Peter Mace, School of Biomedical Sciences: One Step Closer to Cancer Treatment

Left to Right: Associate Professor Peter Mace, Sam Jamieson, Dr Anita Dunbier

Participants interviewed for the case study

Principal investigator

Associate Professor Peter Mace
Senior Lecturer, Department of Biochemistry

Researcher

Sam Jamieson Senior Technician
Department of Biochemistry

Stakeholder

Dr Anita Dunbier Senior Lecturer
Department of Biochemistry

Summary of the impact

Associate Professor Peter Mace is a biomedical scientist who discovered several structures of a protein with an important role in inflammation, as well as potential roles in some cancers. Impacts of Peter's research to date include building capability in students and staff, creating collaborations and advancing knowledge. Peter has achieved this by addressing knowledge gaps, trying new ideas, building relationships, and disseminating his research findings widely. Potential future impacts include using the protein as a drug target for the treatment of cancer.

Underpinning research

Associate Professor Peter Mace is a structural biologist. The wider aim of his research is to discover the 3D structure of proteins and the influence of structure on function. From his initial discovery in 2014, several structures of a protein called Tribbles have been solved^1,2. Tribbles is encoded by the TRIB1 gene, which is important in inflammation and cancer. The Tribbles protein family is named after a small, furry creature from Star Trek that reproduce rapidly³. Within the cell, the protein produced from the TRIB1 gene plays diverse roles in cell development and signalling⁴.

In 2013 Peter established his laboratory with funding from a Rutherford Discovery Fellowship in the Department of Biochemistry at the University of Otago. Peter initially looking at the basic biology of proteins similar to Tribbles, then investigating Tribbles sequences. There was no structural information about these proteins, so there was space in the field to research fundamental aspects of the 3D shape of these proteins and how they work. Peter found that Tribbles proteins were highly expressed in many cancers, such as breast cancer, and finding their structure and function could potentially lead to using them as a therapeutic target for drug development. Peter is leading the discovery of the structure of these proteins internationally, with several groups interested in the protein's function. Overall, Peter's research has resulted in a greater understanding of how Tribbles proteins are interacting at a cellular level, and what the consequences are of those interactions^{1, 2}.

Peter and his collaborators* produced the first 3D images of the Tribble-1 using the Australian Synchrotron, which uses powerful X-ray beams to image a protein's structure5. Peter's team discovered that Tribble-1 does not have kinase activity, but has a switch-type mechanism when it binds substrates as the active site opens up. The major implication of this is that a large pocket then becomes available where potential small molecule drugs could bind. Research has shown that Tribbles-1 promotes acute myeloid leukaemia, and suggest it could also be involved in breast cancer, so the development of a drug targeting Tribbles-1 could improve outcomes for cancer patients. Breast cancer and leukaemia have the greatest and the 10th-greatest incidence of all cancers in New Zealand, with 87.3 people and 8.8 people affected per 100 000 respectively. The annual public cost of breast cancer is $76.8 million (based on 2008 figures) and $68.5 million for leukaemia^{6, 7}.

Breast cancer researcher Dr Anita Dunbier, who is also in the Department of Biochemistry, collaborates with Peter to explore the connection between breast cancer and Tribbles. Peter approached Anita after he found that Tribble-1 was over-expressed in breast cancer; together they have co-supervised a PhD student Hamish McMillan whose work is focused upon understanding the protein's interactions. A key part of the project used a novel technique called Rapid Immunoprecipitation of Endogenous Proteins (RIME), enabling researchers to examine the protein in the cell in a natural situation to identify the other proteins with which it is interacting, revealing more about its function and potential role in breast cancer.

Peter is also collaborating with Dr Karen Keeshan's (University of Glasgow) laboratory to investigate the role of Tribbles proteins in leukemia. Her lab is working with mouse and human models of leukemia, which is one further step nearer to human studies. They are also developing protein reagents that specifically change levels of Tribbles proteins, which may be applicable in cancer-specific models.

After receiving additional funding from the Health Research Council (HRC), Peter continued to carry out structure determination studies and develop research capability through supervision of an assistant research fellow and senior technician in the lab, and co-supervision of PhD students.

Funding

• HRC, $1.13 million over 3.5 years.
• 2012 Rutherford Discovery Fellowship from the Royal Society of New Zealand, $920,000 over 5 years – generation of preliminary insight
• Lotteries Health Research – indirect funding of equipment that was integral to the research
• New Zealand Synchrotron Group (MBIE and Otago)
• Contract research income from the drug company

Research snapshot

• Peter has two academic publications on Tribbles^{6, 7}. These publications have been cited in 38 academic articles from 13 different countries.
• Peter has been invited to present his research three times in the USA and three times in Europe. Conferences were organised by the Biochemical Society and European Molecular Biology Organization in Europe, and the American Society for Biochemistry and Molecular Biology in the USA (twice). Other seminars were at research institutes or companies.
• Peter spoke about his research on Channel 9 news, and articles were published on his research in the New Zealand Herald⁸, the Otago Daily Times⁹, and stuff.co.nz¹⁰.
• Peter has academic collaborations with James Murphy and Isabelle Lucet (Walter and Eliza Hall Institute, Melbourne) Anita Dunbier (University of Otago) Natarjan Kannan (University of Georgia), and Alison Axtman (University of North Carolina).
• Peter is collaborating internationally with one drug and one biotechnology company.

Details of the impact

Capacity building

• Peter has taught biomedicine to students who go on to work in different fields. For example, Peter teaches in the Bachelor of Science programme, with students going on to a variety of science careers, and some into medicine.
• Peter also plays a major role in the Department of Biochemistry crystallography group and through this is assisting and training a wider group of researchers in synchrotron science and structural biology.
• Hamish McMillan is a PhD student of Māori descent co-supervised by Peter and Anita who won the European Society for Medical Oncology award at the NZ Society for Oncology Conference in 2018, for his talk The Role of Pseudokinase TRIB1 in Breast Cancer. He was the Elman-Poole Scholarship and Majorie McCallum travel award in 2018 to travel to the UK and learn further techniques.
• Senior technician Sam Jamieson, who is of Māori descent, now manages the structural biology resources in the department (after building experience specifically in this project), and will continue to be an integral member of the research workforce.

Economic

• Through the relationship with the drug company, the lab has been able to undertake contract work, screening samples, thus bringing income to the department to support more research.

Advancing knowledge

• Discovery of the Tribbles-1 structure has advanced scientific knowledge in this area. Other research groups have gone on to use the structural findings with Tribbles-1 to draw conclusions on related Tribbles proteins, which also have roles in cancer and metabolic diseases.
• The knowledge generated has drawn attention in the wider field of pseudokinase biology, by demonstrating potential for drug targeting of this type of protein.

Potential impacts

• Several industry groups are now interested in partnering with Peter to characterise Tribbles-binding drugs. This means that they are screening for compounds that bind to Tribbles-1, or will develop these compounds themselves.
• The ultimate impact that this research is working towards is that a drug will be designed and applied that targets Tribbles and reduces the burden of cancer and helps people to achieve better health outcomes.
• Through collaborations with a biotechnology company, it is hoped Peter's lab may be able to both advance compound development and aid workforce development by giving researchers at Otago experience in collaborative drug discovery.

“The work we do is at one end of the process, it might be several steps removed from getting to a patient, but I feel like if we can see how proteins work by solving their 3D structures, inherently other people who're studying those proteins are going to find they're useful. I feel like that's having impact.”

Associate Professor Peter Mace – Department of Biochemistry, School of Biomedical Sciences

Pathway to impact

Characteristics of the research

• Peter has identified that an important part of this research has been filling a knowledge gap of the structure of the Tribbles proteins. Interest has been created around his work as it is novel and of high quality. Novel research also helps to attract grant funding.
• Peter feels it is important that this research is of benefit to other researchers. By working with researchers looking at the function of Tribbles proteins, Peter's research is able to inform other people's research and thus broadens the opportunities for the knowledge to be translated into outcomes.
• Being prepared to try new things is important in this type of discovery research. This includes trying to come up with new analytical techniques in order to push the boundaries of novel science. However, with Peter's research he emphasizes that it is important to choose targets carefully, as this will determine what scientific route will be taken.

“ Peter's good at finding new techniques, and I help to get them to work. You certainly have to be prepared to try a lot of new things, that seems to yield results”.

Sam Jamieson – Senior Research Technician, Department of Biochemistry, School of Biomedical Sciences

• Understanding the problem is important, with the ability to link basic science research through to ultimate impacts, even though these may be a long way off. Anita emphasises the need to understand the clinical problem when working in healthcare. This involves talking to clinicians to gain a good understanding of current issues.

“If you're going for impact in the health sector, you need to be thinking about the use of your research. Make sure you understand the problem, and the clinical problem, and know what's relevant”.

Dr Anita Dunbier – Senior Lecturer, Department of Biochemistry, School of Biomedical Sciences

Grant applications

• Peter feels that the process of writing grants, though sometimes laborious, is useful for developing ideas. It gets you thinking about possible impacts, and framing the research in its most impactful sense can be useful. Impact is an important component in engaging the assessment panel and saying why they should fund the research.

Relationships

• Building personal relationships is a key component to achieving impact. Peter has identified people to work with, for example he approached Anita, in order to collaborate, after he initially found the link between Tribbles and breast cancer. This relationship has informed his knowledge of the clinical relevance of his own work.
• Similarly, other scientists have been interested in forming relationships with Peter because of the quality of his research and because he filled a gap of knowledge in the field.

Funding

• Obtaining consecutive grants (firstly from the Rutherford Discovery Fellowship for the preliminary work, then from the HRC) has enabled the research to develop, whilst also funding the capability-building of staff in this research area. For example, the ongoing HRC funding received in 2015 allowed Sam to be employed as a research technician.

Dissemination

• Peter has observed that people are inherently interested in science, so it is important to talk to the public through the media. Peter finds this is generally received very positively – that it helps as a fundamental science researcher to realistically consider the ultimate potential for impact.
• Conferences are important for networking and exploring new collaborations. This leads to a 'snowball effect', where researchers are able to collaborate more.
• Scientists have become more interested in the Tribbles work the more that it has been disseminated.
• Peter sees his job as providing useful information to people, so that other scientists who are studying these proteins are going to find the work useful.

What next?

• Further funding applications are now being considered to advance Tribbles work in leukaemia, generating reagents that can control protein levels in cells and assisting in structure-based drug design.

References

1. Jamieson SA, Ruan Z, Burgess AE, Curry JR, McMillan HD, Brewster JL, et al. Substrate binding allosterically relieves autoinhibition of the TRIB1 pseudokinase. bioRxiv. 2018:313767.
2. Murphy JM, Nakatani Y, Jamieson SA, Dai W, Lucet IS, Mace PD. Molecular mechanism of CCAAT-enhancer binding protein recruitment by the TRIB1 pseudokinase. Structure. 2015;23(11):2111-21.
3. Wikipedia. TRIB1. 2018.
   https://en.wikipedia.org/?curid=15182086
4. University of Otago. Researchers unlock secrets of troublesome Tribble protein. phys.org. 2015.
   https://phys.org/news/2015-10-secrets-troublesome-tribble-protein.html
5. ANSTO. What is synchrotron light? 2019.
   https://www.ansto.gov.au/education/nuclear-facts/what-is-synchrotron-light
6. Ministry of Health. The price of cancer: The public price of registered cancer in New Zealand. 2011.
   https://www.health.govt.nz/system/files/documents/publications/the-price-of-cancer-0811.pdf
7. World Health Organisation. Estimated age-standardized incidence rates (World) in 2018, Oceania, New Zealand, both sexes, all ages. 2018.
   http://gco.iarc.fr/today/online-analysis-multi-bars?v=2018&mode=cancer&mode_population=countries&population=900&populations=909_554&key=asr&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=10&group_cancer=1&include_nmsc=1&include_nmsc_other=1&type_multiple=%257B%2522inc%2522%253Atrue%252C%2522mort%2522%253Afalse%252C%2522pr ev%2522%253Afalse%257D&orientation=horizontal&type_sort=0&type_nb_items=%257B%2522top%2522%253Atrue%252C%2522bottom%2522%253Afalse %257D&population_group_globocan_id=#collapse-group-0-5
8. Kiwi scientist unlocks secrets of troublesome protein 2015.
   https://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=11526600
9. Gibb J. Research on signalling protein sheds new light on disease processes. Otago Daily Times 2017.
   https://www.odt.co.nz/news/dunedin/research-signalling-protein-sheds-new-light-disease-processes
10. Tarrant P. Science classes pay off for Mace. Stuff.co.nz 2015.
    https://www.stuff.co.nz/waikato-times/73249877/science-classes-pay-off-for-mace