Date of Award
Doctor of Philosophy (PhD)
Wafik S. El-Deiry, M.D. Ph.D.
Emerging targeted therapeutics hold great promise for the treatment of human cancer. However there are still challenges for selecting patients that most likely will benefit from targeted drugs. One of the major limitations of classical imaging methods is the significant delay to provide quantifiable and objective evidence of response to cancer therapy. Molecular imaging may be useful in targeted drug development by assessing the target expression and drug-target interaction, and predicting therapeutic response in both preclinical and clinical settings. The apoptosis pathway triggered by the Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) receptors is a potential target for therapeutic intervention. TRAIL and its proapoptotic receptor agonistic monoclonal antibodies are being developed as targeted therapeutics in the treatment of human cancer. It is our hypothesis that visualization of proapoptotic receptors and binding of their agonists to proapoptotic receptors can noninvasively predict proapoptotic response if the pathway is intact. Hence the objective of this work is to develop efficient multimodality molecular imaging methods to predict proapoptotic anticancer therapy response before or at the very early stage of treatment. Towards this goal, we have labeled proapoptotic receptor agonists (PARAs) with near-infrared (NIR) fluorescent dyes to image PARAs binding to their targets expressed on the cell surface in cultured cells and in human tumor xenografts grown subcutaneously in immunodeficient mice. Both in vitro and in vivo studies demonstrated that imaging PARAs binding to their targets was well correlated with proapoptotic anticancer therapeutic response when TRAIL signaling pathway was intact. To pursue a more general molecular imaging marker that can predict anticancer therapeutic response even when the signaling pathway is impaired, we explored a novel radiotracer for positron emission tomography (PET) imaging [(18)F]-3'-fluoro-3'-deoxy-L-thymidine ([(18)F]-FLT), an analogue of thymidine and a specific marker of DNA replication and cellular proliferation. Our results suggested that early changes in [(18)F]-PET may not only predict the tumor histological response to anticancer therapeutics but also determine superiority of one treatment regimen over another. In summary our proof-of-concept studies show that multimodality molecular imaging will greatly aid in accelerating anticancer drug approval process and improving survival and response rates in hard-to-treat cancer.
Zhou, Lanlan, "Prediction of Proapoptotic Anticancer Therapeutic Response Based on Visualization of Death Ligand-Receptor Interaction and Specific Marker of Cellular Proliferation" (2010). Publicly Accessible Penn Dissertations. 457.