测癌症患者接受靶向的激酶抑制剂治疗。肿瘤代谢将通过临床建立的葡萄糖([18F]氟脱氧葡萄糖)、核苷([18F]氟胸苷)和氨基酸([18F]氟多巴)利用的分子成像探针进行评估。目标1既包括与加州大学洛杉矶分校肺癌孢子合作监测肿瘤代谢对吉非替尼的反应变化，也包括合作评估实验性mTOR和EGFR激酶抑制剂对 胶质母细胞瘤。在目标2中，我们将在细胞培养中阐明激酶抑制剂引起新陈代谢变化的机制。在目标3中，我们使用异种移植模型来确定-在这种临床前环境-如何优化PET分析对靶向激酶抑制剂的代谢影响的能力，以区分治疗特异性应答者和无应答者。 综上所述，我们将扩展目前使用的分子成像方法，并将引入PET的“代谢表型”技术，以监测癌症患者对靶向激酶抑制的治疗反应。

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.