PROJECT 3: Malignant gliomas are uniformly fatal tumors and there is an urgent need for improving ourbiological understanding of these lesions in order to rationally develop treatments. Molecular imaging can beadopted for interrogating the complex oncogenic pathways which impact their aggressive phenotype.Furthermore, targeted disruption of one or several signaling processes at once may provide an avenue forimproving the overall survival of patients. However, the interconnecting pathways can provide tumors withredundancies in the signaling cascades allowing for it to adapt and thereby evade treatment. Moreover,recent studies have shown that gliomas also contain a therapeutically resistant subpopulation of cancer stemcells which can provide for repopulation of the mass following conventional therapeutic interventions.Therefore, in this Project, we seek a paradigm shift in approaching the development of improved therapeuticstrategies for neurooncology patients by development and incorporation of novel molecular imaging tools toaddress three key aspects believed to frustrate current treatment of gliomas: (1) Unknown effects ofinhibiting signaling molecules on other signaling pathways and how the glioma cell can evade treatmentusing redundancies (escape routes) within the interconnected signaling pathways (2) How these signalingpathways differ in the glioma stem cell population and; (3) How we can use this information to eliminate theglioma stem cell population along with the bulk mass of cells within the tumor site. Optical molecular imagingreporters for key molecular events including Met kinase activity, Akt kinase activity, EGFR activity andCaspase-3 will be expressed in human glioma cells and used as readouts for evaluating the response oftreatment interventions on the oncogenic signaling activities in the glioma stem and non-stem cellpopulations both in vitro and in vivo. We will engineer a human glioma cell line such that CD133 expressionwill correlate with bioluminescence activity. This will enable us to quantify the growth and survival of thetumor stem cell population. The ability to monitor tumor burden using MRI as well as the cancer stem cellpopulation using this engineered reporter line will result in the identification and validation of noveltreatments/combinations wherein cancer stem cell dependent repopulation is delayed and thereby improvingthe clinical outcome of brain tumor patients. Public Health: The studies proposed here will provide thefoundation of incorporating molecular imaging reporters and applications into the drug development andevaluation process for improving our understanding treatment resistance which should lead to a morerationale approach for selection of treatments. Overall, the success of this Project will lead to improvedsurvival of patients with gliomas.
Showing the most recent 10 out of 161 publications
