Preclinical assessment of PLK 1 inhibitors for the treatment of recessive dystrophic epidermolysis bullosa associated with squamous cell carcinoma (South 2)Completed
|Project lead||Dr Andrew South|
|Organisation||University of Dundee, Dundee, UK|
|Project budget||GBP 66,138.00|
|Start date / Duration||01. Nov 2013 / 24 months|
|Funder(s) / Co-Funder(s)||DEBRA UK, MSAP/EBEP Recommended|
|Research area||Skin cancer & fibrosis|
Short lay summary
People with Recessive Dystrophic EB (RDEB) often develop a type of skin cancer called squamous cell carcinoma (SCC), for reasons we do not fully understand. This cancer is life-threatening so poses a serious problem for RDEB patients. An important driver, causing cells to multiply, in several types of cancer is a molecule called Polo-Like Kinase 1 (PLK1). It acts like the car accelerator to make the tumour grow faster. This research group, working with previous DEBRA funding, have shown that PLK1 is indeed acting as a driver in SCC in RDEB patients and that inhibiting the action of PLK1 kills SCC keratinocytes (the most common cell type in the outermost layer of the skin). This inhibition can be regarded as taking a foot off the accelerator and pressing the brake in the car! Importantly, it does this without affecting normal skin cells. Many compounds are capable of inhibiting PLK1 in the laboratory under experimental conditions. The next challenge is to find one or more that are effective, yet safe to use in patients and act without detrimental side effects. As part of this challenge this project aimed to screen a panel of eight available PLK1 inhibitors to find the one(s) that may be effective in SCC cells from RDEB patients. This was done firstly in the test tube and then in a laboratory model.
What is important about this research?
The study identified three potentially useful compounds that kill cancer cells from this piece of research. One was not sufficiently specific for PLK1, but the research group hope to further develop the other two compounds to bring them towards clinical use for the treatment of RDEB SCC in the years to come.
What did this project achieve?
Individuals with dystrophic EB develop skin cancer that is life threatening, the reasons for which remain unclear. Efficient ways to treat this complication of the disease are needed. Through DEBRA funded research this laboratory has identified that inhibition of PLK1, a protein important for cell division, kills skin cancer cells and has little effect on normal skin cells. Many different drugs which inhibit PLK1 are being developed by pharmaceutical companies and some of these drugs are already in phase II clinical trial for the treatment of aggressive non-EB cancers. The researchers have now tested 8 different drugs and have identified 3 which efficiently kill cancer cells in a preclinical setting (RDEB and non-RDEB) without harming normal cells (RDEB and non-RDEB). Through this invaluable funding from DEBRA International the team is now ready to further develop these compounds to bring them towards clinical use for the treatment of RDEB SCC.