Our research is based on exploiting DNA repair defects in cancer for the identification of new personalised therapies. We use compound and siRNA screening to identify new therapeutics for tumours based on their specific DNA repair status.
Drug-Repositioning Screens Identify Triamterene as a Selective Drug for the Treatment of DNA Mismatch Repair Deficient Cells. Clin Cancer Res (2017) 23(11):2880-2890. PMID: 27913567
Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1. Cell Rep (2016) 16(6): 1604-1613. PMID: PMC4978703
Parallel High Throughput RNA interference Screens Identify PINK1 as a Potential Therapeutic Target for the Treatment of DNA Mismatch Repair Deficient Cancers. Cancer Res (2011) 71(5):1836-48. PMID: 21242281
DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins, MSH2 or MLH1. Cancer Cell (2010) 17(3): 235-48. PMID: 20227038
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 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.
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.
We are also investigating the role of mitochondrial DNA repair in cancer and whether this can be targeted as a therapeutic strategy.
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
MLH1 deficiency leads to deregulated mitochondrial metabolism Martin S Cell Death and Disease (2019) 10(1) 795-795
MA 19.05 Pegylated Arginine Deiminase Potentiates PD-1/PD-L1 Immune Checkpoint Blockade in Malignant Mesothelioma Szlosarek P, Khadeir R, Sheaff M et al. Journal of Thoracic Oncology (2017) 12(10) s1884
Abstract A31: Targeting APC loss using synthetic lethality in Colorectal Cancer Shailes H, Bridge G, Foxler D et al. (2017) (10) a31-a31
Targeting APC loss using synthetic lethality in Colorectal Cancer Shailes H, Bridge G, Foxler D et al. MOLECULAR CANCER THERAPEUTICS (2017) 16(11)
Drug-repositioning screens identify triamterene as a selective drug for the treatment of DNA mismatch repair deficient cells Guillotin D, Austin P, Begum R et al. Clinical Cancer Research (2017) 23(7) 2880-2890
Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1 Locke M, Ghazaly E, Freitas MO et al. Cell Reports (2016) 16(1) 1604-1613
Abstract 1050: Inhibition of the polyamine synthesis pathway is synthetically lethal with loss of argininosuccinate synthase 1 in cancer Szlosarek PW, Locke M, Ghazaly E et al. (2016) (10) 1050-1050
570 RAD51 and BRCA2 enhance oncolytic adenovirus type 5 activity in ovarian cancer Tookman L, Ashley B, Connell C et al. European Journal of Cancer (2016) 61(10) s124
RAD51 and BRCA2 enhance oncolytic adenovirus type 5 activity in ovarian cancer Tookman L, Ashley B, Connell C et al. EUROPEAN JOURNAL OF CANCER (2016) 61(11) S124-S124
Postdoctoral Researchers in this group
Dr Danilo Cucchi
Ms Josephine Carpentier, Ms Rebecca Downing, Ms Charlotte Smith, Ms Wai Yiu (Betty) Tse
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.