Development of Molecularly Targeted Imaging Agents for KRAS activity in vivo

描述（由申请人提供）：KRAS的激活突变是人类癌症中最常见的致癌突变，几乎存在于100%的胰腺癌、30%的肺癌以及各种其他恶性肿瘤中。治疗这类癌症的一种方法可能是针对由KRAS调节的生化信号通路。值得注意的是，PI3K和MEK信号通路受KRAS调控，针对这些通路的特异性药物已经开发出来，并在小鼠模型中显示出对KRAS突变肿瘤的疗效。随着这些药物被引入临床实践，追踪途径活性的检测方法将是重要的。我们建议寻找新的分子标记，开发成像探针来检测KRAS的活性状态及其在体内的替代途径。该提案的总体目标是确定新的分子标记物和开发成像探针，这些探针将为患者分层进行特定治疗提供合理的方法，并作为新的靶向治疗的反应生物标记物或“替代品”。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模型和初级人类异种移植系统，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、蛋白质组学方法和偶联化学来1)筛选已知的和新的PI3K和MEK信号的细胞表面标记物，2)从这些筛选中结合导联肽到临床可行的磁荧光纳米颗粒，以开发针对PI3K和MEK生物标记物的靶向显像剂，3)使用人类异种移植物在体内测试新型显像剂。这些药物将立即应用于临床试验，为患者选择、给药和用药计划提供合理的标准，并作为治疗效果的早期标志。

DESCRIPTION (provided by applicant): Activating mutations in KRAS are the most common oncogenic mutations in human cancers, present in virtually 100% of pancreatic cancers, in 30% of lung cancers, as well as in a variety of other malignancies. One approach to treating such cancers may be to target biochemical-signaling pathways that are regulated by KRAS. Notably, the PI3K and MEK signaling pathways are regulated by KRAS and specific drugs against these pathways have been developed and have shown efficacy against KRAS mutant tumors in mouse models. As these agents are introduced into clinical practice, it will be important to have detection methods to track pathway activity. We propose to identify novel molecular markers and develop imaging probes to detect the activity state of KRAS and its surrogate pathways in vivo. The overall goal of this proposal is to identify novel molecular markers and develop imaging probes that will provide rational approaches to stratify patients for specific treatments and serve as response biomarkers or "surrogates" for new targeted therapies. 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 models and primary human 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 conjugation chemistry to 1) screen against known and novel cell surface markers of PI3K and MEK signaling, 2) conjugate lead peptides from these screens to clinically viable magnetofluorescent nanoparticles in order to develop targeted imaging agents against biomarkers of PI3K and MEK, and 3) test the novel imaging agents in vivo using human xenografts. These agents would find immediate application in clinical trials, providing rational criteria for patient selection and for drug dosing and scheduling, and serving as early markers of therapeutic efficacy. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop new imaging approaches for the detection of KRAS and its surrogate signal transduction pathways in vivo. 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 levels of KRAS activity in tumors and also determine whether a drug against these pathways is effective. We hope to use these tags in conjunction with commonly used imaging approaches such as MRI or endoscopic detection.