Chemoprevention of recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma
Lay summary
Squamous cell carcinoma (SCC) of the skin is the biggest cause of death in patients with RDEB. The research team has identified 11 FDA-approved drugs that inhibit an enzyme responsible for cancer-causing mutations in RDEB. This research will use in vitro (laboratory) and in vivo (animal) preclinical models of skin SCC to determine the optimal dosing and timing of delivery of FDA-approved drugs for preventing cancer development through the enzyme inhibition. These studies will pave the way for clinical trial development with the ultimate goal of delaying or inhibiting completely the onset of cancer in patients with RDEB.
Scientific Summary
We will validate initial hits from a screen of FDA-approved drugs that inhibit APOBEC activity as APOBEC mutations have been shown to drive early-onset SCC in RDEB (Cho RJ, et al. 2018). The 11 FDA-approved drugs identified will be tested to determine which are the best inhibitors of APOBEC-driven mutation in RDEB keratinocytes in culture. The 11 drugs will be systematically screened using the maximum dose in clinical use using our long term culture model of APOBEC mutagenesis. We predict that a number of drugs that target APOBEC in an in vitro setting will inhibit APOBEC mutagenesis in keratinocyte culture and those inhibitors that show the best efficacy will be taken forward and tested in murine skin cancer models.
We have developed a number of APOBEC models of skin carcinogenesis and we will use these models to test the most effective inhibitors from in vitro and keratinocyte culture assays in mouse models of APOBEC-driven skin cancer. We anticipate testing the top 4 drugs in these assays and we will initially treat animals for the duration of tumorigenesis but also look at timing, treating after mutation induction or during mutation induction in order to determine the optimal utility of APOBEC inhibition.
Ultimately, these studies will identify FDA-approved drugs for repurposing in clinical trials of chemoprevention of cancer development in patients with RDEB SCC.
