In their NHMRC-funded research, Professor David Craik and his team aimed to stabilise peptides and thus unleash their potential as drugs and imaging agents. Using the venom of a scorpion, the team created synthetic versions of a naturally occurring peptide called chlorotoxin. In turn, these peptides were used to optimise a revolutionary tumour imaging agent for brain surgery operations.
Photo credit: Tony Phillips
Professor Norelle Daly
Dr Jim Olson
Dr Muharrem Akcan
Ms Paola Ojeda
Dr Conan Wang
Dr Richard Clark
Dr S nia Troeira Henriques
Dr Yen-Hua Huang
Professor David Craik and his team set out to make synthetic derivatives of a naturally occurring peptide, chlorotoxin, from the venom of a scorpion to use for brain tumour imaging. The work was based on a discovery by collaborator, Dr Jim Olson, that through attaching a dye to chlorotoxin it could be used to ‘light up’ tumours. This allows surgeons to pick up small amounts of cancerous tissue during surgery, reducing the risk of the tumour reoccurring.
Brain cancer kills more children in Australia than any other disease.1
In their NHMRC-funded research, Professor David Craik and his team aimed to stabilise peptides and thus unleash their potential as drugs and imaging agents.
Using the venom of a scorpion, the team created synthetic versions of a naturally occurring peptide called chlorotoxin. In turn, these peptides were used to optimise a revolutionary tumour imaging agent for brain surgery operations.
“Peptides have often been regarded as great drug leads, but the pharmaceutical industry has shied away from them because they can be unstable,” Professor Craik explained.
“The broad goal of our research is to overcome current limitations on the use of conventional peptides as drugs.”
The team stabilised the peptides through cyclisation, a process where the head and tail ends of the protein chain are joined together to make a circular protein that is exceptionally stable.
They developed chemical methods for synthesising chlorotoxin, and tested its ability to bind to tumour cells to use as a diagnostic tumour imaging agent.
“We found that by cyclising the natural chlorotoxin we were able to stabilise it to improve one of its biopharmaceutical properties, that is its stability in serum.
“This process also improved our ability to more specifically label the peptide with a fluorescent dye to be used in tumour imaging.”
The ultimate benefit of this work is that surgeons will be able to better define the margins of tumours during brain surgery.
“Using labelled chlorotoxin molecules to ‘light up’ tumours, surgeons will be able to pick up small amounts of cancerous tissue on the margins of tumours and thereby reduce the possibility of the tumour reoccurring,” he adds.
"This work will improve the outcomes for brain cancer patients by reducing the risk of tumours reoccurring."
Professor Craik attributes a key collaboration with Dr Jim Olson from the Fred Hutchinson Cancer Research Centre and Seattle Children’s Hospital to the success of the project.
Dr Olson had already discovered that coupling a fluorescent dye with chlorotoxin allowed the dye to target brain tumours in order to ‘light up’ the tumour during surgery.
“He came to my lab to learn peptide synthesis so that we might be able to improve the initial molecule,” Professor Craik explained.
Although the molecules made when Dr Olson worked in the Craik lab were not ultimately chosen for the clinical product, relationships built during his Australian visit led to the first clinical trials of BLZ-100 “tumor paint” being conducted in Queensland.
Blaze Bioscience, the company that developed the current clinical investigational agent, set up a subsidiary in Australia and ran the first phase 1 study of BLZ-100 in skin cancer patients. The molecule is now being tested in additional clinical trials, including one more in Australia.
The research paves the way for an exciting future in imaging and combatting the devastating effects of brain tumours.
Professor Craik now seeks to understand exactly how the chlorotoxin peptide targets tumours. Over the years, various theories have been proposed, but so far there is still no definitive information on how exactly this molecule crosses the blood brain barrier to reach tumours. More fundamental work needs to be done to understand this, and Professor Craik is excited to find out.
Brain cancer: the harsh truths
Brain cancer costs more per patient than any other cancer because it is highly debilitating, affects people in their prime and often means family members cannot work if they become carers.2 On average, approximately 1600 brain cancers are diagnosed each year in Australia; approximately one person diagnosed every five hours.3 Only two in ten people diagnosed with brain cancer will survive for at least five years.4
1 ABS (2010 – 2014), 3303.0 Causes of Death, Australia (2009 – 2013), ‘Table 1.3: Underlying cause of death, Selected causes by age at death, numbers and rates, Australia, Ages 1 - 14 (2009 – 2013)
2 The Cost of Cancer NSW – report by Access Economics, Australia wide, April 2007.
3 AIHW 2015. ACIM (Australian Cancer Incidence and Mortality) Books. AIHW: Canberra. Five year average incidence figure (2007 – 2011) http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=10737422721
4 AIHW 2012. Cancer survival and prevalence in Australia: period estimates from 1982 to 2010. Cancer Series no. 69. Cat. No. CAN 65. Canberra: AIHW pg 42.