Professor Brian Gabrielli
|Associate Professor Brian Gabrielli|
Cancer Program Head
Over time, cells collect mutations that slip through the normal DNA repair mechanisms, yet melanoma cells collect far more than expected, even compared to other cancers. This is curious, considering the primary DNA repair mechanism is intact in most melanomas. Professor Brian Gabrielli is searching for cell cycle defects responsible for this, and believes it is the key to developing improved melanoma diagnostics and selective cancer treatments with long term benefits.
Gabrielli credits a high school chemistry teacher with inspiring him to pursue science. He went on to earn both a Bachelors and Honours degree in Biochemistry and Chemistry from James Cook University in Queensland, where his natural affinity for science opened up new opportunities. During his PhD at La Trobe University in Melbourne, Gabrielli was introduced to the world of cell cycle biology. His first post-doctoral position at the University of Colorado in the US only strengthened his interest.
“They were at the forefront of cell cycle research,” he recalls. “It was exciting and brand new. Just the sort of thing for a young post-doc.”
His work led him to the laboratory of Professor Helen Piwnica-Worms at Harvard Medical School. Together they worked on a class of proteins called CDC25s, which were known to regulate part of the cell cycle called mitosis. Because cancer arises from unchecked cell cycle defects that occur during mitosis, looking at key regulators was the next big thing.
Gabrielli returned to Australia to characterise a new CDC25 at the Queensland Institute for Medical Research. He then moved his research team to the Pathology Department at the University of Queensland. By looking at how drugs and UV radiation affected mitosis, Gabrielli and his colleagues were able to identify new regulatory mechanisms in the cell cycle. He admits his interest in UV was influenced in part by his Queensland location, which meant numerous colleagues were working on melanoma.
In 2002, Gabrielli moved his cell cycle research to UQ’s Centre for Immunology and Cancer Research (CICR), which later became incorporated into the UQ Diamantina Institute (UQDI). He is now a Professor and Head of the Cancer Program at UQDI, and his goal is to identify and target cell cycle defects in melanoma.
“We want to see if we really can deliver tumour-selective, cytotoxic insults to melanoma,” he says. “We can use tools developed at UQDI to improve that targeting and we also want to identify the markers of these defects so we can identify precisely which patients can benefit from selective treatments.”
Because melanomas are extremely difficult to completely eliminate, he believes the best strategy will be to integrate specific anti-tumour treatments with immunotherapies that enable long term cancer surveillance, essentially using the body’s own immune system to keep melanoma in check.
Already his group has identified a defect most likely responsible for the increased mutation load in melanoma. They found that, in normal skin cells, UV radiation causes the cell cycle to pause at the ‘G2 phase-checkpoint’, just before mitosis begins. This checkpoint arrest then triggers a secondary DNA repair mechanism that fixes any damage missed by the primary repair mechanism. Gabrielli found that this coupled checkpoint-repair mechanism is defective in a substantial number of melanoma cell lines, allowing UV-induced genetic damage to accumulate.
Gabrielli believes there are numerous advantages in carrying out his melanoma research at UQDI. “The combination of Professor Matt Brown’s ability to look at coding regions of the genome together with our ability for functional assessment places us in a very unique position,” he says. Taken together with the clinical collaborations with the PA Hospital, he believes only a few places in the world can boast such a combined advantage, particularly in melanoma research.
“It’s a combination of interest, facilities, resources and expertise. On top of that,” he adds, “there’s a really good group of collaborative colleagues here to work with.”
Telephone: +61 7 3443 7092
Dr Colin DeSouza – Research Fellow, Ohio State University, USA.
Dr Andrew Burgess – Research Fellow, Garvan Institute, Sydney, Australia
Dr Kelly Brooks - Postdoctoral Fellow, Patterson Institute of Medical Research, Manchester UK
Dr Tanya Pike - Postdoctoral Fellow, London Research Institute, UK
Dr Puji Astuti - Lecturer, Faculty of Pharmacy Universitas Gadjah Mada, Yogyakarta, Indonesia
Dr Vanessa Oakes - Clinical Research Associate, LEO Pharma, Brisbane
Dr Melissa Brown - Research Officer, Australian Centre for Blood Diseases, Monash University, Melbourne
10 Recent Publications
Spoerri, Loredana, Oo, Zay Yar, Larsen, Jill E., Haass, Nikolas K., Gabrielli, Brian and Pavey, Sandra (2015). Cell cycle checkpoint and DNA damage response defects as anticancer targets: from molecular mechanisms to therapeutic opportunities.. In Georg T. Wondrak (Ed.), Stress response pathways in cancer: from molecular targets to novel therapeutics (pp. 29-49) Dordrecht: Springer Science+Business Media. doi:10.1007/978-94-017-9421-3_3
Ravindran Menon, D., Das, S., Krepler, C., Vultur, A., Rinner, B., Schauer, S., Kashofer, K., Wagner, K., Zhang, G., Bonyadi Rad, E., Haass, N. K., Soyer, H. P., Gabrielli, B., Somasundaram, R., Hoefler, G., Herlyn, M. and Schaider, H. (2015) A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene, 34 34: 4448-4459. doi:10.1038/onc.2014.372
Pinder, Alex, Loo, Dorothy, Harrington, Brittney, Oakes, Vanessa, Hill, Michelle M. and Gabrielli, Brian (2015) JIP4 is a PLK1 binding protein that regulates p38MAPK activity in G2 phase. Cellular Signalling, 27 11: 2296-2303. doi:10.1016/j.cellsig.2015.08.009
Irvine, Katharine M., Skoien, Richard, Bokil, Nilesh J., Melino, Michelle, Thomas, Gethin P., Loo, Dorothy, Gabrielli, Brian, Hill, Michelle M., Sweet, Matthew J., Clouston, Andrew D. and Powell, Elizabeth E. (2014) Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration. World Journal of Gastroenterology, 20 47: 17851-17862. doi:10.3748/wjg.v20.i47.17851
Ainger, Stephen A., Yong, Xuan L., Wong, Shu S., Skalamera, Dubravka, Gabrielli, Brian, Leonard, J. Helen and Sturm, Richard A. (2014) DCT protects human melanocytic cells from UVR and ROS damage and increases cell viability. Experimental Dermatology, 23 12: 916-921. doi:10.1111/exd.12574
Oakes, Vanessa, Wang, Weili, Harrington, Brittney, Lee, Won Jae, Beamish, Heather, Chia, Kee Ming, Pinder, Alex, Goto, Hidemasa, Inagaki, Masaki, Pavey, Sandra and Gabrielli, Brian (2014) Cyclin A/Cdk2 regulates Cdh1 and claspin during late S/G2 phase of the cell cycle. Cell Cycle, 13 20: 3302-3311. doi:10.4161/15384101.2014.949111
Brooks, Kelly, Ranall, Max, Spoerri, Loredana, Stevenson, Alex, Gunasingh, Gency, Pavey, Sandra, Meunier, Fred, Gonda, Thomas J. and Gabrielli, Brian (2014) Decatenation checkpoint defective melanomas are dependent on PI3K for survival. Pigment Cell and Melanoma Research, 27 5: 813-821. doi:10.1111/pcmr.12268
Sierecki, Emma, Stevers, Loes M., Giles, Nichole, Polinkovsky, Mark E., Moustaqil, Mehdi, Mureev, Sergey, Johnston, Wayne A., Dahmer-Heath, Mareike, Skalamera, Duka, Gonda, Thomas J., Gabrielli, Brian, Collins, Brett M., Alexandrov, Kirill and Gambin, Yann (2014) Rapid mapping of interactions between human SNX-BAR proteins measured in vitro by AlphaScreen and single-molecule spectroscopy. Molecular and Cellular Proteomics, 13 9: 2233-2245. doi:10.1074/mcp.M113.037275
Sturm, Richard A., Fox, Carly, McClenahan, Phil, Jagirdar, Kasturee, Ibarrola-Villava, Maider, Banan, Parastoo, Abbott, Nicola C., Ribas, Gloria, Gabrielli, Brian, Duffy, David L. and Soyer, H. Peter (2014) Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients. Journal of Investigative Dermatology, 134 1: 141-149. doi:10.1038/jid.2013.272
Pavey, Sandra, Spoerri, Loredana, Haass, Nikolas K. and Gabrielli, Brian (2013) DNA repair and cell cycle checkpoint defects as drivers and therapeutic targets in melanoma.. Pigment Cell and Melanoma Research, 26 6: 805-816. doi:10.1111/pcmr.12136
- Identifying the molecular basis for defective checkpoints in melanoma.
- Targeting defective cell cycle responses to ultraviolet radiation and TopoII inhibitors in melanoma.
- Defining the molecular changes in moles underpinning morphological changes detectable by non-invasive imaging techniques to improve their diagnostic and prognostic ability for early stage melanoma.