Development of Molecularly Targeted Imaging Agents for Early Detection of PDAC

描述（由申请人提供）：胰腺导管腺癌（Pancreatic ductal adenocarcinoma， PDAC）是一个难以解决的临床问题，通常在诊断时表现为转移，并且对现有治疗具有深刻的耐药性。早期发现和完全手术切除是延长生存期的最大希望。不幸的是，目前还没有合适的生物标志物用于早期检测。本提案的总体目标是确定新的分子标记物并开发早期PDAC的成像探针，这将：a)允许基于分子特征更早地检测病变，b)提供合理的方法来分层患者进行特定治疗，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记物或“替代品”，e)区分良性肿瘤和恶性PDAC。我们的团队一直积极参与技术和分子显像剂的开发，这些技术和分子显像剂能够通过分子显像早期检测原发性癌症、转移性扩散和早期评估治疗效果。我们还开发了基因工程小鼠PDAC模型和原发性人类原位异种移植系统，用于临床前早期检测和治疗研究。在我们之前工作的延伸中，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)筛选已知的PDAC靶点，2)识别PDAC组织和侵袭前前体病变（PanINs）中的新靶点。我们的目标是开发针对肿瘤及其微环境的非侵入性成像的靶向药物，并识别新的生物标志物。我们将使用我们相关的PDAC小鼠模型和原位人类异种移植物在体内测试新型显像剂。公共卫生相关性：本提案的总体目标是开发胰腺癌早期检测的新成像方法。我们将利用最近开发的再现人类疾病遗传学的小鼠模型来做到这一点。复杂的化学生物学方法将被用来寻找新的标签，这将使我们能够确定癌症的早期形式。我们希望将这些标签与常用的成像方法（如MRI或内窥镜检测）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.