The prognosis for patients with malignant brain tumors has improved minimally in the last two decades;median survival is less than one year for patients with malignant glioma, the most common primary brain tumor. These statistics provide a strong rationale for coordinated efforts to identify innovative approaches to treat these tumors. The unifying hypothesis of this program project is that novel therapeutic strategies that take into account the unique features of these tumors will induce tumor regression, and potentiate conventional therapies. Each project is translationally oriented, with a common goal of addressing fundamental biological issues relevant to tumor growth and evaluating innovative treatment approaches using a series of preclinical models, as a basis to identify promising strategies to advance into clinical therapies. Project 1 is based on the hypothesis that inhibition of aberrantly activated signal transduction pathways, or activation of apoptosis signaling, will induce glioma cell killing, potentially in a genotype-specific fashion, and that this approach will have independent activity in glioma models, and potentiate other approaches. Project 2 postulates that vaccination with glioma-associated antigen epitopes, in conjunction with systemic therapy designed to enhance immunoreactivity in the brain tumor microenvironment, will be an effective mechanism for antigen delivery to antigen-presenting cells, and that the conditions for immunization can be optimized using signaling or vector-mediated strategies that promote dendritic cell maturation and function, in collaboration with Projects 1 and 3. Project 3 postulates that gene delivery to the brain tumor microenvironment, using oncolytic Herpes virus vectors incorporating novel multigene constructs engineered to facilitate virus incorporation, spread, and transduction efficiency, can achieve tumor killing and enhance the effects of other treatment strategies. This project will also generate many of the vector constructs that will be used in Projects 1 and 2. The Administrative/Biostatistics/Clinical Support Core (A) provides essential infrastructure support for the activities of this program. The Cellular and Tissue Imaging Core (B) provides a panoply of advanced microscopic imaging capabilities used in each of the projects. The Immunological Monitoring and Cellular Products Laboratory Core (C) provides banking of tissue and serum samples, maintenance of cell lines, preparation of biological products, and therapeutic monitoring essential for the clinical protocols in this program. Relevance: Taken together, the multidisciplinary interactions that have evolved in this program optimize our chances to identify and refine promising approaches that can be applied clinically to improve the prognosis of patients with malignant gliomas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS040923-10
Application #
8265856
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fountain, Jane W
Project Start
2000-12-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$1,237,376
Indirect Cost
$420,626
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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 :
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
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
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
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
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
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
Pollack, Ian F (2014) Management of low-grade gliomas in childhood. World Neurosurg 81:265-7

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