Intralesional Treatment of Basal Cell Carcinoma in a Genetically Inducible Mouse Model

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.