Malignant astrocytomas are the most common and deadly primary brain tumors. Their limited response to conventional therapy reflects resistance to undergoing apoptosis in response to DMA damage or mitogen depletion, resulting from tumor suppressor gene mutations and aberrant activation of growth factor signaling. However, our studies during the previous funding period indicated that despite the limitation in apoptotic triggering, effector pathways of apoptosis may remain intact and can be activated by inhibiting growth factor-mediated signaling or stimulating death receptor pathways. These studies also demonstrated that although a subset of gliomas were responsive to modulation of individual signaling pathways, many showed incomplete growth inhibition, reflecting activation of parallel pathways or intrinsic resistance mechanisms. This led us to examine the efficacy of combinatorial strategies for signaling inhibition, using agents targeting distinct pathways. Our initial studies suggested the potential for intriguing, synergistic interactions 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, we hypothesize that therapeutic approaches that block rationally selected combinations of growth signaling pathways 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 inhibiting combinations of parallel pathways, such as PKC, Ras/Raf, and STAT, which transmit proliferative signals from aberrantly activated upstream receptors. These studies will incorporate a panel of cell lines with defined genetic alterations to assess whether genotypic features influence efficacy, and establish biological surrogates of response. Second, we will examine whether signaling mediators that promote caspase expression can enhance apoptosis induced by stimulation of death receptor pathways by TRAIL, and evaluate biological factors that predict efficacy. Both studies will be integrated with Project 3, which will provide viral vectors for delivery of TRAIL, caspase 8, and dominant negative PKCe, which may enhance TRAIL efficacy. Third, we will determine whether signaling modulation can enhance efficacy of radiotherapy and conventional chemotherapy in all, or a genotypically defined subset of, gliomas. Fourth, because our preliminary studies indicate that induction of glioma cell apoptosis by signal transduction modulation may promote uptake of tumor antigens by dendritic cells, we will build on longstanding interactions with Project 2 to determine whether signal transduction modulatory strategies can potentiate the effectiveness of peptide-based vaccination. Relevance: Taken together, these studies will provide a foundation for the translation of signal transduction inhibition and death receptor activation as therapeutic approaches for gliomas, and indicate ways in which these strategies can be used to enhance efficacy of other therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS040923-09
Application #
8232994
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2011
Total Cost
$319,483
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Furtado, Andre D; Ceschin, Rafael; Bl├╝ml, Stefan et al. (2017) Neuroimaging of Peptide-based Vaccine Therapy in Pediatric Brain Tumors: Initial Experience. Neuroimaging Clin N Am 27:155-166
Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2016) Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro Oncol 18:1157-68
Jane, Esther P; Premkumar, Daniel R; Cavaleri, Jonathon M et al. (2016) Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines. J Pharmacol Exp Ther 356:354-65
Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2016) Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study. J Neurooncol 130:517-527
Foster, Kimberly A; Jane, Esther P; Premkumar, Daniel R et al. (2015) NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis-inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5. Int J Oncol 47:506-16
Ceschin, R; Kurland, B F; Abberbock, S R et al. (2015) Parametric Response Mapping of Apparent Diffusion Coefficient as an Imaging Biomarker to Distinguish Pseudoprogression from True Tumor Progression in Peptide-Based Vaccine Therapy for Pediatric Diffuse Intrinsic Pontine Glioma. AJNR Am J Neuroradiol 36:2170-6
Mazzacurati, Lucia; Marzulli, Marco; Reinhart, Bonnie et al. (2015) Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Mol Ther 23:99-107
Premkumar, Daniel R; Jane, Esther P; Pollack, Ian F (2015) Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells. Cancer Biol Ther 16:233-43
Ohkuri, Takayuki; Ghosh, Arundhati; Kosaka, Akemi et al. (2014) STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res 2:1199-208
Foster, Kimberly A; Jane, Esther P; Premkumar, Daniel R et al. (2014) Co-administration of ABT-737 and SAHA induces apoptosis, mediated by Noxa upregulation, Bax activation and mitochondrial dysfunction in PTEN-intact malignant human glioma cell lines. J Neurooncol 120:459-72

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