My laboratory uses cutting edge molecular and cellular biology techniques to identify vulnerabilities in leukaemia and lymphoma cells that could be exploited for cancer therapy.
Through our research projects we investigate the contribution of key cellular genes that control proliferation and cell death for the growth and chemosensitivity of both normal and malignant cells.
My laboratory also has a strong interest in virus-associated cancers, in particular in Epstein-Barr virus-associated lymphomas. We aim to understand how viral proteins can manipulate host cell proliferation and death to contribute to cancer development, growth and chemoresistance.
We have a wealth of accurate pre-clinical models of leukaemia and lymphoma that we utilise in our experiments, as well as expertise in the following techniques:
United Kingdom, University of Birmingham, PhD
United Kingdom, Durham University, BSc (Hons)
2018 Victorian Cancer Agency Mid-Career Fellowship
2017 Burnet Prize, The Walter and Eliza Hall Institute
2009 Kay Kendall Leukemia Fund Intermediate Fellowship
2009 Dorothy Hodgkin’s Royal Society Fellowship (declined)
2018-2021 Grant-In-Aid, Cancer Council Victoria
2018-2019 Project Grant, Leukemia Foundation Australia
2017 Philanthropic funding, Craig Perkins Cancer Research Foundation
2015-2018 Project Grant, NHMRC
Aubrey BJ, Janic A, Chen Y, Chang C, Lieschke EC, Diepstraten ST, Kueh AJ, Bernardini JP, Dewson G, O’Reilly LA, Whitehead L, Voss AK, Smyth GK, Strasser A, Kelly GL. Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development. Genes Dev. 2018;32(21-22):1420-1429. PMID: 30366906
Brennan MS, Chang C, Tai L, Lessene G, Strasser A, Dewson G, Kelly GL, Herold MJ. Humanized Mcl-1 mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use. Blood. 2018;132(15):1573-1583. PMID: 30139826
Fitzsimmons L, Boyce AJ, Wei W, Chang C, Croom-Carter D, Tierney RJ, Herold MJ, Bell AI, Strasser A, Kelly GL, Rowe M. Coordinated repression of BIM and PUMA by Epstein-Barr virus latent genes maintains the survival of Burkitt lymphoma cells. Cell Death Differ. 2018;25(2):241-254. PMID: 28960205
Baell JB, Leaver DJ, Hermans SJ, Kelly GL, Brennan MS, Downer NL, Nguyen N, Wichmann J, McRae HM, Yang Y, Cleary B, Lagiakos HR, Mieruszynski S, Pacini G, Vanyai HK, Bergamasco MI, May RE, Davey BK, Morgan KJ, Sealey AJ, Wang B, Zamudio N, Wilcox S, Garnham AL, Sheikh BN, Aubrey BJ, Doggett K, Chung MC, de Silva M, Bentley J, Pilling P, Hattarki M, Dolezal O, Dennis ML, Falk H, Ren B, Charman SA, White KL, Rautela J, Newbold A, Hawkins ED, Johnstone RW, Huntington ND, Peat TS, Heath JK, Strasser A, Parker MW, Smyth GK, Street IP, Monahan BJ, Voss AK, Thomas T. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018;560(7717):253-257. PMID: 30069049
Merino D, Kelly GL, Lessene G, Wei AH, Roberts AW, Strasser A. BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines. Cancer Cell. 2018;34(6):879-891. PMID: 30537511
Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, Chanrion M, Kelly GL, Gong JN, Moujalled DM, Bruno A, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Ondi L, Blasko G, Robertson A, Surgenor A, Dokurno P, Chen I, Matassova N, Smith J, Pedder C, Graham C, Studeny A, Lysiak-Auvity G, Girard AM, Gravé F, Segal D, Riffkin CD, Pomilio G, Galbraith LC, Aubrey BJ, Brennan MS, Herold MJ, Chang C, Guasconi G, Cauquil N, Melchiore F, Guigal-Stephan N, Lockhart B, Colland F, Hickman JA, Roberts AW, Huang DC, Wei AH, Strasser A, Lessene G, Geneste O. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538(7626):477-482. PMID: 27760111
Aubrey BJ, Kelly GL, Kueh AJ, Brennan MS, O’Connor L, Milla L, Wilcox S, Tai L, Strasser A, Herold MJ. An inducible lentiviral guide RNA platform enables the identification of tumor-essential genes and tumor-promoting mutations in vivo. Cell Rep. 2015;10(8):1422-1432. PMID: 25732831
Kelly GL, Grabow S, Glaser SP, Fitzsimmons L, Aubrey BJ, Okamoto T, Valente LJ, Robati M, Tai L, Fairlie WD, Lee EF, Lindstrom MS, Wiman KG, Huang DC, Bouillet P, Rowe M, Rickinson AB, Herold MJ, Strasser A. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev. 2014;28(1):58-70. PMID: 24395247
Kelly GL, Long HM, Stylianou J, Thomas WA, Leese A, Bell AI, Bornkamm GW, Mautner J, Rickinson AB, Rowe M. An Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in burkitt lymphomagenesis: the Wp/BHRF1 link. PLoS Pathog. 2009;5(3):e1000341. PMID: 19283066
Kelly G, Bell A, Rickinson A. Epstein-Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Nat Med. 2002;8(10):1098-1104. PMID: 12219084
BH3 mimetic drugs aim to trigger cell death for cancer therapy through inhibiting cellular pro-survival proteins of the BCL-2 family.
In earlier work we found that expression of the pro-survival protein MCL-1 was required for the continued growth of MYC-driven lymphomas. We have been working with the pharmaceutical company Servier to test novel BH3 mimetic drugs targeting MCL-1 for cancer therapy and related drugs entered clinical trials in 2018.
We are currently seeking to identify factors that could confer resistance, either primary or acquired, to these MCL-1 targeting drugs with the aim to find strategies that could overcome resistance.
Team members: Dr Sarah Diepstraten and Ms Catherine Chang
Approximately 50 per cent of human cancers harbor mutations in the tumour suppressor p53 that result in reduced sensitivity to many conventional chemotherapeutics and a poor prognosis for the patients. We seek to understand how exactly these mutations in p53 contribute to the growth of cancer cells, in particular we are interested to know if there are neomorphic gain-of-function effects of mutant p53. Additionally, we aim to determine if mutant p53 contributes to the growth of established tumours, thereby identifying it as a therapeutic target. For these experiments we have generated novel and sophisticated pre-clinical models of mutant p53 cancers.
Team members: Ms Elizabeth Lieschke and Dr Zilu Wang, PhD students co-supervised by Dr Gemma Kelly and Professor Andreas Strasser
Approximately 200,000 cancers annually are associated with the Epstein-Barr virus (EBV). We are researching the role of EBV in two types of lymphoma – Burkitt’s lymphoma (an aggressive B cell lymphoma), and T/NK cell lymphoma.
In a subset of Burkitt’s lymphomas, EBV expresses a viral homologue of the cellular pro-survival BCL-2 proteins, called BHRF1. We seek to understand how BHRF1 interacts with the cellular apoptotic machinery to block cancer cell death. In the setting of EBV-associated T/NK cell lymphomas we aim to understand how viral proteins contribute to tumour growth and to find alternative therapeutic options since these patients currently have a very poor prognosis.
Team members: Mr Nenad Sejic and Ms Catherine Chang and also a collaboration with the group of Dr Claire Shannon-Lowe at The University of Birmingham
BH3 mimetic drugs targeting the pro-survival protein BCL-2 have shown efficacy in the clinic for the treatment of patients with chronic lymphocytic leukemia (CLL).
More recently, BH3 mimetics targeting the related BCL-2 family protein, MCL-1, have shown promise for the treatment of certain blood cancers in pre-clinical models and entered clinical trials for these cancers in 2018.
Two of the other BCL-2 pro-survival proteins, BCL-W and BFL-1/A1, are by comparison relatively understudied. We are using genetically engineered pre-clinical lymphoma models and CRISPR/Cas9 genome editing of blood cancer cells to determine if drugs targeting BCL-W and BFL-1/A1 would have therapeutic potential.
Team members: Dr Sarah Diepstraten, working in collaboration with the groups of Professor Andreas Strasser and Associate Professor Marco Herold