In order to improve the notoriously poor outcome of patients with malignant glioma, we developed a novel oncolytic adenovirus, Delta-24-RGD. In the initial funding period of this SPORE grant, we made the significant translational step of completing a first-in-human phase I clinical trial in patients with recurrent malignant glioma (NCT00805376). In this trial several dramatic complete responses were seen, and analyses of post treatment surgical specimens proved for the first time that Delta-24-RGD was capable of replicating in and killing human tumor cells, emphasizing the urgent need to further develop this approach. However, our analyses also suggested that the efficacy of Delta-24-RGD could be improved by 1) augmenting viral spread, and 2) improving the method of delivery. In this context, preclinical studies proposed in Aim 2 of our initial grant showed that the efficacy of Delta-24-RGD was synergistically enhanced by combining it with temozolornide (TMZ). Other observations showed for the first time that viral mediated autophagy and autophagy-related cell death are critical to oncolysis, and that promoting autophagy may further improve the efficacy of Delta-24-RGD. Equally important, preclinical studies from Aim 3 of our initial proposal showed that the delivery of Delta-24-RGD could be improved by the use of intravascularly administered bone marrow mesenchymal stem cells (BM-hMSCs) loaded with Delta-24- RGD. Based on these results, we now hypothesize that the efficacy of Delta-24-RGD can be enhanced without adversely affecting safety by combining Delta-24-RGD with TMZ, by harnessing autophagy, and by improving delivery via BM-hMSCs. To test this hypothesis, we wi|l: explore the role of autophagy in the synergy of TMZ and viral oncolysis using glioma stem cells, and develop a next generation autophagy- targeted oncolytic adenovirus (Aim 1);assess the safety, efficacy, and biological effects of combining Delta-24-RGD with TMZ in a phase l/ll clinical trial (Aim 2), and validate the effectiveness of BM-hMSCs to delivery Delta-24-RGD in preclinical glioma stem cell models and in patients with recurrent GBM. This project is the next step in achieving our long-term goal of legitimizing these viral and stem cell therapies as standard treatments of malignant gliomas.
Because malignant gliomas are among the most deadly human cancers, enhancing Delta-24-RGD anti- glioma effects represents a major step forward in broadening our arsenal of treatments for patients with this deadly disease for whom there are currently only minimally effective therapies.
|Gressot, Loyola V; Doucette, Tiffany A; Yang, Yuhui et al. (2015) Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB-dependent proneural glioma model by suppressing apoptosis. Int J Cancer 136:2047-54|
|Chen, James C; Alvarez, Mariano J; Talos, Flaminia et al. (2014) Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell 159:402-14|
|Schrand, Brett; Berezhnoy, Alexey; Brenneman, Randall et al. (2014) Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. Cancer Immunol Res 2:867-77|
|Lang, Frederick F; Barker 2nd, Fred G (2014) A history of the AANS/CNS Section on Tumors Biennial Satellite Symposium. J Neurooncol 119:593-600|
|Olar, Adriana; Aldape, Kenneth D (2014) Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol 232:165-77|
|Singh, Mamata; Leasure, Justin M; Chronowski, Christopher et al. (2014) FANCD2 is a potential therapeutic target and biomarker in alveolar rhabdomyosarcoma harboring the PAX3-FOXO1 fusion gene. Clin Cancer Res 20:3884-95|
|Congdon, Kendra L; Gedeon, Patrick C; Suryadevara, Carter M et al. (2014) Epidermal growth factor receptor and variant III targeted immunotherapy. Neuro Oncol 16 Suppl 8:viii20-5|
|Conrad, Charles A; Fueyo, Juan; Gomez-Manzano, Candelaria (2014) Intratumoral heterogeneity and intraclonal plasticity: from warburg to oxygen and back again. Neuro Oncol 16:1025-6|
|Zhao, Jun; Wallace, Michael; Melancon, Marites P (2014) Cancer theranostics with gold nanoshells. Nanomedicine (Lond) 9:2041-57|
|Jiang, Hong; Clise-Dwyer, Karen; Ruisaard, Kathryn E et al. (2014) Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model. PLoS One 9:e97407|
Showing the most recent 10 out of 70 publications