Development of Molecularly Targeted Imaging Agents for KRAS activity in vivo

描述（由申请人提供）：KRAS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%的肺癌以及多种其他恶性肿瘤中。治疗这种癌症的一种方法可能是靶向由KRAS调节的生物化学信号通路。值得注意的是，PI3K和MEK信号传导途径受KRAS调节，并且已经开发出针对这些途径的特异性药物，并且已经在小鼠模型中显示出针对KRAS突变肿瘤的功效。随着这些药物被引入临床实践，拥有跟踪途径活性的检测方法将非常重要。我们建议确定新的分子标记物和开发成像探针，以检测体内KRAS及其替代途径的活性状态。 该提案的总体目标是确定新的分子标记物，并开发成像探针，这些探针将提供合理的方法来对患者进行分层以进行特定治疗，并作为新靶向治疗的反应生物标志物或“替代物”。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模型和原代人类异种移植系统，用于临床前早期检测和治疗研究。在我们先前工作的延伸中，我们将使用先前优化的噬菌体展示技术、蛋白质组学方法和缀合化学来1）针对PI3K和MEK信号传导的已知和新的细胞表面标志物进行筛选，2）将来自这些筛选的前导肽缀合至临床上可行的磁荧光纳米颗粒，以开发针对PI3K和MEK的生物标志物的靶向成像剂，和3）使用人异种移植物在体内测试新的显像剂。这些药物将立即应用于临床试验，为患者选择和药物剂量和时间表提供合理的标准，并作为治疗效果的早期标志物。 公共卫生相关性：该提案的总体目标是开发新的成像方法，用于检测KRAS及其替代信号转导通路。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用于寻找新的标签，使我们能够精确定位肿瘤中KRAS活性的水平，并确定针对这些途径的药物是否有效。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): 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.