Our pancreatic cancer research
Garvan’s pancreatic cancer research is diverse, focusing on translating basic scientific discoveries into the clinic. In the Cancer Theme, Dr Paul Timpson and Dr Marina Pajic are working to define the genetic characteristics of pancreatic cancer, developing biomarkers prognosis and therapeutic responsiveness, and understanding the molecular mechanisms of resistance in order to develop new treatment strategies.
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Key areas of investigation
Dr Marina Pajic leads a team applying genomic data to unlock the molecular biology of pancreatic cancer for new cancer treatments tailored towards individual patients. Working as part of the Australian Pancreatic Cancer Genome Initiative (APGI) and drawing on the expertise of 13 clinical sites across the country, Dr Pajic’s team is testing new drugable targets and therapeutic regimens.
‘We are looking at developing new ways to treat pancreatic cancer where the right treatments are given to the right patients and the therapy is tailored according to the biology of each individual patient tumour.’
Dr Pajic’s collaboration with Professor Andrew Biankin and his research in cancer genomics at Garvan began in 2010 as part of the Australian Pancreatic Cancer Genome Initiative (APGI) work to provide a detailed map of 400 pancreatic tumour genomes. As part of the sequencing effort, Dr Pajic built new patient-derived models of the disease and established a unique personalised medicine project for pancreatic cancer. Dr Pajic and her group are applying a wealth of genomic data to test innovative personalised approaches for the treatment of both primary operable and spreading (metastatic) pancreatic cancer.
‘We are looking at developing new ways to treat pancreatic cancer where the right treatments are given to the right patients and the therapy is tailored according to the biology of each individual patient tumour,’ Dr Pajic said.
Dr Pajic’s group aims to validate new drugable targets and therapeutic regimens in early development for the treatment of pancreatic cancer, develop preclinical models of pancreatic cancer as a platform for comprehensive preclinical screening, and to drive the discovery of prognostic biomarkers and clinically useful biomarker-guided treatment combinations for pancreatic cancer.
‘The molecular make-up of pancreatic tumours varies greatly, with different combinations of thousands of genetic mutations possible, but some tumour subtypes can be targeted with known drugs. We will be testing therapies in models of operable and metastatic pancreatic cancer which target specific molecular aberrations.’
Working with colleagues in Australia and the UK, the group has conducted the most indepth analysis yet of 100 pancreatic cancer genomes and highlighted four subtypes that may help guide future patient treatment. Using whole genome sequencing, the team revealed broad patterns of ‘structural variation’ previously invisible when it was possible to sequence only protein-coding gene – around 1% of the genome.
Four kinds of genomic rearrangement were detected, including ‘stable’, ‘locally rearranged’, ‘scattered’ and ‘unstable’. A promising lead from this study was the suggestion that patients with ‘unstable’ genomes showing defective DNA repair mechanisms tend to respond well to platinum-based drugs which damage DNA, or even newer agents called PARP inhibitors, that prevent cancer cells from repairing their damaged DNA.
Ultimately Dr Pajic and her colleagues aim to isolate and characterise the spectrum of genetic mutations involved in pancreatic cancer to develop a personalised medicine strategy for the disease.
The Australian Pancreatic Cancer Genome Initiative (APGI)
The APGI is an extensive collaborative network of research groups and clinical teams, spanning across local, national and international levels. The APGI has mapped the genome of pancreatic cancer in a landmark effort as part of Australia’s contribution to the International Cancer Genome Consortium (ICGC). This work has revealed valuable information about the extreme complexity of how pancreatic cancer develops, which is proving to be unique for each patient from a genetic standpoint.
The genomic data has provided researchers with the power to identify key genetic “targets” for which new treatment strategies can be designed to pinpoint. This work lead to the first Australian personalised medicine clinical trial in pancreatic cancer, called the Individualised Molecular Pancreatic Cancer Therapy (IMPaCT) trial.
The APGI has a vast program of studies underway, including those studying mistakes in our inherited material that put us at risk for cancer, how our immune system responds to cancer, looking at how to slow a cell that is genetically predisposed to cancer from actually progressing to cancer and the way populations of cancer cells change as they develop.
What is genomics, and why is it essential to improving outcomes for those diagnosed with pancreatic cancer?
All cancer is caused by genetic change; some of that genetic change is inherited, but most genetic damage that causes change occurs in cells as we go through life. A particular genetic change will affect the wrong gene in the wrong cell and that will push that cell along a path to cancer.
The genome is the entire DNA content that is present within one cell of an organism. Genomics involves the study of entire DNA sequences, and using this genetic mapping to help understand disease, such as how these tumours develop and how the tumour cells differ from normal cells.
Genomics is essential to improving outcomes for those diagnosed with pancreatic cancer. It allows researchers to learn about the reasons people develop pancreatic cancers, and how they may best be treated. More specifically, we want to understand how patients may respond to different treatments and how the unique genetic makeup we are born with influences the risk of developing pancreatic cancer.
These efforts are helping improve the ways in which we diagnose pancreatic cancer early, leading to better outcomes for patients. Genomics is also helping to identify better treatments for pancreatic cancer, targeting the specific genetic changes within individual tumours. This makes it possible to customise treatment options based on the genetic make-up of a person’s tumour.
What is the Australian Pancreatic Cancer Genome Initiative (APGI)?
In 2009 the Australian Pancreatic Cancer Genome Initiative (APGI) was formed to undertake a world-first, global study investigating all the underlying genetic events that define pancreatic cancer. Our scientists would decode the instructions of the cells inside a patient’s tumour- their genome- to catalogue the genetic changes (known as “mutations”) important in cancer development.
The APGI evolved as an expansion of the NSW Pancreatic Cancer Network and was established in 2009 as the Australian arm of the International Cancer Genome Consortium (ICGC). The goal was to obtain a comprehensive description of genetic changes in 50 different tumour types which are of clinical and societal importance across the globe, and provide this comprehensive data to the research community.
This was a global and far-reaching effort and remains one of the largest biomedical programs ever undertaken in Australia. It also established the APGI as world leaders in the cancer genomics setting as well as international leaders in biobanking, through the collection, management, processing and distribution of appropriately qualified biospecimens and associated clinical data.
The APGI worked with 11 active clinical sites, and has successfully engaged over 150 clinical and scientific staff from various disciplines in this venture. This collaborative team is extensive, multidisciplinary and global. The APGI has studied over 450 pancreatic cancer patients as part of this effort.
Any researcher looking to study pancreatic cancer now has free access to thousands of data sets, provided by the APGI containing detailed information of hundreds of patients tumours in a summarised, usable format. This is important as it means that researchers who want to test an early idea, or investigate if a particular genetic change they see in another cancer is present in pancreatic cancer, they can do so without having to invest years of work and resources into a project.
Stopping the spread
Dr Paul Timpson leads a group using cutting-edge imaging technologies to pinpoint the molecular drivers of pancreatic cancer as part of its surrounding environment in order to stop it from spreading. Nanotechnology shows in real time that pancreatic cancer tumour cells spread by ‘unzipping’ from each other.
‘Our aim is to effectively “rezip” the tumour cells back together using particular drugs called “anti-invasives” to retard cancer spread.’ Dr Paul Timpson.
‘In pancreatic ductal adenocarcinoma (PDAC) the tumour readily spreads to other organs, thereby increasing the number of sites that require monitoring and treatment. Consequently, we need more effective strategies to predict and counteract cancer spread before it occurs,’ said Dr Timpson, Head Invasion and Metastasis Laboratory.
Cancer invasion and metastasis occur in a complex three-dimensional environment, with reciprocal feedback from the surrounding tissues governing cancer cell behaviour. Intravital or ‘live’ imaging is providing new insights into how cells behave in their native microenvironment, improving our understanding of disease progression and spread.
‘We use novel state-of-the-art intravital imaging and microscopic biosensors as tools to assess cancer invasiveness in live tumours. In real time and in three dimensions, this nanotechnology can show us that pancreatic cancer prepares to spread by the “unzipping” of the tumour cells from each other. Our aim is to effectively “rezip” the tumour cells back together using particular drugs called “anti-invasives” to retard cancer spread.
‘These technologies can also tell us how much, how often and how long to administer anti-invasive drugs for maximised outcomes. Finally, in collaboration with global pharmaceutical companies, we can use our preclinical models of the disease to guide the development of effective anti-invasive treatments that reduce cancer spread and improve patient outcomes.’
Recent studies of the signaling protein ‘Src’, which becomes activated to drive the spread of invasive pancreatic cancer and other cancers, looked at how it could best be deactivated by the cancer drug dasatinib that is already in phase II clinical trials. Dasatinib inhibited invasion of primary PDAC cells generated from this model and significantly reduced the development of metastases by about 50%.
‘Using our intravital imaging technology, we can now show that dasatinib in fact rezips tumour cells back together, thereby keeping pancreatic tumours in place and reducing cancer spread. Our technology has allowed us to identify an early event, prior to invasion and metastasis, that can be treated with drugs to reduce cancer spread in a pre-clinical model of pancreatic cancer.’
‘Through the (Australian Pancreatic Cancer Genome Initiative) APGI samples we have found that a proportion of patient tumours have a Src family kinase signature, making them ideal candidates to directly examine the capacity of anti-invasive treatment in pancreatic cancer,’ Dr Timpson added.