Research

Our research group is involved in investigating nuclear and mitochondrial DNA repair as a therapeutic target in cancer. In particular, we have focused on the DNA mismatch repair (MMR) pathway, the system for recognising and repairing mistakes in DNA replication and so preventing genetic mutations.

MMR deficiency results in an increased predisposition to cancer, in particular colorectal and endometrial. We have previously carried out high-throughput screening of small interfering RNA (siRNA) and compounds and identified DNA polymerases, POLB & POLG, and the mitochondrial kinase PINK1 as novel targets for the treatment of MMR deficient disease. This work also led to the elucidation of MLH1 as a regulator of mitochondrial metabolism. We have also identified the drug Methotrexate as a selective, cytotoxic agent for cancers that are deficient in the mismatch repair gene, MSH2. These findings have led to a Phase 2 clinical trial in patients with metastatic colorectal cancer.

More recently, we are investigating the role of MMR loss and the differential response to immune checkpoint inhibition. In addition, we are involved in the identification of novel players in the DNA damage response and how they may be therapeutically targeted.

Other Activities

• Research Advisory Committee for Wellbeing of Women
• Editorial Board member for Scientific Reports
• Scientific Advisory Panel for Breast Cancer UK
• Member of the British Lung Foundation College of Experts
• Editorial Advisory Panel for the Biochemical Journal
• Member of The British Association for Cancer Research
• Member of the  Biochemical Society
• External examiner - Newcastle University
• Grant evaluator panel - "Le Caixa Foundation" Spain

Major Funding

• 2020-2024- Cancer Research UK, Defining the genetic determinants of mismatch repair deficient tumours that predicts response to immune checkpoint blockade, £110,000 
• 2019-2020- Barts Charity, Dissecting the role of DNA mismatch repair loss in Endometrial Cancer Metastasis, £46,000
• 2018 - 2022- Barts Charity, Identification of DNA damage signatures that predict response to immune checkpoint blockade, £252,000
• 2017-2021- Medical Research Council (MRC), Identification of biomarkers that predict response to immune checkpoint blockade in DNA Mismatch Repair deficient cancers, £110,000
• 2017-2021- Cancer Research UK, Targeting ADI-PEG20 resistance in mesothelioma, £110,000
• 2016-2019- British Lung Foundation, Overcoming resistance to arginine deprivation therapy in mesothelioma, £149,076

Recent Publications

Microtubule-associated proteins MAP7 and MAP7D1 promote DNA double-strand break repair in the G1 cell cycle phase Dullovi A, Ozgencil M, Rajvee V et al. iScience (2023) 26(7)

Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy Hoare JI, Osmani B, O’Sullivan EA et al. Communications Biology (2022) 5(7)

The combination of the metabolism-based targeted therapies ADI-PEG20 and GC7 are a promising strategy for the treatment of malignant pleural mesothelioma Carpentier J, Szlosarek P, Martin SA European Journal of Cancer (2022) 174(7) S64

Statin Treatment as a Targeted Therapy for APC-Mutated Colorectal Cancer Shailes H, Tse WY, Freitas MO et al. Frontiers in Oncology (2022) 12(7)

A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma Dell’anno I, Melani A, Martin SA et al. Cancers (2022) 14(7)

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes Davidson K, Grevitt P, Contreras-Gerenas MF et al. Cell Death and Disease (2021) 12(7)

Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer Silva VL, Saxena J, Nicolini F et al. Cell Death and Disease (2021) 12(7)

The emerging relationship between metabolism and DNA repair Cucchi D, Gibson A, Martin SA Cell Cycle (2021) 20(7) 943-959

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma. Dell'Anno I, Martin SA, Barbarino M et al. Invest New Drugs (2020) 39(1) 1-14
https://www.ncbi.nlm.nih.gov/pubmed/33300108

MLH1 deficiency leads to deregulated mitochondrial metabolism Martin S Cell Death and Disease (2019) 10(1) 795-795

Team

Postdoctoral Researchers

• Dr Betty Tse

PhD Students

• Amy Gibson
• Kirsten Brooksbank
• Sapna Manglani

Biography

I studied a BSc (Hons) in Microbiology at the National University of Ireland, Galway and completed my PhD in molecular biology from the same University in 2003. During my PhD, I studied the gene expression profiles of the hepatic and ocular tissues of the Atlantic salmon with Dr Richard Powell.

I then moved to a postdoctoral position in the Mount Sinai School of Medicine in New York to join Dr. Toru Ouchi’s group, where I investigated the role of BRCA1 and its functional binding partners, specifically investigating the regulation of caspase-3 activation by BRCA1 phosphorylation. I was awarded a postdoctoral fellowship from the New York State Health Research Science Board.

In 2006, I joined Prof Alan Ashworth’s group in the Breakthrough Breast Cancer Research Centre in the Institute of Cancer Research, London. Here, I carried out high-throughput RNAi and compound screens to identify synthetic lethal interactions with deficiency in the DNA mismatch repair pathway.

I joined Barts Cancer Institute as a principal investigator in September 2010. My research group is focused on DNA mismatch repair deficiency and identifying new ways of treating cancer by targeting defects in nuclear and mitochondrial DNA repair. I was awarded the 2011 CRUK Future Leader in Cancer Research Prize.