Abstract
Oncolytic gene therapy using viral vectors may provide an attractive therapeutic option for malignant gliomas. These viral vectors are designed in a way to selectively target tumor cells and spare healthy cells. To determine the translational impact, it is imperative to assess the factors that interfere with the anti-glioma effects of the oncolytic adenoviral vectors. In the current study, we evaluated the efficacy of survivin-driven oncolytic adenoviruses pseudotyping with adenoviral fiber knob belonging to the adenoviral serotype 3, 11 and 35 in their ability to kill glioblastoma (GBM) cells selectively without affecting normal cells. Our results indicate that all recombinant vectors used in the study can effectively target GBM in vitro with high specificity, especially the 3 knob-modified vector. Using intracranial U87 and U251 GBM xenograft models we have also demonstrated that treatment with Conditionally Replicative Adenovirus (CRAd-S-5/3) vectors can effectively regress tumor. However, in several patient-derived GBM cell lines, cells exhibited resistance to the CRAd infection as evident from the diminishing effects of autophagy. To improve therapeutic response, tumor cells were pretreated with tamoxifen. Our preliminary data suggest that tamoxifen sensitizes glioblastoma cells towards oncolytic treatment with CRAd-S-5/3, which may prove useful for GBM in future experimental therapy.
Highlights
Glioblastoma multiforme (GBM) are malignant brain tumors in adults and children with no known cure [1]
To circumvent the problem associated with low level of primary receptor, in the current study we have evaluated the application of adenoviral vectors pseudotyped with subgroup B type fibers as novel anti-GBM therapeutic agents
We analyzed whether GBM specimens express any primary adenoviral receptors, such as desmoglein 2 (DSG2), cluster of differentiation 46 (CD46), or CAR on the membrane surface
Summary
Glioblastoma multiforme (GBM) are malignant brain tumors in adults and children with no known cure [1]. Recent preclinical studies have shed light on the utility of adenovirus as a vector for anti-GBM therapy [2,3,4,5]. These adenoviruses represent an attractive mode of delivering therapeutic load as these viruses exhibit high transduction efficiency for cancer cells and spread effectively within the tumor tissues. To circumvent the problem associated with low level of primary receptor, in the current study we have evaluated the application of adenoviral vectors pseudotyped with subgroup B type fibers as novel anti-GBM therapeutic agents
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