Structural Biology of Cancer
The work undertaken by SVI scientists has provided major contributions to identification of targets for cancer therapy, and understanding the mechanisms of cancer growth and spread. This work was recognised in 2012 by a generous grant from the Australian Cancer Research Foundation to help establish the ACRF Rational Drug Discovery Centre. Examples of the cancer projects currently being pursued include:
GM-CSF and IL-3 receptors (with Professors Angel Lopez and Tim Hughes, Centre for Cancer Biology, Adelaide)
Cytokine receptors are transmembrane cell surface glycoproteins that bind specifically to cytokines and transduce their signals that can direct cells to proliferate, differentiate or even die. The GM-CSF, IL-3 and IL-5 family of cytokines regulates the survival, proliferation, differentiation and functional activation of hematopoietic cells. These same cytokines have also been implicated in multiple pathologies resulting from the excessive or aberrant expression of the cytokine or their receptors, in conditions such as certain types of leukaemia. We determined the structure of a GM-CSF:receptor ternary complex, representing the first structure of an "activated" receptor of this family of cytokines. Inspection of the structure revealed exciting insights into the mechanism of receptor activation and provided a unifying molecular explanation for the diverse functional properties of related cytokine:receptor systems. To maximise the drug development opportunities of this discovery we have formed a partnership with the biopharmaceutical company CSL Limited to discover and develop therapeutic antibodies that will disrupt aberrant signalling by the receptor. More recently we have determined the structure of the related IL-3 receptor bound to an antibody discovered by Angel Lopez’s lab and currently being tested in clinical trials for leukaemia treatment by CSL. The structure reveals how the antibody inhibits IL-3 signalling.
Glutathione transferases (with Professor Giorgio Ricci, University of Rome, Italy; Professor Paul Dyson, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Professor Philip Board, Australian National University, Canberra)
Glutathione S-transferases (GSTs) are a supergene family of enzymes that play a pivotal role in the detoxification of foreign chemicals and toxic metabolites. Paradoxically, the detoxifying activity of these enzymes is in part responsible for the development of cellular multi-drug resistance towards a number of chemotherapeutic agents. We have determined more than 50 GST crystal structures which have contributed to an understanding of the molecular basis of substrate recognition and catalysis by the enzyme superfamily. Inhibitors of GSTs have been used in clinical trials as adjuvants in cancer chemotherapy with some success. However, the use of these inhibitors has produced undesirable side effects and more suitable inhibitors are urgently being sought.
Dr Sophie Broughton, Post-doctoral Fellow
Dr Urmi Dhagat, Post-doctoral Fellow|
Dr Craig Morton, Post-doctoral Fellow
Dr Jessica Holien, Post-doctoral Fellow
Dr Tracy Nero, Post-doctoral Fellow
Karen Steffi Cheung Tung Shing, PhD Student
Brendan Stevenson, Honours Student
Professors Angel Lopez and Tim Hughes, Centre for Cancer Biology, Adelaide
Professor Giorgio Ricci, University of Rome, Italy
Professor Paul Dyson, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Professor Philip Board, Australian National University, Canberra
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