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Full NameDr Laure Marignol
Organisation:Trinity College Dublin
Postgrad Medical Specialties
Other Medical Specialties:
Urology, Radiation Oncology
My research aims to generate new prognostic algorithms that detect patients at high risk of failure following radiation therapy, and design new therapeutic options that prevent tumour regrowth after radiotherapy. My research is mainly focused on high risk prostate cancer.
We have successfully selected for radioresistant prostate cancer cells, establishing a unique model to characterise the molecular mechanisms of the radiation response (1,2). This supports our ongoing participation in the debate on the protective effect of hypoxia after radiation exposure (3), and its ability to affect the efficacy of commonly used chemotherapeutic agents (4,5). We more recently proposed the prognostic potential of miRNAs, small, non-coding RNAs that negatively regulate gene expression (6). We have demonstrated this role in oesophageal cancer with colleagues (7,8) and identified novel miRNAs regulating radioresistance in prostate cancer cells (9).
This work complements ongoing studies investigating the ability of the signaling pathways that regulate several cancer cells capabilities such as Notch and YB-1 to serve as key to the survival of cancer cells to radiation (10). We have already identified deregulation of the Notch-3 receptor across cell line models of advancing disease stages and in patient specimens of high grade disease (11,12). Very preliminary data supports the novel hypothesis that an interaction between YB-1 and Notch-3 exists, bringing this work to the frontier of the field.
(1) McDermott, N., Meunier, A., Lynch, T. H., Hollywood, D. & Marignol, L. Isogenic radiation resistant cell lines: development and validation strategies. Int J Radiat Biol 90, 115-126, doi:10.3109/09553002.2014.873557 (2014).
(2) McDermott, N. et al. Fractionated radiation exposure amplifies the radioresistant nature of prostate cancer cells. Sci. Rep. 6, 34796, doi:10.1038/srep34796 (2016).
(3) Hennessey, D. et al. Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells. Urol Oncol, doi:S1078-1439(11)00373-5 [pii]
(4) Forde, J. C. et al. Downregulation of HIF-1 A and lowered TUBB3 expression levels leads to preferential sensitivity of hypoxic prostate cancer cells tol docetaxel. Br. J. Surg. 98, E8-E8 (2011).
(5) Forde, J. C. et al. Docetaxel maintains its cytotoxic activity under hypoxic conditions in prostate cancer cells. Urol Oncol, doi:S1078-1439(10)00234-6 [pii]
(6) O'Kelly, F. et al. MicroRNAs as putative mediators of treatment response in prostate cancer. Nat Rev Urol, doi:10.1038/nrurol.2012.104 (2012).
(7) Lynam-Lennon, N. et al. Low miR-187 expression promotes resistance to chemoradiation therapy in vitro and correlates with treatment failure in patients with esophageal adenocarcinoma. Mol Med 22, doi:10.2119/molmed.2016.00020 (2016).
(8) Lynam-Lennon, N. et al. MicroRNA-31 modulates tumour sensitivity to radiation in oesophageal adenocarcinoma. J Mol Med (Berl) 90, 1449-1458, doi:10.1007/s00109-0120924-x (2012).
(9) McDermott, N., Meunier, A., Wong, S., Buchete, V. & Marignol, L. Profiling of a panel of radioresistant prostate cancer cells identifies deregulation of key miRNAs. Clinical and Translational Radiation Oncology 2, 63-68, doi:http://doi.org/10.1016/j.ctro.2017.01.005 (2017).
(10) Marignol, L., Rivera-Figueroa, K., Lynch, T. & Hollywood, D. Hypoxia, notch signalling, and prostate cancer. Nat Rev Urol 10, 405-413, doi:10.1038/nrurol.2013.110 (2013).
(11) Meunier, A. et al. Hypoxia regulates Notch-3 mRNA and receptor activation in prostate cancer cells. Heliyon 2, Article e00104, doi:http://dx.doi.org/10.1016/j.heliyon.2016.e00104 (2016).
(12) Danza, G. et al. Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer. Int J Cancer 133, 2577-2586, doi:10.1002/ijc.28293 (2013).
A PhD project in our lab would likely test the hypothesis that the interaction between the YB-1 and Notch cancer pathways regulates radioresistance in prostate cancer cells. This project will aim: (1) To establish this interaction as a novel molecular switch to the multiple biological effects of radiation exposure in prostate cancer cells In cell culture models, the candidate would manipulate the expression of the molecular markers of these pathways and study the consequences on the radiation response of these cancer cells.
(2) To demonstrate that the detection of this interaction in patient specimens is relevant to clinical outcome in prostate cancer patients treated with radiotherapy. The candidate would collect and evaluate the expression levels of these markers in parafilm embedded formalin fixed biopsy specimens of patients treated with radiotherapy that are both in remission or in relapse.
(3) To evaluate the ability of this interaction to affect the ability of Notch and YB-1 inhibitors to enhance the biological effects of radiation in prostate cancer In cell culture models, the candidate would examine how the manipulation of the expression of the molecular markers of these pathways affects the toxicity and radiosensitizing effects of known YB-1 and Notch inhibitors.
This PhD work addresses the limitations of the current state-of-the-art for the assessment of the utility of radiotherapy for the optimal management of prostate cancer. Considering the body of evidence for the deregulation of the Notch pathway and YB-1 in cancer, this type of work could be conducted in cancer sites other than the prostate, and in particular would be highly relevant in lung cancer. In the longer-term, this type of project will lead to the development of novel diagnostic clinical tests and guide future radiosensitising strategies with significant commercial potential.