Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans -Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer

• Published in: International journal of molecular sciences Vol. 23; no. 1; p. 575
• Main Authors: Woess, Katharina, Sun, Yuchen, Morio, Hanae, Stierschneider, Anna, Kaufmann, Anna, Hainzl, Stefan, Trattner, Lisa, Kocher, Thomas, Tockner, Birgit, Leb-Reichl, Victoria, Steiner, Markus, Brachtl, Gabriele, South, Andrew P, Bauer, Johann W, Reichelt, Julia, Furihata, Tomomi, Wally, Verena, Koller, Ulrich, Piñón Hofbauer, Josefina, Guttmann-Gruber, Christina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05-01-2022; MDPI
• Subjects: Animals; Antiviral drugs; cancer gene therapy; Cancer therapies; Cell Line; Cell Survival - drug effects; Cell Survival - genetics; Colorectal cancer; Colorectal carcinoma; Ct-SLCO1B3; Disease Management; Disease Models, Animal; Disease Susceptibility; Dystrophic epidermolysis bullosa; Enzymes; Epidermolysis bullosa; Epidermolysis Bullosa - complications; Epidermolysis Bullosa - genetics; Epidermolysis Bullosa Dystrophica - complications; Epidermolysis Bullosa Dystrophica - genetics; Ganciclovir; Ganciclovir - pharmacology; Gene expression; Gene Expression Regulation - drug effects; Genetic Loci; Genetic Therapy - adverse effects; Genetic Therapy - methods; herpes simplex virus thymidine kinase; Humans; Kinases; Malignancy; Mice; mRNA; Mutation; Patients; Proteins; Radiation therapy; RNA Splicing; Skin; Skin cancer; Skin diseases; Skin Neoplasms - diagnosis; Skin Neoplasms - etiology; Skin Neoplasms - metabolism; Skin Neoplasms - therapy; spliceosome mediated RNA trans-splicing; Splicing; Squamous cell carcinoma; Suicide; Suicide genes; Thymidine; Thymidine kinase; Trans-Splicing; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; cancer gene therapy; herpes simplex virus thymidine kinase; epidermolysis bullosa; spliceosome mediated RNA trans-splicing; Ct-SLCO1B3; ganciclovir; squamous cell carcinoma
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23010575

Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA
-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA
-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy.