Development of Molecularly Targeted Imaging Agents for Early Detection of PDAC

描述(申请人提供)：胰腺导管腺癌(PDAC)是一个棘手的临床问题，通常在诊断时出现转移，并对现有的治疗方法表现出深刻的抵抗力。早期发现和完全手术切除是延长生存期的最好希望。不幸的是，目前还没有合适的生物标志物来进行早期检测。这项建议的总体目标是识别新的分子标志物，并为早期PDAC开发成像探针，这些探针将：a)根据分子签名更早地发现病变，b)为特定治疗提供合理的方法来对患者进行分层，c)更可靠地监测局部复发和远处转移，d)作为新的靶向治疗的反应生物标志物或“替代品”，以及e)鉴别良性肿瘤和恶性PDAC。我们的团队一直积极参与技术和分子成像试剂的开发，使之能够更早地检测原发癌症、转移扩散和通过分子成像早期评估治疗效果。我们还开发了用于临床前早期检测和治疗研究的基因工程小鼠PDAC模型和初级人类原位异种移植系统。在我们之前工作的扩展中，我们将使用先前优化的噬菌体展示技术、蛋白质组学方法和临床相关的纳米颗粒来1)针对已知的PDAC靶点进行筛选，以及2)在PDAC组织和侵袭前前体病变(PAIN)中识别新的靶点。我们的目标是开发用于肿瘤及其微环境的非侵入性成像的靶向试剂，并识别新的生物标记物。我们将使用我们相关的PDAC小鼠模型和原位人类异种移植模型在体内测试新的显像剂。公共卫生相关性：这项提案的总体目标是开发新的成像方法，用于胰腺癌的早期检测。我们将利用最近开发的小鼠模型来实现这一点，这些模型概括了人类疾病的遗传学。先进的化学生物学方法将被用来寻找新的标签，使我们能够精确定位最早的癌症形式。我们希望将这些标签与核磁共振或内窥镜检测等常用的成像方法结合使用。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is an intractable clinical problem, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. Early detection and complete surgical resection offers the best hope for longer survival. Unfortunately, there are currently no suitable biomarkers for early detection. The overall goal of this proposal is to identify novel molecular markers and develop imaging probes for incipient PDAC that would: a) allow much earlier detection of lesions based on molecular signatures, b) provide rational approaches to stratify patients for specific treatments, c) monitor more reliably local recurrence and distant metastases, d) serve as response biomarkers or "surrogates" for new targeted therapies, and e) differentiate benign tumors from malignant PDAC. Our group has been actively involved in the development of techniques and molecular imaging agents that enable earlier detection of primary cancer, metastatic spread, and early evaluation of therapeutic efficacy by molecular imaging. We have also developed genetically engineered mouse PDAC models and primary human orthotopic xenograft systems for preclinical early detection and therapeutic studies. In an extension of our previous work, we will use previously optimized phage display technology, proteomics methods, and clinically relevant nanoparticles to 1) screen against known PDAC targets, and 2) identify novel targets in PDAC tissues, and in pre-invasive precursor lesions (PanINs). Our goals are to develop targeted agents for the non-invasive imaging of the tumor and its microenvironment and to identify novel biomarkers. We will test the novel imaging agents in vivo using our relevant PDAC mouse models and orthotopic human xenografts. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop new imaging approaches for the early detection of pancreatic cancer. We will do this by utilizing recently developed mouse models that recapitulate the genetics of human disease. Sophisticated chemical biology approaches will be used to find novel tags that will allow us to pinpoint the earliest forms of cancer. We hope to use these tags in conjunction with commonly used imaging approaches such as MRI or endoscopic detection.