Tropism Enhanced Oncolytic Adenovirus for the treatment of Brain Tumors

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Malignant brain tumors are among the most deadly human cancers, with a median survival of only one year. However, we have shown that Delta-24-RGD, a new, tumor-selective, infectivity-augmented, replicationcompetent oncolytic virus developed by our group may be an effective treatment against gliomas. Delta-24- RGD is unique, because its tumor selectivity is based on an alteration of the viral E1A gene, which renders it more selective and potent than previous oncolytic adenoviruses, and because of the addition of an RGD motif in the fiber knob, which increases its infectivity of tumor cells. Indeed, preclinical studies demonstrated the capacity of Delta-24-RGD to eradicate human gliomas in animal models, and a Phase I clinical trial of Delta-24-RGD in patients with recurrent malignant gliomas is scheduled to begin in January 2007. Here we hypothesize that Delta-24-RGD will be efficacious in human gliomas, and this efficacy can be improved by combining it with chemotherapeutic agents and by exploiting the tumor tropic properties of human bone marrow-derived mesenchymal stem cells to improve viral delivery. The Specific Aims to test our hypothesis are: AIM 1. Determine the extent to which Delta-24-RGD can replicate in and spread through gliomas in situ in patients. In order to assess viral infection, replication, and spread in situ, post-treatment glioma specimens obtained by "en bloc" surgical procedures in patients enrolled in our Phase I clinical trial will be examined to establish qualitative assessments of the pattern of Delta-24-RGD distribution in the tumor, and quantitative assessments of the distance of spread from the initial point of injection will be made. AIM 2. Determine the extent to which Delta-24-RGD and temozolomide are synergistic anti-glioma agents and exam of the underlying mechanisms of the synergy. Preliminary data indicate that the combination of Delta-24-RGD and temozolomide results in a significant anti-glioma effect. We hypothesize that this increased efficacy is due to adenovirally-mediated inhibition of the DMA-repair pathways and the G2 arrest involved in temozolomide resistance. Results of this Aim, including expression of DMA repair genes and cell cycle modifications by oncolytic adenoviruses, will be compared with the data obtained from human patient samples in Aim 1 to ascertain whether adenovirus infection would result in the generation of favorable conditions for temozolomide sensitivity in vivo. AIM 3. Determine the extent to which bone marrowderived human mesenchymal stem cells can improve the delivery of Delta-24-RGD to glioma. Preliminary data demonstrate that hMSC localize to gliomas after systemic injection in vivo and that this tropism for gliomas can be exploited to deliver therapeutic agents. To test this hypothesis, in vivo studies will be undertaken to demonstrate the extent to which hMSCs infected with Delta-24-RGD are capable of integrating into human gliomas after systemic injection, and are capable of eradicating brain tumors.