Final Report Summary - TREATSKIN (Tissue engineering to evaluate novel treatments for skin cancer and genetic disease)
Cutaneous squamous cell carcinoma (cSCC) is an increasing problem throughout Europe as a result of the ageing population and high levels of recreational and occupational sun exposure producing DNA damage in the skin. It is estimated that 1 in 4 Europeans will develop skin cancer and nearly all over the age of 80 will have extensive precancerous changes in their skin. Although cSCC is less common than basal cell carcinoma, metastasis can occur, so is potentially lethal and causes 1 in 4 skin cancer deaths. Patients who suffer from Recessive Dystrophic Epidermolysis Bullosa (RDEB) a hereditary deficiency of type VII collagen, inherited as an autosomal recessive trait, have a life of pain and misery due to widespread blistering and scarring of the skin. Unfortunately they then develop cSCC within the scarred and wounded areas and rapidly succumb to this in late teenage and early adult life. There are a number of other genetic and acquired predisposing causes of cSCC including the use of immunosuppressive drugs in organ transplant recipients. There are few effective treatments for aggressive and metastatic cSCC in either RDEB or non RDEB patients.
The primary aim of this project was to progress translational research towards therapy of these patients by forming a pipeline of preclinical tests and using advanced genomics, and transcriptomics to identify possible therapeutic targets. Subsequently examining the functional effects of down-regulating the identified genes using siRNA screens and small molecules would aid in their selection. The therapeutic needs in the treatment of non-melanoma skin cancer are to develop further treatments for field cancerization and early stage carcinogenesis as well as for aggressive and metastatic disease.The preclinical pipeline is based around a well-characterized series of tumour keratinocyte lines, which have then been tissue engineered into skin substitutes, subcutaneous and surface xenotransplants, together with control normal and RDEB keratinocytes and fibroblasts.
During the time course of this project, next generation sequencing has become widely available and so extensive studies of somatic genetic changes in cSCC have added to an understanding of the key molecular mechanisms and pathways for cSCC development. Some surprising results have been found and reported. Unlike the common chemical carcinogenesis model for cSCC, there are few mutations in the RAS gene family but high levels of mutation in TGFBIR and TGFB2R as well as NOTCH genes and CDKN2A. This emphasizes the need for specific human models although engineered genetic models are critical for understanding downstream signaling. In addition to selected signaling pathways, an unbiased approach to drug treatment has been adopted. A large chemical library has been screened against multiple cell lines for effects on cell growth and has identified a number of novel and established anti cancer agents. The finding of bortezomib as a hit in this screen has led to screening with siRNA screens focused on ubiquitylation. Possible therapies now include bortezomib and PLK1 inhibitors, and topical formulations are being delivered for testing in the preclinical pipeline with the possibility of moving to phase I studies.