2018-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658656摘要：根據衛生福利部統計惡性腫瘤連續35年蟬聯國人十大死因之首。其中肺癌、肝癌、女性乳癌及胰臟癌皆是十大癌症死因。細胞的特性是無限制分裂生長，癌細胞為獲取生長所需養分改變新陳代謝方式，此方式即分子影像學偵測癌細胞設計的原理。有鑑於臨床上使用最廣泛的正子掃描放射製劑：2-去氧-[18F]去氧葡萄糖(FDG)，有諸多因素如炎症病變等亦會攝取FDG顯影，混淆腫瘤組織判讀影響臨床診斷準確性。本計畫藉由胰臟癌利用麩醯胺酸的特殊代謝方式，設計麩胺酸的類似物：(4S)-4-(3-18F-fluoropropyl)-l-麩胺酸(FSPG)，藉由細胞xC-轉運子(xCT)控制其進入細胞內可專一用來反應xCT之活性。正常組織除了腦、胰、脾及胸腺外xCT的表現都很低，然而細胞受氧化壓力後xCT的表現會大幅增加進行抗氧化反應，此現象亦會發生在癌細胞。本計畫獲經費贊助（MOST104-2314-B-002-134）使能成功合成FSPG並改進放射化學產率，此成果取得經濟部智慧財產局專利(發明字第I597259號)：“18F正子放射性同位素標誌麩胺酸衍生物之腫瘤造影劑的製造方法及其裝置”。以正常老鼠（對照組）與有轉移腫瘤之老鼠進行動物實驗證實FSPG正子掃描偵測癌轉移的能力比FDG更靈敏，發炎組織攝取極低，鑑別癌病變能力優於FDG，具巨大臨床應用潛力。本研究團隊於2016年同步向美國專利和商標局提出臨時專利申請(EPAS ID：24829877)。2016年6月經衛生福利部食品藥物管理署允許，2016年8月通過台大醫院倫理委員臨床試驗許可。本計畫為延續之前計畫，構想上分三年進行人體臨床試驗。第一年：比較FSPG與FDG PET在第四期肺癌、肝癌、乳癌及胰臟癌病人(CT或MRI己診斷遠端轉移)偵測癌細胞的能力；第二年：第一年收的病患將再接受FSPG與FDG PET以比較兩者評估化療反應的能力；第三年：比較FSPG與FDG PET在第一至三期肺癌、肝癌、乳癌及胰臟癌病人偵測微小轉移(CT或MRI未看到的遠端轉移)的能力。目的在比較在不同腫瘤對同位素藥物攝取之差異及診斷敏感度、特異性與準確度。以切下來的組織標本做anti-xC-antibody及CD44的免疫螢光染色看染色程度是否與FSPG uptaktake成正比。雖然本院正子中心有合成FSPG的技術能力但製作成本昂貴，本計畫亟需獲得研究經費贊助。<br> Abstract: Cancer mortality has ranked the first in the cause of mortality in Taiwan for more than 30 years. Lung and liver cancer ranked the first and 2nd causes in cancer mortality, closely followed by female breast cancer and pancreatic cancers. Metabolic imaging with 2-deoxy-[18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is used clinically to detect, diagnosis, and monitor treatment response in oncology. However, many tumors show low glycolytic activities, uptake not exceeding physiologic background or high activity in inflammatory tissues. To overcome these limitations, we focused on the development of imaging agents for visualization of tumor-induced biomarkers that can potentially improve the overall detectability of tumor lesions and overcome the disadvantages encountered with FDG.Cancer showed not only increased glucose utilization but also increased uptake and turnover of amino acids such as glutamine and glutamate. The high rate of glucose and glutamine influx results in an excessive reactive oxygen species. Glutathione and L-cysteine, regulated by the system xC- transporter (xCT), are needed in the antioxidant process. The xCT normally shows low basal expression in normal tissues, but is upregulated during oxidative stress in cancer cells. A new PET tracer targeting xCT activity, (4S)-4-(3-[18F]fluoropropyl-)-L-glutamate (FSPG), was developed by Koglin et al in 2011. Published pilot studies revealed several advantages of FSPG compared to FDG, including excellent tumor visualization, high tumor to background ratios and low uptake in normal tissues.In our previous study supported by Ministry of Science and Technology (grant number: MOST 104-2314-B-002-134), we have successfully labeled FSPG and obtained the patent on the method of FSPG synthesis from Intellectual Property Office in Ministry of Economic Affairs of R.O.C. (發明字第I597259號). A provisional patent was also filed to United States Patent and Trademark office (EPAS ID: 24829877). A preclinical animal model revealed FSPG consistently detected cancer metastases earlier, and with more lesions at an advanced stage than FDG. FSPG clinical trial was approved by both Taiwan Food and Drug Administration in June 2016 and the Research Ethics Committee of NTUH in August 2016.Herein, we propose a 3-year phase II clinical trial of FSPG PET/CT as a continuum of our previous study. In the 1st-year, FSPG and FDG PET will be performed in patients with stage IV lung, breast, HCC, and pancreatic cancer (distant metastases shown in CT or MRI) to evaluate and compare their ability in detecting tumor lesions. In the 2nd-year, FSPG and FDG PET will be performed again in the patients enrolled in the 1st-year to evaluate FSPG ability to prognosticate and monitor treatment response. In the 3rd-year, patients with non-metastatic lung, breast, HCC, and pancreatic cancer will be enrolled to compare the efficiency of FSPG and FDG PET in detecting micro-metastases, i.e., distant metastases not shown in CT or MRI. The PET parameters will be correlated with histology, immunohistochemistry of xCT and CD44 expression. Based on this study, the strength and limitations of FSPG will be evaluated.18F-FSPG麩胺酸正子掃描惡性腫瘤system xC- transporterpositron emission tomography(4S)-4-(3- [18F] fluoropropyl)-l-glutamate (FSPG)glutamatesystem xC- transportermalignancy