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.
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.
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