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Boosting the infection and oncolysis of adenovirus VCN-01 with topotecan

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Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut

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[eng] Dysregulation of the retinoblastoma (RB1) pathway is a frequent oncogenic event and results in high levels of the free (not bound to the retinoblastoma protein) transcription factor E2F-1 in cancer cells. The oncolytic adenovirus VCN-01 was engineered to use E2F-1 to activate its replication and lyse tumors. However, efficient viral delivery and infection of cancer cells remains a challenge. In this study, we show that the topoisomerase I inhibitor topotecan increases the ability of VCN- 01 to infect and lyse several pediatric cancers through the upregulation of E2F-1 and the induction of S-phase arrest in the tumor cells. We observed a powerful synergistic activity of local VCN-01 injections and systemic topotecan in human cancer xenografts in mice, including intraocular and leptomeningeal retinoblastoma, and aggressive models of Ewing sarcoma and neuroblastoma. At the selected dosages, individual treatments were not active, while the combination significantly increased mouse survival. In a patient with chemo-refractory intraocular retinoblastoma receiving intravitreal VCN-01 in the frame of a phase 1 clinical trial, we observed a ten-fold increase in viral genomes in the aqueous humor after the administration of topotecan. The patient achieved complete response and remains disease free four years following therapy. These results support new clinical trials.

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Tesis Doctorals - Facultat - Medicina i Ciències de la Salut

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Boosting the infection and oncolysis of adenovirus VCN-01 with topotecan