Malignant astrocytomas are the most common primary brain tumors, and are the group most poorly controlled with current treatments. Their limited response to conventional therapies in part reflects a resistance to undergoing apoptosis in response to DNA damage or mitogen depletion, which results from a combination of tumor suppressor gene mutations and aberrant activation of growth factor-stimulated pathways. However, our recent in vitro studies indicate that, despite the limitation of apoptotic triggering in these tumors, the effector pathways of apoptotic signaling remain intact and can be activated by inhibition of growth factor signaling or stimulation of death receptor pathways. Our preliminary studies also suggest a number of intriguing interactions between these strategies and other treatment approaches. We hypothesize that agents which block aberrantly activated growth signaling pathways, or directly activate apoptotic signaling, will have efficacy for inducing glioma apoptosis in vivo and will potential the efficacy of other therapeutic modalities. To test this hypothesis, we will examine the effects of glioma growth and viability in vitro and in vivo inhibitors of protein kinase C and ras, proteins that play critical roles in prolifer4ative signaling induced by aberrantly activated upstream receptors. These studies will incorporate a panel of established and low-passage cell lines with defined genetic alterations to assess whether genotypic features influence the response to these agents, and to establish reliable biological surrogates of tumor response. Second, we will examine whether apoptotic signaling can be directly induced by Apo2L/TRAIL, a ligand for the DR4 and DR5 members of the TNF4 family of death receptors, and evaluate TRAIL receptor expression patterns, genotypic features, and biological surrogates that may predict efficacy in vivo. Both studies will be integrated with Project 3, which will provide viral vectors for local delivery of TRAIL and for reversing selected tumor suppressor gene deletions. Third, we will determine whether signal transduction inhibition or activation of apoptotic signaling can enhance the efficacy of radiotherapy and conventional chemotherapy for promoting cytotoxicity in all, or a genotypically defined subset of, malignant gliomas. Fourth, because our preliminary studies indicate that induction of glioma cell apoptosis by signal transduction modulation may be an effective mechanism for "priming" dendritic cells to promote an anti-tumor immune response, we will build on longstanding interactions with Project 2 to determine whether signal transduction modulation can potentiate the efficacy of DC-based immunotherapy approaches. Taken together, these studies will provide a foundation for the clinical translation of signal transduction inhibition and death receptor activation as therapeutic approaches for malignant gliomas, and indicate ways in which these strategies can be used to enhance the efficacy of other therapies.