Suicide gene therapy targeting ewing sarcoma via an ewing-specific GGAA promoter.

Abstract

We recently demonstrated that GGAA promoters (GGAAprom) can be used to drive the expression of therapeutic genes (i.e., Cas9) in vitro and in vivo in a highly specific way in Ewing sarcoma cells. In this study, we take advantage of this strategy to express the suicide gene thymidine kinase from herpes simplex virus (HSV-TK), a suicide gene frequently used as an antitumoral therapy in clinical settings. The expression of HSV-TK in Ewing sarcoma cells under the control of the GGAA promoter resulted in cell death in the presence of ganciclovir both in vitro and in vivo. Interestingly, in vitro studies revealed a strong bystander effect. In preclinical models, the tumor volume of Ewing sarcoma xenografts expressing HSV-TK was dramatically reduced upon valganciclovir treatment. When adenoviral vectors were used as suitable therapeutics for clinical translation, HSV-TK expression in Ewing sarcoma cells reduced cell viability in vitro and reduced tumor growth in vivo. Interestingly, the death of Ewing sarcoma cells was accompanied by massive infiltration of the residual tumor by immune cells. Our results demonstrate that suicide genes can be delivered in a specific way to Ewing sarcoma cells by combining Ewing-specific GGAA promoters and adenoviral vectors, paving the way for the development of cancer gene therapies based on the selective expression of genes with therapeutic potential.