Gene therapy for squamous cell carcinoma of the head and neck

Abstract

Head and Neck Squamous Cell Carcinomas (HNSCCs) refer to malignant tumours originated from epidermoid cells, arising from the mucosal lining of the upper aerodigestive tract, salivary glands, paranasal sinuses, and skin of the head and neck. It represents the sixth world cause ofcancer-related death. Despite vigorous molecular and clinical knowledge about HNSCCs, the median survival of newly diagnosed patients remains at 60% in 5 years. The main goal of this project is the construction and in vitro validation of an HSV-1-derived oncolytic virus armed with a trimeric soluble form of the Apo2L/TRAIL ligand (TRAILTRIM), specifically directed against HNSCC tumor cells by the introduction of complementary sequences of miRNAs (miRNA-tag), down-regulated in HNSCC tumours, on the 3'UTR of the ICP27 viral essential gene. The construction of this oncolytic virus will imply genetic engineering of the HSV-1 genome, which will be achieved through homologous recombination in bacteria using the Recombineering System. For this, a bacterial artificial chromosome containing the full wild type HSV-1 genome (strain F) will be used. Apoptosis, citotoxicity, cellular viability and proliferation will be analyzed in vitro.Finally, we believe that the oncolytic virus proposed in this project will be able to attack HNSCC tumor cells by three different pathways: (i) apoptosis activation in tumor cells induced byTRAILTRIM; (ii) direct oncolysis of tumor cells produced by the natural lytic properties of the HSV-1 virus; and (iii) enhancing of the HSV-1-triggered apoptotic process of host defence by elimination of the Us3 anti-apoptotic HSV-1 viral gene.