Integrated pharmacological and genetic identification of therapeutic targets for RDEB Squamous Cell Carcinoma

Prof Gareth Inman, Prof Karen Blyth and Dr Kirsteen Campbell

Labs: Growth Factor Signalling and Squamous Cancers & In Vivo Cancer Biology
Duration: 4 years, starting October 2025
Closing Date: Friday 14 March 2025
Interviews for this position will take place in April 2025

Background

Recessive Dystrophic Epidermis Bullosa (RDEB) is caused by inherited mutations in the COL7A1 gene that encodes type VII collagen (C7), the principal component of anchoring fibrils that are required for the structural integrity of the epidermal-junction in the skin. RDEB patients suffer from severe skin fragility, persistent skin blistering and wounding and have an exceptionally high risk of developing early-onset, aggressive and ultimately lethal cutaneous squamous cell carcinoma (cSCC). There is currently an incomplete understanding of the pathogenesis of RDEB cSCC and no currently clinically approved targeted treatment therapies. Integration of our findings from a drug re-purposing screen of over 3,000 drugs already approved for use in patients with other disease conditions with analysis of gene expression data from RDEB patient samples and cSCC cell lines has revealed several drugs and their targets as potential therapeutic targets for treatment of these devastating cancers.

Research Question

There is a pressing need to develop a deeper understanding of RDEB cSCC to identify novel targets for therapeutic intervention and improved models in which to test these interventions. Ongoing studies in several laboratories including our own are beginning to shed light on the underpinning biology of RDEB cSCC, stimulating drug development ventures to target the pathways and processes required for cancer progression. Whilst this forward approach of biology to target to drug has great merit a reverse approach of drug to biological response to therapeutic evaluation may help speed up the processes of treatment development and clinical implementation which is urgently needed for this patient population. Here we will exploit an integrated approach combining our ongoing drug screening and biological approaches to identify and robustly preclinically validate promising drugs and their targets for RDEB cSCC therapy. We will develop biomarkers for therapy use in patients and further explore the possibility of inducing cancer cell death with a novel class of death inducers called BH3 mimetics. We will then go on to identify new potential drug targets genome wide. These studies will illuminate the biology of RDEB cSCC and pave the way for rapid deployment of drug therapies for use in clinical trials for RDEB cSCC sufferers.

Skills/Techniques that will be gained

In this project we bring together a cross city supervisory team with complimentary internationally renowned expertise in RDEB cSCC (Inman, Prof Jemima Mellerio, co-applicant and co-supervisor, St John’s Institute of Dermatology, London), RDEB clinical management (Mellerio), tumour cell death and BH3 mimetics (Campbell) and in-vivo cancer biology (Blyth). We will build upon our integrated gene expression and drug screening analysis that has highlighted the role of regulators of the cell cycle, apoptosis, inflammatory signalling and MAPK and PI3K signalling pathways in RDEB cSCC. To test the on-target efficacy of our identified lead candidate drugs and BH3 mimetics we will perform a knockdown siRNA screen of the gene targets of these drugs in a panel of patient derived cell lines using the Opera Phenix high content imaging system. Gene hits from this screen and an expanded panel of drugs that target them will be taken forward into our more complex in-vitro suite of assays to measure cell proliferation and survival in 2D and 3D culture, co-culture and in organotypic invasion assays. Working with Professor Mellerio and our collaborator Professor John Le Quesne we will assess protein expression and pathway activity in patient samples using multiplexed spatial proteomic approaches to both deepen our understanding of RDEB cSCC and to develop biomarkers for drug deployment. We will also employ an unbiased genome wide Crispr screening approach to identify further therapeutic vulnerabilities. Lead drug and gene candidates from this integrated analysis will ultimately be tested in-vivo using xenograft approaches. The student will also have opportunities to visit Professor Mellerio in the St John’s Institute of Dermatology, present their work at international conferences and meet patients and families at outreach events. 

For questions regarding the application process, PhD programme/studentships at the CRUK Scotland Institute or any other queries, please contact phdstudentships@beatson.gla.ac.uk.

Closing date: Friday 14 March 2025

Applications are open to all individuals irrespective of nationality or country of residence.

 APPLY HERE

Relevant Publications

1. South AP, Laimer M, Gueye M, Sui JY, Eichenfield LF, Mellerio JE, Nyström A. Type VII Collagen Deficiency in the Oncogenesis of Cutaneous Squamous Cell Carcinoma in Dystrophic Epidermolysis Bullosa.J Invest Dermatol. 2023 Nov;143(11):2108-2119. 
   
   

2. Bailey P, Ridgway RA, Cammareri P, Treanor-Taylor M, Bailey UM, Schoenherr C, Bone M, Schreyer D, Purdie K, Thomson J, Rickaby W, Jackstadt R, Campbell AD, Dimonitsas E, Stratigos AJ, Arron ST, Wang J, Blyth K, Proby CM, Harwood CA, Sansom OJ, Leigh IM, Inman GJ. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nat Commun. 2023 Aug 25;14(1):5211. 

3. Dayal JHS, Mason SM, Salas-Alanis JC, McGrath JA, Taylor RG, Mellerio JE, Blyth K, South AP, Inman GJ. Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma. Br J Dermatol. 2021 Apr;184(4):697-708. 

4. Campbell KJ, Mason SM, Winder ML, Willemsen RBE, Cloix C, Lawson H, Rooney N, Dhayade S, Sims AH, Blyth K, Tait SWG. Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. Cell Death Differ. 2021 Sep;28(9):2589-2600. 

5. Koessinger AL, Cloix C, Koessinger D, Heiland DH, Bock FJ, Strathdee K, Kinch K, Martínez-Escardó L, Paul NR, Nixon C, Malviya G, Jackson MR, Campbell KJ, Stevenson K, Davis S, Elmasry Y, Ahmed A, O'Prey J, Ichim G, Schnell O, Stewart W, Blyth K, Ryan KM, Chalmers AJ, Norman JC, Tait SWG. Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics. Cell Death Differ. 2022 Oct;29(10):2089-2104.