Metabolic Phenotyping with PET to Monitor and Predict Response to Kinase

通过正电子发射断层扫描（PET）对肿瘤代谢进行成像是评估激酶抑制剂在癌症患者中疗效的一种有吸引力的方法。(1)在恶性肿瘤中改变的许多信号传导途径在细胞代谢的调节中起核心作用（例如MEK/MAPK、PI 3 K和mTOR）。(2)代谢活动增加是大多数恶性肿瘤患者的共同特征。(3)有许多临床上建立的分子成像探针靶向肿瘤代谢的各个方面。(4)通过使用这些探针，可以在临床上以高灵敏度测量肿瘤代谢的变化。与胃肠道间质瘤和慢性髓性白血病相反，只有一小部分常见实体瘤患者似乎受益于靶向激酶抑制剂治疗。治疗反应的分子决定因素目前知之甚少。因此，肿瘤的早期识别 通过分子成像的反应将为治疗临床医生和患者以及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提供明显的优势。我们提出了一个3-aim项目，其中采用PET进行代谢表型分析，用于监测接受靶向激酶抑制剂治疗的癌症患者。将通过临床确立的葡萄糖（[18 F]氟脱氧葡萄糖）、核苷（[18 F]氟胸苷）和氨基酸（[18 F]氟多巴）利用的分子成像探针评估肿瘤代谢。目标1包括与UCLA肺癌SPORE合作监测吉非替尼对肿瘤代谢的影响，以及评估实验性mTor和EGFR激酶抑制剂对肿瘤代谢的影响。 胶质母细胞瘤在目标2中，我们将阐明，在细胞培养中，负责激酶抑制剂诱导的代谢变化的机制。在目标3中，我们使用异种移植模型来确定-在这种临床前环境中-如何优化PET分析对靶向激酶抑制剂的代谢效应的能力，以区分治疗特异性应答者和无应答者。 总之，我们将扩大目前使用的分子成像方法，并将引入“代谢表型”与PET作为一种技术，以监测治疗反应的靶向激酶抑制癌症患者。

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.