Horae Gene Therapy Center; Department of Neurology; Department of Microbiology and Physiological Systems
Cancer Biology | Genetics and Genomics | Neoplasms | Oncology | Therapeutics
The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard-of-care treatment and thus a direct cause of death. Previously, we have shown that intracranial interferon-beta (IFN-beta) gene therapy by locally administered adeno-associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN-beta eliminates invasive human GBM8 tumors and promotes long-term survival. Next, we screened five AAV-IFN-beta vectors with different promoters to drive safe expression of mouse IFN-beta in the brain in the context of syngeneic GL261 tumors. Two AAV-IFN-beta vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2-Int-mIFN-beta vector. We also assessed the therapeutic effect of combining AAV-IFN-beta therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second-strand DNA synthesis of single-stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV-IFN-beta abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV-IFN-beta therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency.
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Citation: Mol Oncol. 2017 Feb;11(2):180-193. Epub 2017 Jan 18. Link to article on publisher's site
DOI of Published Version
adeno-associated virus, glioblastoma, interferon-beta, intracranial, syngeneic, xenograft
Guhasarkar, Dwijit; Neiswender, James; Su, Qin; Gao, Guangping; and Sena-Esteves, Miguel, "Intracranial AAV-IFN-beta gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model" (2017). Open Access Articles. 3057.
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