Multimodality Imaging of GI Cancers for Diagnosis and Directed Therapy

理解和控制胃肠道从发育不良到肿瘤的转变需要对疾病的分子和解剖标记进行协调评估，使用特定的生化探针来识别细胞生理学和细胞表面标记的改变，以及可以检测和询问结构和功能的成熟技术。为了提高Gl癌的检测，我们建议在光学成像和光谱方面进行合作转化研究，使用多模式平台检测Gl上皮引起的早期肿瘤病变。我们建立了一个由斯坦福大学、范德比尔特大学、佛罗里达大学和加州大学戴维斯分校的研究人员组成的综合专业研究资源中心。该计划的总体目标是开发基于光学和超声的共识过程和方法，通过检查超微结构变化背景下的分子标记来优化疾病早期分子标记的检测。我们将使用荧光造影剂进行功能分析，并使用光学和超声来评估解剖变化。在宽视场荧光内窥镜和超声的辅助下，光纤光学探针将用于分析疾病的分子特征。该项目的工程组成部分旨在利用已建立的白光/荧光内窥镜和超声系统以及最先进的小型化传感器进行系统集成，用于针对癌症标志物的分子探针的高分辨率/高灵敏度检测。探针的化学性质是建立在现有目标的基础上的。探针包括选择用于结合发育不良上皮的肽，以及针对COX-2作为恶性肿瘤细胞内标记物的化合物。该计划提供了一个基础设施，以支持旨在将良好开发的工具和技术转化为临床的子项目。在每个子项目中，现有技术的坚实基础支持改进集成和增强早期检测的创新方法。临床团队由具有转化研究记录的内窥镜医师组成，将评估患者的综合工具和试剂。我们拥有一支强大的病理团队，由具有光学成像和光谱学专业知识的病理学家组成，以促进组织病理学标准的验证。该计划的主要项目有四个具体目标，每个目标都以多学科和直接的方式解决。这些包括：i)验证Gl癌分子标记物作为成像和治疗靶点；ii)推进Gl癌成像和治疗的分子探针和集成仪器组合；iii)基于已验证的分子标记物优化探针-治疗组合；iv)临床评估仪器和探针组合。这些目标由两个任务特定项目和5个核心支持，并由执行委员会监督。

Understanding and controlling the transition from dysplasic growth to neoplasia in the gastrointestinal tract requires coordinated evaluation of the molecular and anatomic markers of disease using both specific biochemical probes to recognize alterations in cellular physiology and cell surface markers, and established technologies that can detect and interrogate both structure and function. To improve detection of Gl cancers we propose to perform collaborative translational research in optical imaging and spectroscopy using multimodal platforms for the detection of early neoplastic lesions arising from the Gl epithelium. We have established an integrated Specialized Research Resource Center comprised of investigators from Stanford University, Vanderbilt University, University of Florida and University of California, Davis. The overarching aim of this program is develop a consensus process and methodology based on optics and ultrasound to optimize detection of early molecular markers of disease by examining molecular markers in the context of ultrastructural changes. We will use fluorescence contrast agents for functional analyses and both optics and ultrasound for assessing anatomic changes. Aided by wide-field fluorescence endoscopy and ultrasound, fiberbased optical probes will be used to analyze the molecular signatures of disease. The engineering components of this program are aimed at systems integration using established white light/fluorescence endoscopy and ultrasound systems and state-of-the-art miniaturized sensors for high resolution/high sensitivity detection of molecular probes directed at markers of cancer. The probe chemistries are well-established and based on existing targets. Probes include peptides, selected for binding to dysplastic epithelium, and compounds directed at COX-2 as an intracellular marker of malignancy. The program provides an infrastructure to support subprojects that are aimed at translating well-developed tools and techniques into the clinic. In each subproject, a strong foundation of established technologies supports innovative approaches to improve integration and enhance early detection. The clinical team consists of endoscopists with a track record of translational research that will evaluate the integrated tools and reagents in patients. We have a strong pathology team comprised of pathologists with expertise in optical imaging and spectroscopy to facilitate validation with histopathological standards. The major project in this program has four specific aims that are each addressed in a multidisciplinary and directed approach. These include: i) validation of molecular markers of Gl cancer as targets for imaging and therapy, ii) advancing molecular probes and integrated instrument combinations for imaging and therapy of Gl cancer, iii) optimization of probe-therapy combinations based on validated molecular markers, and iv) clinically evaluate instrument and probe combinations. These aims are supported by two task specific projects and 5 cores with oversight by an executive committee.