Intralesional Treatment of Basal Cell Carcinoma in a Genetically Inducible Mouse Model
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Keywords
Basal Cell Carcinoma, BCC, Skin Cancer, Keratinocyte Cancer, KC, intralesional, intralesional injection, intralesional therapy, BCC mouse model, Feldan shuttle, ASO, antisense oligonucleotide, inducible NBCCS-like mouse model, mouse model, Gli1, FLD103
Abstract
Introduction: Patients with nevoid basal cell carcinoma syndrome (NBCCS), also termed Gorlin syndrome, develop numerous basal cell carcinomas (BCCs). Current treatment options include systemic hedgehog pathway inhibitors, with significant side effects when used long term, and multiple surgeries with the risk of scarring and sometimes even disfigurement over the long term. We have developed an intralesional treatment for BCC based on the intracellular delivery of an antisense oligonucleotide (ASO) targeting Gli1, the main protein active in the hedgehog pathway responsible for BCC. To test the efficacy of our treatment, we developed an inducible NBCCS-like mouse model, genetically modified at the level of the expression of the Ptch1 and p53 genes in the skin.
Methods: The inducible mouse model uses Ptch1- and P53-knockdown mice irradiated with UVB three times a week until BCCs appear. These BCCs were treated once or twice a week with injections of an antisense oligonucleotide (ASO) targeting the production of the Gli1 protein, with and without the use of a peptide (the “Feldan shuttle") designed to introduce the ASO into the tumor cells. The evolution of the tumors was monitored several times a week with caliper measurements and photography. Following the treatments, the tumor site tissue was harvested and analyzed by both routine (H&E) and specialized (IHC, IF) histologic methods .
Results: Intralesional treatment of BCCs in the inducible mouse model using the ASO and peptide combination (FLD103) resulted in rapid and marked tumor regression, and sometimes complete eradication, over a few weeks. In addition, healthy perilesional skin appeared unaffected by the treatment, demonstrating targeted treatment specificity. The healed skin appeared grossly normal. Histologic examination of the treated sites after recovery showed no residual BCC as well as complete healing of the epidermis, dermis and subcutaneous tissue. We also observed that intralesional treatment with the ASO alone is not associated with tumor regression and in fact permits continued tumor growth.
Conclusion: We have demonstrated the utility of a specific intralesional treatment for BCC in a genetically inducible mouse model. This alternative and novel treatment produces rapid results with normal healing of the treated site. This treatment could offer an attractive option for patients with multiple BCCs who wish to avoid systemic treatments or multiple surgeries.
References
2. Juan HY et al. Arch Dermatol Res (2022). https://doi.org/10.1007/s00403-022-02447-8
3. Witmanowski H et al. Adv Dermatol Allergol 2017; XXXIV (4): 381–387
4. Gorlin, RJ. Medicine (Baltimore). 1987 Mar; 66(2):98-113
5. Evans DG, Ladusans EJ, Rimmer S et al. J Med Genet 1993; 30:460–4
6. Kimonis VE et al. Am J Med Genet 1977; 69:299–308
7. Bree AF et al. Am J Med Genet A 2011; 155A:2091–7
8. Bakshi A et al. Mol Carcinog 2017 Dec; 56(12): 2543–2557
9. Basset-Seguin et al. J Eur Acad Dermatol Venereol 2014 May; 28(5):626-32
10. Ng JM, Curran T. Nat Rev Cancer. 2011;11(7):493-501.
11. Peer E, Tesanovic S, Aberger F. Cancers (Basel). 2019; 11(4):538
12. Sekulic A et al. PLoS One. 2022 Jan 14; 17(1)
13. Sekulic A et al. J Am Acad Dermatol 2015; 72:1021-6
14. Migden MR et al. Cancer Treatment Reviews 64 (2018) 1–10
15. Sabol M et al. Int J Mol Sci 2018; 19(9):2562.
16. Pandolfi, S., & Stecca, B. Expert Reviews in Molecular Medicine, 17, E5. doi:10.1017/erm.2015.3
17. Khoo ABS et al. Acta Derm Venereol 2019; 99: 1266–1269
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