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Full NameDr Steven Gray
Organisation:Trinity College Dublin
- genetics, genomics and molecular biology
- cell and developmental biology/regenerative medicine
Other Research Fields:
Postgrad Medical Specialties
- Clinical Trials
- Respiratory Medicine
Research in my lab includes:
1. Epigenetic mechanisms underpinning drug resistance in cancer.
2. Targeting Epigenetic Readers, Writers and Erasers in cancer
3. Circulating Tumour Cells in cancer
4. non-coding RNA repertoires in Prostate Cancer, Mesothelioma and Thoracic malignancy.
6. Cancer Stem Cells
7. Utilizing epigenetic targeting agents to enhance onco-immunology
1. MacDonagh L, Gray SG, et al. (2018). “Reversing cisplatin resistance in non‐small cell lung cancer using BBI608, a cancer stemness inhibitor”. Cancer Lett. 2018 Apr 10. pii: S0304-3835(18)30269-6. doi: 10.1016/j.canlet.2018.04.008.
2. Mohamed BM, Boyle NT, Schinwald A, Murer B, Ward R, Mahfoud OK, Rakovich T, Crosbie-Staunton K, Gray SGet al. (2018). “Induction of protein citrullination and auto-antibodies production in mice exposed to nickel nanomaterials”. Scientific Reports;8(1):679.
3. MacDonagh L, Gallagher MF, Ffrench B, Gasch C, Breen E, Gray SG, et al. (2017). “Targeting the cancer stem cell marker, aldehyde dehydrogenase 1, to circumvent cisplatin resistance in NSCLC.” Oncotarget. 8(42):72544-72563.
4. Dockry É, O’Leary S, Gleeson LE, Lyons J, Keane J, Gray SG*, Doherty DG* “Epigenetic induction of CD1d expression primes lung cancer cells for killing by invariant natural killer T cells” OncoImmunology In Press (* contributed equally to the direction of this study)
A prickly conundrum: Porcupine as a therapeutic target in Malignant Pleural Mesothelioma (MPM)
WNT signalling is critical to controlling development and tissue homeostasis in all metazoans. Regulation of WNT signalling is tightly controlled by various proteins to prevent diseases caused by excess or ectopic signalling, and one such key protein is Porcupine (PORCN). Aberrant WNT signalling occurs in hard-to-treat cancers with poor prognosis such as pancreatic, biliary and gastric cancers. Several inhibitors targeting Porcupine are in pre-clinical development. One such compound is WNT974 (Novartis). Interestingly, there is some evidence that therapeutically targeting Porcupine in combination with an immune checkpoint inhibitor (anti-PD-1) has synergistic immune system modifying effects, and can target the cancer stem cell (CSC) niche.
MPM is a rare cancer associated with prior exposure to asbestos. Clinically it is difficult to treat with few therapeutic options, but recent evidence suggests that MPM also has a CSC component, and clinical trials of anti-PD1 show encouraging activity. WNT signalling is therefore a potential area of interest for therapy in MPM.
Currently there is no published data with respect to either the expression of Porcupine, or the effects of its inhibition in MPM.
Aims and Objectives:
Preliminary in silico analysis of a mesothelioma dataset indicates that high expression of PORCN is associated with poor OS in patients with MPM.
This project will:
• Examine the expression of Porcupine in a panel of MPM cell lines and patient material (both normal and tumour) at the level of mRNA and protein
• Assess the effects of a Porcupine inhibitor (WNT974) on mesothelioma cell lines for therapeutic benefit
• Assess the effects of WNT974 on a CSC MPM tumorsphere assay to see if the CSC component of MPM can be targeted.
• Monitor the effects of WNT974 on gene expression, in particular on the expression of PD-L1