Glioblastoma multiforme(GBM) is a devastating disease that almost invariably leads to patient death despite best efforts using standard therapies that include surgery, radiation and chemotherapy. New therapeutic interventionsare needed which may be used in combination with standard medical practice. Among these treatments, gene therapy potentially holds promise for treatment of GBM however impediments to effective gene delivery remain. Highly attenuated replication competent HSV-1 vectors providea powerful opportunityto provide effective gene delivery in additionto the natural lytic features (oncolysis) and early phase human trials support the safety of this approach. In this proposal, experiments are outlinedto explore methodsto enhancethe potency of HSV oncolyticvectors through improvedvector distribution within the tumor mass, the testing of additional mutant vector backbones whose performance may be improved by enhanced and more specific intra-tumoralreplicationand through the use of additionaltransgenes that may be more effective in destruction of the tumor mass including locally infiltrating tumor cells into normal brain tissue. Throughout this investigationvector performanceand tumor killing will be evaluated in combinationwith radiosurgery. We will use the performance of G207 as a benchmark with which to compare any vector improvements. In four related specific aims we will: (i) Exploit the use of collagenases to enhance intra-tumoral vector distribution as visualized by advanced vital microscopy;(ii) Examine new genetic alterations in the HSV genome in a search for more active mutant oncolytic vectors that have the same or better safety profiles as vectors currently used in early phasepatient studies (e.g. G207);(iii) Develop retargeting strategies to enable tumor-specific HSV infection through recognition of tumor-cell receptors;and (iv) Introduce novel anti-tumor transgenes into the vector backbone that include (a) purine nucleoside phosphorylase (PNP) in combination with 6-methylpurine(MeP) treatment, (b) chlorotoxin (CltX), a peptide that inhibits tumor cell migration and may induce tumor cell apoptosis (c) tumor necrosis factor (TNFoc)that acts to sensitize tumor cells and the tumor vasculature to radiosurgical methods. The outcome of these studies are intended to discover new vectors, more effective transgenes and delivery strategies which together may provide gene therapy as an effective approach to at least prolong the survival of patients with recurrent GBM over currently available treatment methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119298-04
Application #
7579909
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Daschner, Phillip J
Project Start
2006-04-21
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$359,173
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Goins, William F; Hall, Bonnie; Cohen, Justus B et al. (2016) Retargeting of herpes simplex virus (HSV) vectors. Curr Opin Virol 21:93-101
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
Wang, P-Y; Currier, M A; Hansford, L et al. (2013) Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV. Gene Ther 20:761-9
Uchida, Hiroaki; Marzulli, Marco; Nakano, Kenji et al. (2013) Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol Ther 21:561-9
Uchida, Hiroaki; Chan, Janet; Shrivastava, Indira et al. (2013) Novel mutations in gB and gH circumvent the requirement for known gD Receptors in herpes simplex virus 1 entry and cell-to-cell spread. J Virol 87:1430-42
Simonato, Michele; Bennett, Jean; Boulis, Nicholas M et al. (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9:277-91
Yoo, Ji Young; Pradarelli, Jason; Haseley, Amy et al. (2012) Copper chelation enhances antitumor efficacy and systemic delivery of oncolytic HSV. Clin Cancer Res 18:4931-41
Haseley, Amy; Boone, Sean; Wojton, Jeffrey et al. (2012) Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma. Cancer Res 72:1353-62
Goss, James R; Stolz, Donna Beer; Robinson, Andria Rasile et al. (2011) Premature aging-related peripheral neuropathy in a mouse model of progeria. Mech Ageing Dev 132:437-42
Niedernhofer, Laura J; Glorioso, Joseph C; Robbins, Paul D (2011) Dedifferentiation rescues senescence of progeria cells but only while pluripotent. Stem Cell Res Ther 2:28

Showing the most recent 10 out of 27 publications