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Projects	Project Description	Faculty Member
Project 1	Imaging Cancer Therapeutic Response	Wafik S. El-Deiry, MD, PhD
Project 2	Optical Imaging of Tumor Physiologic and Metabolic Changes with Antiangiogenic Therapy	William M.F. Lee, MD, PhD
Project 3	Imaging Molecular Changes During Colon Tumorigenesis	Margie Clapper, PhD

 

Project 1 - Imaging Cancer Therapeutic Response

Wafik S. El-Deiry, MD, PhD, Project Leader

University of Pennsylvania School of Medicine

This project focuses on the use of optical imaging to observe apoptosis in a human colon cancer xenograft model of mice undergoing cytotoxic therapy. Efforts are being made to image gene expression changes in the therapeutic response with a focus on the p53 pathway. P53 is a major determinant of therapeutic response and also represents an attractive target for drug development because of its frequent mutational inactivation in cancer. Drugs being tested include novel derivatives of mutant p53 conformation modifying drugs that also target stabilization of p53. The expectation in use of therapeutic agents in animal imaging xenograft models is that apoptosis may correlate with tumor response and that for agents that act through induction or stimulation of the p53 pathway, p53-specific reporter activity will be induced. Bioluminescence imaging measurements of apoptosis and gene expression that correlate with therapeutic outcome will have great impact as predictive tools for drug testing in preclinical studies. Efforts are being directed at optimization of sensitivity of imaging and validation of measurements using alternative imaging techniques. Collaborators include Dr. Abass Alavi, Dr. Britton Chance, Dr. Ronen Marmorstein at Wistar, Dr. Gang Zheng. It is anticipated that the preclinical phase of drug development, testing and validation, as well as the establishment of response determinants in terms of gene expression and apoptotic endpoints will in the future lead to design of a Phase I clinical trial incorporating the most promising therapeutic combinations.

 

Project 2 - Optical Imaging of Tumor Physiologic and Metabolic Changes with Antiangiogenic Therapy

William M.F. Lee, MD, PhD, Project Leader

University of Pennsylvania School of Medicine

This project focuses on therapeutic inhibition of tumor angiogenesis as a target for optical imaging. This project will characterize, through imaging, changes induced in murine tumors associated with exposure to antiangiogenic agents, such as recombinant IL-12 and thalidomide analogs. The project employs near infrared (NIR) optical imaging of vascular, physiological and metabolic parameters to monitor changes in tumor blood volume, blood flow, oxygenation and glucose utilization. The work uses syngeneic murine melanoma and other tumor models in which it has been shown by the PI that antiangiogenic agents reduce microvessel density by histologic and immunohistochemical methods, reduce blood flow by Doppler-ultrasound, induce or exacerbate hypoxia by EF5 and induce glycolysis by 13C glucose NMR. Collaborators include Dr. Britton Chance, Dr. David Wilson, and Dr. Gang Zheng. The ultimate goal of Project 2 is to use the NTROI to develop clinical trials that will test optical imaging techniques for monitoring therapy with antiangiogenic and other antitumor agents by noninvasively assessing tumor blood volume and flow, oxygenation and glucose utilization. In anticipation of clinical trials, efforts will be made to use alternative imaging techniques for cross validation and cross comparison in the mouse studies as well.

 

Project 3 - Imaging Molecular Changes During Colon Tumorigenesis

Margie Clapper, PhD, Project Leader

Fox Chase Cancer Center

This project includes Drs. Harvey Hensley and Alfonso Bellacosa as co-investigators at the Fox Chase Cancer Center and focuses on the optical imaging of molecular changes in intestinal tumor development. This project involves detection and characterization of intestinal tumors in the FCCC-MIN (Multiple Intestinal Neoplasia) mice. Unlike other strains of min mice that develop small intestinal tumors, the FCCC-MIN inbred strain which has gone through 20 generations develop multiple colonic tumors in addition to small intestinal adenomas which progress to carcinomas. Because min tumors arise due to mutations in the APC tumor suppressor gene that leads to nuclear translocation of beta-catenin and subsequent beta-catenin/TCF-mediated transcriptional events, this project is imaging beta-catenin target gene expression in colonic tumors. A major focus of this project, through efforts of Dr. Clapper, is to develop chemopreventative agents that can suppress colon tumor progression, including further development of sulindac derivatives. Dr. Bellacosa is introducing both bioluminescent or fluorescent reporters as well as retroviral-mediated transduction of oncogenes that can accelerate tumor development. Dr. Hensley is using optical fibers in a miniature endoscope to visualize colonic tumors in FCCC-MIN mice, as well as provide validation for gene expression imaging. This project interacts with Dr. Britton Chance. The use of optical imaging to visualize colonic tumors as well as molecular changes important in their progression will allow efficient preclinical testing of a promising chemopreventative strategy as well as the introduction of novel agents derived through screening for animal studies that can then be brought into the clinic as a future goal.