Journal
MOLECULAR CANCER
Volume 21, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12943-022-01641-6
Keywords
Ewing sarcoma; Rhabdomyosarcoma; Fusion oncogene; Targeted therapy; Cancer gene therapy; GPR64
Categories
Funding
- Rolf M. Schwiete Foundation
- Society for Science and Research at the medical faculty of the LMU Munich (WiFoMed)
- Wilhelm-Sander Foundation
- Matthias-Lackas Foundation
- Dr. Leopold and Carmen Ellinger Foundation
- German Cancer Aid [DKH-70112257, DKH-70114111, DKH-70114278]
- Gert und Susanna Mayer Foundation
- SMARCB1 association
- Federal Ministry of Education and Research (BMBF)
- Boehringer-Ingelheim Foundation
- Deutsche Forschungsgemeinschaft [DFG-458891500]
- Barbara und Wilfried Mohr Foundation
- Chinese Scholarship Council (CSC)
- German Cancer Aid
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This study demonstrates the potential of utilizing chimeric fusion transcription factors for targeted gene therapy in cancer. By capitalizing on the DNA-binding preferences of these factors, the researchers were able to design a highly potent expression cassette that can express therapeutic genes in pediatric sarcomas. They also identified a specific cell surface antigen, GPR64, for targeted transduction strategies. The results showed that the designed expression cassette can specifically transduce cancer cells and promote the expression of therapeutic genes, resulting in strong anti-tumor effects. The study suggests that this approach could be applicable to other types of cancer addicted to oncogenic transcription factors.
Chimeric fusion transcription factors are oncogenic hallmarks of several devastating cancer entities including pediatric sarcomas, such as Ewing sarcoma (EwS) and alveolar rhabdomyosarcoma (ARMS). Despite their exquisite specificity, these driver oncogenes have been considered largely undruggable due to their lack of enzymatic activity. Here, we show in the EwS model that - capitalizing on neomorphic DNA-binding preferences - the addiction to the respective fusion transcription factor EWSR1-FLI1 can be leveraged to express therapeutic genes. We genetically engineered a de novo enhancer-based, synthetic and highly potent expression cassette that can elicit EWSR1-FLI1-dependent expression of a therapeutic payload as evidenced by episomal and CRISPR-edited genomic reporter assays. Combining in silico screens and immunohistochemistry, we identified GPR64 as a highly specific cell surface antigen for targeted transduction strategies in EwS. Functional experiments demonstrated that anti-GPR64-pseudotyped lentivirus harboring our expression cassette can specifically transduce EwS cells to promote the expression of viral thymidine kinase sensitizing EwS for treatment to otherwise relatively non-toxic (Val)ganciclovir and leading to strong anti-tumorigenic, but no adverse effects in vivo. Further, we prove that similar vector designs can be applied in PAX3-FOXO1-driven ARMS, and to express immunomodulatory cytokines, such as IL-15 and XCL1, in tumor entities typically considered to be immunologically 'cold'. Collectively, these results generated in pediatric sarcomas indicate that exploiting, rather than suppressing, the neomorphic functions of chimeric transcription factors may open inroads to innovative and personalized therapies, and that our highly versatile approach may be translatable to other cancers addicted to oncogenic transcription factors with unique DNA-binding properties.
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