I am a translational researcher based at the Children’s Cancer Institute, where I lead a team of postdoctoral researchers and students focused on the childhood solid tumour neuroblastoma. Children with high-risk neuroblastoma frequently relapse with incurable, drug resistant disease, resulting in long-term survival rates below 50%. We seek to understand the biology of neuroblastoma and to improve patient survival rates through:
- Identifying molecular mechanisms underlying drug resistance
- Developing small molecule inhibitors targeting drug resistance mechanisms, with particular focus on multidrug resistance proteins
- Developing improved pre-clinical testing models for high-risk neuroblastoma, including patient-derived xenograft (PDX) models and models of metastatic disease
- Modelling personalised medicine strategies, including molecular profiling and ex vivo drug sensitivity screening
My team applies high-throughput drug screening, genomic analysis, mouse models, cell biology and tissue-culture based approaches to the study of drug resistance mechanisms, personalised medicine and new drug development in high-risk neuroblastoma. Our high-risk neuroblastoma research is published in leading journals, including JNCI, Cancer Res, Oncogene, Eur J Cancer, Nature Reviews Cancer and Science Translational Medicine.
Kamili A, Gifford AJ, Li N, Mayoh C, Chow SO, Failes TW, Eden GL, Cadiz R, Xie J, Lukeis RE, Norris MD, Haber M, McCowage GB, Arndt GM, Trahair TN, Fletcher JI (2020) Accelerating development of high-risk neuroblastoma patient-derived xenograft models for preclinical testing and personalised therapy. British Journal of Cancer Jan 10, 2020. doi: 10.1038/s41416-019-0682-4.
Koach J, Holien JK, …24 authors…Fletcher JI, Perini G, Parker MW, Cheung BB, Marshall GM. Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface. Cancer Research 79(21):5652-5667.
Huynh T, Murray J, Flemming CL, Kamili A, Hofmann U, Cheung L, Roundhill EA, Yu DMT, Webber HT, Schwab M, Henderson MJ, Haber M, Norris MD, Fletcher JI. (2019) CCI52 sensitizes tumors to 6-mercaptopurine and inhibits MYCN-amplified tumor growth. Biochemical Pharmacology 172:113770.
Gana CC, Hanssen KM, Yu DM, Flemming CL, Wheatley MS, Conseil G, Cole SPC, Norris MD, Haber M, Fletcher JI (2019) MRP1 modulators synergize with buthionine sulfoximine to exploit collateral sensitivity and selectively kill MRP1-expressing cancer cells. Biochemical Pharmacology 168:237-248.
Gamble LD…24 authors…Fletcher JI, Marshall GM, Ziegler DS, Hogarty MD, Burns MR, Perini G, Norris MD, Haber M (2019) Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. Science Translational Medicine 11 (477), eaau1099.
Fletcher JI, Ziegler DS, Trahair TN, Marshall GM, Haber M, Norris MD. (2018) Too many targets, not enough patients: rethinking neuroblastoma clinical trials. Nature Reviews Cancer 18(6):389-400
Murray J, Valli E, Yu DMT, Truong AM, Gifford AJ, Eden GL, Gamble LD, Hanssen KM, Flemming CL, Tan A, Tivnan A, Allan S, Saletta F, Cheung L, Ruhle M, Schuetz JD, Henderson MJ, Byrne JA, Norris MD, Haber M, Fletcher JI (2017) Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumor growth and sensitizes to irinotecan in vivo European Journal of Cancer 83:132-141.
Jung M, Russell AJ, Liu B, George J, Liu PY, Liu T, DeFazio A, Bowtell DD, Oberthuer A, London WB, Fletcher JI, Haber M, Norris MD, Henderson MJ. A Myc Activity Signature Predicts Poor Clinical Outcomes in Myc-Associated Cancers (2017) Cancer Research 77(4):971-981
O'Brien R, Tran SL, Maritz MF, Liu B, Kong CF, Purgato S, Yang C, Murray J, Russell AJ, Flemming CL, von Jonquieres G, Pickett HA, London WB, Haber M, Gunaratne PH, Norris MD, Perini G, Fletcher JI, MacKenzie KL. (2016) MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin Cancer Research 76(12):3604-17.
Lau DT, Flemming CL, Gherardi S, Perini G, Oberthuer A, Fischer M, Juraeva D, Brors B, Xue C, Norris MD, Marshall GM, Haber M, *Fletcher JI, *Ashton LJ (2015) MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma. Oncotarget 6:15510-23.
Cheung L, Yu DM, Neiron Z, Failes TW, Arndt GM, Fletcher JI (2015) Identification of new MRP4 inhibitors from a library of FDA approved drugs using a high-throughput bioluminescence screen. Biochemical Pharmacology 93:380-8.
Cheung L, Flemming CL, Watt F, Masada N, Yu DM, Huynh T, Conseil G, Tivnan A, Polinsky A, Gudkov AV, Munoz MA, Vishvanath A, Cooper DM, Henderson MJ, Cole SP, Fletcher JI, Haber M, Norris MD. (2014) High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4). Biochemical Pharmacology 91:97-108.
Fletcher JI, Gherardi S, Murray J, Burkhart CA, Russell A, Valli E, Smith J, Oberthuer A, Ashton LJ, London WB, Marshall GM, Norris MD, Perini G, Haber M (2012) N-Myc regulates expression of the detoxifying enzyme glutathione transferase GSTP1, a marker of poor outcome in neuroblastoma. Cancer Research 72(4):845-853.
Fletcher JI, Haber M, Henderson MJ, Norris MD (2010) ABC transporters in cancer: more than just drug efflux pumps. Nature Reviews Cancer 10, 147-56.
Fletcher JI, Meusburger S, Hawkins CJ, Riglar DT, Lee EF, Fairlie WD, Huang DCS, Adams JM (2008) Apoptosis is triggered when pro-survival Bcl-2 proteins cannot restrain Bax. Proceeding of the National Academy of Sciences USA 105, 18081-18087.
Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315, 856-859.