A human Myogenin promoter modified to be highly active in alveolar rhabdomyosarcoma drives an effective suicide gene therapy

TY - JOUR

T1 - A human Myogenin promoter modified to be highly active in alveolar rhabdomyosarcoma drives an effective suicide gene therapy

AU - Prueller, Johanna

AU - Hofer, Isabella

AU - Ganassi, Massimo

AU - Heher, Philipp

AU - Ma, Michelle

AU - Zammit, Peter

PY - 2020/8/4

Y1 - 2020/8/4

N2 - Rhabdomyosarcoma is a rare childhood soft tissue cancer whose cells resemble poorly differentiated skeletal muscle, expressing myogenic proteins including MYOGENIN. Alveolar Rhabdomyosarcoma (ARMS) accounts for ~40% of cases and is associated with poorer prognosis than other rhabdomyosarcoma variants, especially if containing the chromosomal translocation generating the PAX3-FOXO1 hybrid transcription factor. Metastasis is commonly present at diagnosis, with a five-year survival rate of <30%, highlighting need for novel therapeutic approaches. We designed a suicide gene therapy by generating an ARMS specific promoter to drive the herpes simplex virus thymidine kinase (HSV-TK) suicide gene. We modified the minimal human MYOGENIN promoter by deleting both the NF1 and MEF3 transcription factor binding motifs to produce a promoter that is highly active in ARMS cells. Our bespoke ARMS promoter driving HSV-TK efficiently killed ARMS cells in vitro, but not skeletal myoblasts. Using a xenograft mouse model, we also demonstrated that ARMS promoter-HSV-TK causes apoptosis of ARMS cells in vivo. Importantly, combining our suicide gene therapy with standard chemotherapy agents used in treatment of rhabdomyosarcoma, reduced the effective drug dose, diminishing deleterious side effects/patient burden. This modified, highly ARMS-specific promoter could provide a new therapy option for this difficult to treat cancer.

AB - Rhabdomyosarcoma is a rare childhood soft tissue cancer whose cells resemble poorly differentiated skeletal muscle, expressing myogenic proteins including MYOGENIN. Alveolar Rhabdomyosarcoma (ARMS) accounts for ~40% of cases and is associated with poorer prognosis than other rhabdomyosarcoma variants, especially if containing the chromosomal translocation generating the PAX3-FOXO1 hybrid transcription factor. Metastasis is commonly present at diagnosis, with a five-year survival rate of <30%, highlighting need for novel therapeutic approaches. We designed a suicide gene therapy by generating an ARMS specific promoter to drive the herpes simplex virus thymidine kinase (HSV-TK) suicide gene. We modified the minimal human MYOGENIN promoter by deleting both the NF1 and MEF3 transcription factor binding motifs to produce a promoter that is highly active in ARMS cells. Our bespoke ARMS promoter driving HSV-TK efficiently killed ARMS cells in vitro, but not skeletal myoblasts. Using a xenograft mouse model, we also demonstrated that ARMS promoter-HSV-TK causes apoptosis of ARMS cells in vivo. Importantly, combining our suicide gene therapy with standard chemotherapy agents used in treatment of rhabdomyosarcoma, reduced the effective drug dose, diminishing deleterious side effects/patient burden. This modified, highly ARMS-specific promoter could provide a new therapy option for this difficult to treat cancer.

M3 - Article

SN - 0929-1903

JO - Cancer Gene Therapy

JF - Cancer Gene Therapy

ER -