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（PDAC）是一个棘手的临床问题，通常在诊断时出现转移，并对现有疗法表现出严重的耐药性。早期发现和完整的手术切除为延长生存期提供了最好的希望。不幸的是，目前还没有合适的生物标志物用于早期检测。该提案的总体目标是鉴定新的分子标记物并开发用于早期PDAC的成像探针，其将：a）允许基于分子特征更早地检测病变，B）提供合理的方法来将患者分层用于特定治疗，c）更可靠地监测局部复发和远处转移，d）用作新靶向治疗的反应生物标志物或“替代物”，和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成像剂的开发，这些技术和分子成像剂能够通过分子成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模型和原代人类原位异种移植系统，用于临床前早期检测和治疗研究。在我们先前工作的扩展中，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纳米颗粒来1）筛选已知的PDAC靶点，以及2）鉴定PDAC组织中的新靶点，以及在侵入前前驱病变（PanIN）中。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药物，并确定新的生物标志物。我们将使用我们相关的PDAC小鼠模型和原位人异种移植物在体内测试新型显像剂。公共卫生相关性：该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重现人类疾病的遗传学。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.