Malignant astrocytomas are the most common and deadly primary brain tumors. Their limited responseto conventional therapy reflects resistance to undergoing apoptosis in response to DMA damage or mitogendepletion, resulting from tumor suppressor gene mutations and aberrant activation of growth factorsignaling. However, our studies during the previous funding period indicated that despite the limitation inapoptotic triggering, effector pathways of apoptosis may remain intact and can be activated by inhibitinggrowth factor-mediated signaling or stimulating death receptor pathways. These studies also demonstratedthat although a subset of gliomas were responsive to modulation of individual signaling pathways, manyshowed incomplete growth inhibition, reflecting activation of parallel pathways or intrinsic resistancemechanisms. This led us to examine the efficacy of combinatorial strategies for signaling inhibition, usingagents targeting distinct pathways. Our initial studies suggested the potential for intriguing, synergisticinteractions between signaling modulatory approaches, such as inhibition of PKC and Raf or JAK/STAT,and activation of apoptotic signaling by TRAIL, and with conventional therapies. Based on our findings, wehypothesize that therapeutic approaches that block rationally selected combinations of growth signalingpathways or that enhance apoptosis signaling will provide a novel strategy for inducing glioma cytotoxicity.To test this hypothesis, we will examine the effects on glioma growth and viability of inhibitingcombinations of parallel pathways, such as PKC, Ras/Raf, and STAT, which transmit proliferative signalsfrom aberrantly activated upstream receptors. These studies will incorporate a panel of cell lines withdefined genetic alterations to assess whether genotypic features influence efficacy, and establish biologicalsurrogates of response. Second, we will examine whether signaling mediators that promote caspaseexpression can enhance apoptosis induced by stimulation of death receptor pathways by TRAIL, andevaluate biological factors that predict efficacy. Both studies will be integrated with Project 3, which willprovide viral vectors for delivery of TRAIL, caspase 8, and dominant negative PKCe, which may enhanceTRAIL efficacy. Third, we will determine whether signaling modulation can enhance efficacy of radiotherapyand conventional chemotherapy in all, or a genotypically defined subset of, gliomas. Fourth, because ourpreliminary studies indicate that induction of glioma cell apoptosis by signal transduction modulation maypromote uptake of tumor antigens by dendritic cells, we will build on longstanding interactions with Project2 to determine whether signal transduction modulatory strategies can potentiate the effectiveness ofpeptide-based vaccination. Relevance: Taken together, these studies will provide a foundation for thetranslation of signal transduction inhibition and death receptor activation as therapeutic approaches forgliomas, and indicate ways in which these strategies can be used to enhance efficacy of other therapies.
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