Glioblastoma multiforme (GBM) is a uniformly fatal primary brain tumor (glioma) for which there is no effective treatment. Invasion of tumor cells into surrounding brain tissue contributes to GBM malignancy, and is associated with resistance to chemotherapeutic drugs. Clinical responsiveness of GBM to chemotherapy appears enhanced after dendritic cell (DC) vaccination, and is strongly correlated with host T cell levels, as was diminished GBM invasiveness into key brain regions. Similarly, GL26 gliomas in immune competent mice exhibited enhanced chemosensitivity and diminished invasiveness relative to T cell-deficient mice, suggesting that host T cell activity may decrease both glioma invasiveness and chemoresistance in vivo. Glioma invasiveness and chemoresistance are caused by intrinsic genetic factors as well, notably high expression and/or activity of EGF receptors (EGFRs). In this context, EGFR activity can modulate the expression of downstream effectors of both processes, but its role in T cell-mediated tumor behavior remains unknown. Because tumor EGFR expression was also decreased when subjected to increased T cell activity, we hypothesize that diminished EGFR activity confers T cell-mediated affects on glioma invasiveness and chemosensitivity by modulating downstream effector expression. This hypothesis will be tested in the mouse GL26 glioma system as follows:
Aim #1 : To test the hypothesis that EGFR down-regulation confers T cell-mediated decreased glioma invasiveness, we will implant control and EGFR-transfected GL26 tumor cells into T cell-deficient, syngeneic wild-type, and DC-vaccinated syngeneic wild-type host brains, monitoring invasiveness into corpus callosum, ventricles, and cerebral cortex in vivo.
(Aim #1 a). We will also retrieve control and EGFR-transfected tumor cells from brains of the above mice, and test them for stable changes in intrinsic invasiveness in vivo and in vitro.
(Aim #1 b).
Aim #2 : To test the hypothesis that EGFR down-regulation confers T cell-mediated glioma chemosensitivity, we will retrieve control and EGFR-transfected GL26 tumor cells from brains of the T cell-deficient, wild-type, and DC-vaccinated wild-type syngeneic hosts, and test them for changes in intrinsic chemosensitivity by in vitro killing assay.
(Aim #2 a). We will then implant control and EGFR-transfected GL26 tumor cells into T cell-deficient, wild-type, and DC-vaccinated wild-type syngeneic hosts, monitoring survival with and without subsequent treatment with optimal chemotherapeutic agents as defined in Aim #2a (Aim #2b).
Aim #3 : To test the hypothesis that EGFR down-regulation confers T cell-mediated modulation of downstream effectors of invasiveness and chemosensitivity, we will retrieve EGFR-transfected and control tumor cells from brains of nude, C57BI/6, and DC-vaccinated C57BI/6 hosts, and identify EGFR-dependent and EGFR-independent gene sets with T cell-influenced gene expression by microarray (Aim #3a). We will then determine if high and low similarity to expression profiles within the above identified gene sets predicts clinical chemotherapeutic responsiveness and invasiveness within an unselected set of at least 59 genetically-characterized GBM patients (UCLA GBM microarray database), and vaccine responsiveness in GBM patients for whom microarray data is currently available (Aim #3b). Testing these hypotheses will help validate combining vaccination and chemotherapy for the treatment of GBM, and will identify additional protein targets for optimization of anti-invasive, chemotherapeutic, and immunotherapeutic approaches to treat GBM. ? ?
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