Development of Molecularly Targeted Imaging Agents for KRAS activity in vivo

描述(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100%的胰腺癌、30%的肺癌以及各种其他恶性肿瘤中都存在这种突变。治疗这类癌症的一种方法可能是针对受KRAS调控的生化信号通路。值得注意的是，PI3K和MEK信号通路受KRAS调节，针对这些信号通路的特定药物已经开发出来，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，拥有跟踪通路活动的检测方法将是重要的。我们建议寻找新的分子标记并开发成像探针来检测KRAS及其替代途径在体内的活性状态。这项提议的总体目标是识别新的分子标记和开发成像探针，这些探针将提供合理的方法，对特定治疗的患者进行分层，并作为新的靶向治疗的反应生物标记或“替代品”。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。我们还开发了基因工程小鼠模型和初步的人类异种移植系统，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、蛋白质组学方法和结合化学来1)针对已知和新型的细胞表面标记PI3K和MEK信号进行筛选，2)将来自这些屏幕的铅肽与临床上可行的磁性荧光纳米颗粒结合，以开发针对PI3K和MEK生物标记的靶向显像剂，以及3)使用人类异种移植在体内测试新型显像剂。这些药物将立即在临床试验中应用，为患者选择以及药物剂量和时间安排提供合理的标准，并作为治疗效果的早期标记。 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来检测体内KRAS及其替代信号转导途径。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。复杂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): 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.