475 Targeting the JAK/STAT3 pathway with ruxolitinib for RDEB-cSCC therapy

Abstract

The most lethal complication of recessive dystrophic epidermolysis bullosa (RDEB) is the development of aggressive cutaneous squamous cell carcinoma (cSCCs), which lead the high mortality rates in these patients. Elevated levels of phospho-STAT3 have been found in two RDEB-derived cSCC cell lines, demonstrating that constitutive activation and dysregulation of the JAK/STAT pathway may play a role in RDEB-cSCC pathogenesis. Ruxolitininb is an FDA approved JAK1/2 inhibitor that has efficacy in myelofibroblast, human head, and neck squamous cell carcinomas, as well as lung and breast carcinomas. However, its therapeutic effect has not been elucidated in RDEB-cSCC. Here, we investigated the in vivo pharmacological activity of ruxolitinib for locally advanced RDEB-cSCC treatment in a novel mouse xenograft model of RDEB-cSCC. We first built 3D cSCC skin constructs (SCs) using RDEB-cSCC and RDEB fibroblasts (FB), which were then grafted onto immunocompromised mice. The animals developed tumors within 4 weeks post-grafting, with characteristic morphological features of human RDEB-cSCC. We used this model to test ruxolitinib for its in vivo activity to reverse the accelerated tumor growth by oral and topical route of administration. We found that daily oral administration of 70 mg/kg ruxolitinib for 4 weeks has an inhibitory effect on tumor growth. Next, we exploited the ability of ruxolitinib to penetrate skin and its potency for inhibiting tumor growth via topical application. We observed that topical application of 2% ruxolitinib for 4 weeks has an inhibitory effect on smaller than 4 mm in dimeter tumor growth. Moreover, no toxicity or loss of body weight was observed during the treatment period. Taken together, we showed in vivo evidence of the therapeutic potential of ruxolitinib in RDEB-cSCC, thereby making ruxolitinib a promising anti-cancer drug against cSCC development and progression.