1. A human Myogenin promoter modified to be highly active in alveolar rhabdomyosarcoma drives an effective suicide gene therapy
- Author
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Johanna Pruller, Michelle T. Ma, Philipp Heher, Isabella Hofer, Peter S. Zammit, and Massimo Ganassi
- Subjects
0301 basic medicine ,Cancer Research ,Cancer ,Sarcoma ,Biology ,Suicide gene ,medicine.disease ,Article ,3. Good health ,Metastasis ,Gene regulation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Targeted therapies ,Thymidine kinase ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Alveolar rhabdomyosarcoma ,Molecular Medicine ,Rhabdomyosarcoma ,Molecular Biology ,Transcription factor ,Myogenin - Abstract
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 a 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 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 the 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.
- Published
- 2020