Preclinical assessment of PLK 1 inhibitors for the treatment of recessive dystrophic epidermolysis bullosa associated with squamous cell carcinoma

Contents:

• Project information
• Lay summary

Investigator: Dr Andrew South, Associate Professor, Department of Dermatology & Cutaneous Biology Thomas Jefferson University, Philadelphia, USA

Institution: This work was carried out at The Centre for Molecular Medicine,Clinical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK

Grant: £66,138 (01/11/2011-31/10/2013)

Lay summary

People with recessive dystrophic epidermolysis bullosa (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.

Investigator Biography Dr Andrew South is an Associate Professor at Thomas Jefferson University, Philadelphia. His primary interests are to understand the events that lead to the development and progression of squamous cell carcinoma, particularly those cancers arising in patients living with Recessive Dystrophic epidermolysis bullosa. Dr South has worked at institutions with a strong history of epidermolysis bullosa research, in London, Scotland, and now Philadelphia, and is committed to finding cures to this devastating group of diseases through application of basic scientific research.