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BC-DTP_2027_34

Combining MET inhibition with chemotherapy in ovarian cancer to improve patient outcome

Research Themes

Cancer Cell Biology Rare Disease

Skills

Biomarker Discovery Drug Discovery Omics Data Science & Bioinformatics Pre-Clinical In-Vivo Research

Primary Supervisor

Prof Stephanie Kermorgant

Institute/ School: Barts Cancer Institute

s.kermorgant@qmul.ac.uk

Secondary Supervisor

Prof Michelle Lockley

Institute/ School: Barts Cancer Institute

m.lockley@qmul.ac.uk

Project Video

Lay Summary

Women with ovarian cancer are treated with chemotherapy. Unfortunately, the cancer regrows over time and chemotherapy does not work anymore (chemotherapy resistance), leading to patient death. 
This project aims to investigate whether a molecule called MET, a major cancer target, becomes more abundant in chemotherapy resistant ovarian cancer and whether combining chemotherapy with drugs that block MET are better at treating ovarian cancer. Kindly donated ovarian cancer patient samples, new ovarian cancer cells and mouse models which accurately reflect the human disease will be used. 
Objectives (including the training provided)
Year 1: Training in several cell and molecular biology techniques (immunohistochemistry, cell culture, western blot, cell viability assays). 
Results obtained: Evidence that MET is more abundant in chemoresistant ovarian cancer tissue and cells established (Parts I 1.1, 1.2a completed)  
Year 2: Training in 3D cell cultures (spheroid), sample preparation for a specialised technique which assesses expression of all genes (RNA Seq), and specialised microscopy (confocal).
Results obtained: Evidence that chemotherapy treatment induces MET hyperactivity in ovarian cancer cells and that, conversely, MET hyperactivity induces chemoresistance (Parts I1.2b completed).
Presentation of results in a poster at a national conference
Year 3: Training in bioinformatics for RNA Seq analysis completion
Results obtained: Evidence that chemotherapy-MET inhibition treatment reduces survival and spread of ovarian cancer in vitro (Parts I1.3 and II 1. completed)
Presentation of results in a poster at a national conference
Year 4: Training in in vivo experiments and/or sample harvest, in vivo experiment analysis and in manuscript preparation 
Results obtained: Evidence that chemotherapy-MET inhibition treatment reduces survival and spread of ovarian cancer in vivo. Manuscript and thesis submitted (Part II 2. completed). Presentation of results in a poster at an international conference

This proposal describes a novel approach for treating ovarian cancer, using drugs already available. Thus clinical testing will be safer and most importantly will benefit women with ovarian cancer quickly. 

Image of: Combining MET inhibition with chemotherapy in ovarian cancer to improve patient outcome

References

  • The role of MET in chemotherapy resistance.
    Wood GE, Hockings H, Hilton DM, Kermorgant S.Oncogene. 2021 Mar;40(11):1927-1941. doi: 10.1038/s41388-020-01577-5. Epub 2021 Feb 1.
  • A direct role for Met endocytosis in tumorigenesis.
    Joffre C, Barrow R, Ménard L, Calleja V, Hart IR, Kermorgant S.Nat Cell Biol. 2011 Jun 5;13(7):827-37. doi: 10.1038/ncb2257.
    Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control.
  • Hockings H, Lakatos E, Huang W, Mossner M, Khan MA, Bakali N, McDermott J, Smith K, Baker AM, Graham TA, Lockley M.Cancer Res. 2025 Sep 15;85(18):3503-3517. doi: 10.1158/0008-5472.CAN-25-0351.
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