Department of Bioengineering, Rice University, Houston, TX.
Transl Oncol. 2012 Jun;5(3):160-71. doi: 10.1593/tlo.11310. Epub 2012 Jun 1.
Biomarkers of cancer can indicate the presence of disease and serve as therapeutic targets. Our goal is to develop an optical imaging approach using molecularly targeted contrast agents to assess several centimeters of mucosal surface for mapping expression of multiple biomarkers simultaneously with high spatial resolution. The ability to image biomarker expression level and heterogeneity in vivo would be extremely useful for clinical cancer research, patient selection of personalized medicine, and monitoring therapy. In this proof-of-concept ex vivo study, we examined correlation of neoplasia with two clinically relevant biomarkers: epidermal growth factor receptor (EGFR) and metabolic activity. Two hundred eighty-six unique locations in nine samples of freshly resected oral mucosa were imaged after topically applying optical imaging agents EGF-Alexa 647 (to target EGFR) and 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (to target metabolic activity). Quantitative features were calculated from resulting fluorescence images and compared with tissue histopathology maps. The EGF-Alexa 647 signal correlated well with EGFR expression as indicated by immunohistochemistry. A classification algorithm for presence of neoplasia based on the signal from both contrast agents resulted in an area under the curve of 0.83. Regions with a posterior probability from 0.80 to 1.00 contained more than 50% neoplasia 99% (84/85) of the time. This study demonstrates a proof-of-concept of how noninvasive optical imaging can be used as a tool to study expression levels of multiple biomarkers and their heterogeneity across a large mucosal surface and how biomarker characteristics correlate with presence of neoplasia. Applications of this approach include predicting regions with the highest likelihood of disease, elucidating the role of biomarker heterogeneity in cancer biology, and identifying patients who will respond to targeted therapy.
癌症生物标志物可以表明疾病的存在，并可作为治疗靶点。我们的目标是开发一种光学成像方法，使用分子靶向对比剂来评估几厘米的黏膜表面，以高空间分辨率同时对多种生物标志物的表达进行绘图。在体内对生物标志物表达水平和异质性进行成像的能力对于临床癌症研究、患者个体化药物选择和监测治疗将非常有用。在这项概念验证的离体研究中，我们研究了肿瘤与两种临床相关的生物标志物（表皮生长因子受体（EGFR）和代谢活性）之间的相关性。对新鲜切除的口腔黏膜 9 个样本中的 286 个独特位置进行了成像，这些样本分别经表皮应用光学成像剂 EGF-Alexa 647（靶向 EGFR）和 2-（N-（7-硝基苯并-2-氧杂-1,3-二唑-4-基）氨基）-2-脱氧葡萄糖（靶向代谢活性）。从所得荧光图像中计算出定量特征，并与组织病理学图谱进行比较。EGFR-Alexa 647 信号与免疫组织化学所示的 EGFR 表达相关性良好。基于两种对比剂信号的存在，用于诊断肿瘤的分类算法得到的曲线下面积为 0.83。后验概率为 0.80 到 1.00 的区域 99%（84/85）的时间包含 50%以上的肿瘤。这项研究证明了非侵入性光学成像如何可以用作一种工具来研究大黏膜表面上多个生物标志物的表达水平及其异质性，以及生物标志物特征如何与肿瘤的存在相关。这种方法的应用包括预测疾病发生可能性最高的区域、阐明生物标志物异质性在癌症生物学中的作用以及识别对靶向治疗有反应的患者。
