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Centenary Institute - Medical Research
Centenary Institute - Medical Research

Gene discovery suggests new treatment approach for liver cancer

In a comprehensive analysis of human gene activation data, researchers from the Centenary Institute have discovered that the dipeptidyl peptidase-4 (DPP4) gene family is strongly implicated in the development of human hepatocellular carcinoma (HCC), the most common type of primary liver cancer.

Reported in the journal ‘Cancers’, the research suggests that the DPP4 gene family and the four enzymes that it contains should be further studied to support potential new therapeutic approaches to fighting tumours found in the liver.

“In this study we interrogated a number of publicly accessible human gene databases including The Cancer Genome Atlas to identify cancers associated with the DPP4 gene family,” said Dr Hui Emma Zhang, researcher in the Centenary Institute’s Liver Enzymes in Metabolism and Inflammation Program and co-senior author on the paper.

“We were focused on the four enzymes of the DPP4 gene family– DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). The role of the DPP9 enzyme was of particular interest as it hadn’t been studied previously with regard to liver cancer in humans,” Dr Zhang said.

Results from the data mining and subsequent analysis undertaken by the research team were revealing.

An association between high levels of the DPP9 enzyme and uterine and lung cancer was found suggesting that further investigatory work in both areas was required.

Elevated levels of DPP9, DPP4, FAP and DPP8 enzymes were also discovered in liver tumours and critically, were associated with poor survival rates in HCC patients.

“Our analysis indicates that high levels of all enzymes of the DPP4 family occur in liver cancers, which encourages us to target these enzymes as a possible new therapeutic approach to tackling the disease,” said Dr Zhang.

“With liver cancer incidence and mortality rates in Australia rapidly increasing new treatment options are urgently required both to improve and to save people’s lives.”

Over 2,000 Australians die each year from liver cancer. The five year survival rate for liver cancer is below 20%.

[ENDS]

Publication: DPP9: Comprehensive in silico analyses of loss of function gene variants and associated gene expression signatures in human hepatocellular carcinoma.

Dual drug approach to treat deadly melanoma

Research from the Centenary Institute has found that a new dual drug approach could offer up a highly effective treatment strategy for melanoma, the most serious form of skin cancer responsible for more than 1,700 deaths each year in Australia.

Reported in the ‘Journal of Investigative Dermatology’ the findings have the potential to benefit melanoma patients who do not respond favourably to current therapeutic treatments.

In the study, the research team found that the combined use of inhibitors targeting two specific proteins markedly reduced the growth of melanoma both in cellular experiments as well in models with mice. The two proteins targeted were the bromodomain and extra-terminal domain (BET) family of proteins and cyclin-dependent kinase 9 (CDK9). High expression of BET and CDK9 proteins are associated with an adverse prognosis in melanoma patients and also regulate melanoma cellular activity.

According to Dr Abdullah Al Emran (pictured) , researcher in the Melanoma Oncology and Immunology Program at the Centenary Institute and lead author of the study, a key finding from the study was that the combination BET and CDK9 inhibitor treatment demonstrated significantly increased melanoma killing benefits when compared to use of the same inhibitor drugs when tested alone.

“Co-targeting BET and CDK9 proteins with inhibitors killed high numbers of melanoma cells regardless of type or status including melanomas exhibiting both BRAF and NRAS genetic mutations. The inhibitors worked by disrupting separate signalling pathways found within the melanoma cells–those responsible for cell communication and growth and this may explain the effectiveness we saw,” he said.

“We also found molecular gene signatures suggesting biomarkers of which melanoma patients were most likely to respond to this BET and CDK9 inhibitor treatment,” he added.

Dr Jessamy Tiffen, Head of the Centenary Institute’s Melanoma Epigenetics Laboratory and senior author on the research paper believes that use of combination drug treatments may offer up a new strategic approach in the fight against the often fatal skin cancer.

“Over half of all melanoma patients do not respond to current therapies and new treatment approaches are urgently required. We’ve now seen that drugs working in combination are able to produce a synergistic effect when it comes to the killing of melanoma cells. This strategy could lead to higher survival rates for patients and as a result we will be further exploring this exciting avenue of research,” she said.

Publication: A combination of epigenetic BET and CDK9 inhibitors for treatment of human melanoma.

Enzyme may be reason why older people and men are more susceptible to COVID-19

A team of Australian researchers, including from the Centenary Institute, has shown in a new study that older people and men tend to have higher levels of the enzyme ACE2 on the cells of their lower lungs–and that this may be the reason for their increased risk from COVID-19.

“The ACE2 enzyme is the entry receptor for the SARS-CoV-2 virus. The spike of the virus binds to ACE2 on the surface of the cell which is a crucial step to the cell being infected,” said Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation and co-author on the study.

“We found increased ACE2 expression occurring in older people and males which may explain their higher risk profiles for COVID-19,” he said.

“We also discovered lower ACE2 levels in people with asthma which may indicate why this population group appear to suffer less from severe coronavirus complications.”

The study was led by Professor Peter Wark from the Hunter Medical Research Institute and the University of Newcastle and was published in the journal ‘Respirology’.

Research paper: ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma.

New method to assist fast-tracking of vaccines for pre-clinical tests

Scientists in Australia have developed a method for the rapid synthesis of safe vaccines, an approach that can be used to test vaccine strategies against novel pandemic pathogens such as SARS-CoV-2, the virus that causes COVID-19. 

Led by Professor Richard Payne at the University of Sydney and Professor Warwick Britton (pictured) at the Centenary Institute, the team has demonstrated application of the method with a new vaccine for use against tuberculosis (TB), which has generated a powerful protective immune response in mice. 

Researchers are keen to develop the vaccine strategy further to assist in the rapid pre-clinical testing of new vaccines, particularly for respiratory illnesses. 

“Tuberculosis infects 10 million and kills more than 1.4 million people every year,” said joint first author Dr Anneliese Ashhurst from the University of Sydney. “Historically, it is the leading cause of death worldwide from a single infectious agent. So far, a TB vaccine that is highly effective and safe to use in all populations has eluded medical science.” 

The only current vaccine for tuberculosis, the Bacille Calmette-Guerin vaccine, uses an injected live bacterium. It is effective in infants but has reduced effectiveness in adolescents and adults and poses significant health risks for immunocompromised patients, particularly for people living with HIV/AIDS. 

Protein-based vaccines have been shown to be very safe, but they must be mixed with enhancers, or adjuvants, to make them effective, which is not straightforward. 

Dr Ashhurst said: “The challenge is to ensure that our immune cells see both the protein and adjuvant simultaneously. To overcome this difficulty, for the first time we have developed a method that synthesises the protein with an attached adjuvant as a single molecule.” 

The vaccine strategy and synthetic technology could be deployed to rapidly generate new vaccines for pre-clinical testing for a range of diseases, the researchers say, including the respiratory pathogen that causes COVID-19. 

Their results are published today in the Proceedings of the National Academy of Sciences of the United States of America

HOW IT WORKS 

In order for vaccines to be effective, they need to stimulate behaviour in protective T-cells that allows them to recognise the pathogen as an antigen, or foreign body. In the case of tuberculosis, our immune system needs to respond quickly to the bacteria that causes TB – Mycobacterium tuberculosis – to reduce infection in lungs. 

Using the method developed by the Sydney scientists, an inhaled vaccine provides a low-dose immune-stimulating molecule – containing a synthesised bacterial protein attached directly to an adjuvant – to the immune cells in the lungs. 

A major hurdle overcome by the scientists was the difficulty in fusing hydrophobic (water-repellent) adjuvants with a water-soluble protein antigen. 

“We got around this problem of keeping hydrophobic and hydrophilic molecules together in a vaccine by developing a way to permanently bind the protein and adjuvant together as a single molecule using synthetic chemistry. Our approach overcomes the solubility problems faced by other methods,” said Professor Payne from the School of Chemistry and Deputy Director of the ARC Centre for Innovations in Peptide & Protein Science (CIPPS). 

The team says that synthesising an entire bacterial protein with attached adjuvant has not been achieved before. 

Professor Britton from the Tuberculosis Research Program at the Centenary Institute said: “As well as providing a rapid method to develop a range of vaccines for pre-clinical testing, we expect that this pulmonary vaccination approach will be particularly beneficial for protecting against respiratory diseases.” 

He said: “We hope that an inhaled vaccine for tuberculosis using a protein-based immunisation will allow us to develop a universal and safe approach to combatting this deadly disease.” 

The other major advantage with this method is that vaccines for a range of diseases can be developed rapidly and safely in the laboratory. 

“We don’t need to grow the actual pathogen in the lab to make the vaccine,” said Dr Ashhurst, who holds a joint position in the School of Chemistry and the School of Medical Sciences. “Using this new method, we can rapidly and safely synthesise highly pure vaccines in the lab and take them straight into animal models for pre-clinical testing.” 

Research paper: Synthetic protein conjugate vaccines provide protection against Mycobacterium tuberculosis in mice.

Read more about the Centenary Institute’s TB related medical research here.

COMMENT: DPP9 enzyme deficit could be key to severe COVID-19 infection

The first study of human gene associations with severe COVID-19 has just been accepted for publication in the highly prestigious journal ‘Nature’.

In the study, led by Dr Kenneth Baillie at the University of Edinburgh, five genetic sequences associated with severe COVID-19 illness were found. The sequences are known to be involved with inflammation and the body’s defence mechanisms.

Professor Mark Gorrell, Head of the Centenary Institute’s Liver Enzymes in Metabolism and Inflammation Program, comments, “I’m particularly interested in this study because one of the proteins identified by this large UK consortium as being associated with severe COVID is an enzyme that we discovered and which we are continuing to investigate at the Centenary Institute, called dipeptidyl peptidase 9 or DPP9.”

“DPP9, an enzyme encoded by the DPP9 gene, has many functions including several related to immune responses and cell growth and cell movement. Potentially most significant to COVID-19, in which inflammation can get out of control, is that DPP9 restrains inflammation. So, we think that possibly a deficit in DPP9 may be exacerbating inflammation.”

Professor Gorrell says that his ongoing work with DPP9 and this Nature paper show that few people have a deficit in DPP9.

“This may be one of the reasons as to why many people experience no symptoms from the illness, while a small minority of others become critically ill.”

Professor Gorrell and his group first discovered the enzyme DPP9 in 1999.  

Gut microbiome link to deadly lung disease

Research led by the Centenary Institute, the University of Technology Sydney and the University of Queensland has shown for the first time a link between chronic obstructive pulmonary disease (COPD), an often fatal lung condition, and the gut microbiome.

The findings, published in the high impact science journal ‘Nature Communications’, suggest that the gut may be helpful in diagnosing COPD and may also be a potential source of new therapeutic targets to help treat the chronic respiratory disorder.

“It’s already known that the lung microbiome is a contributing factor in COPD,” said Professor Phil Hansbro (pictured), senior author of the study and Director of the Centenary UTS Centre for Inflammation.

“We wanted to see if the gut environment was also somehow involved–to determine whether the gut could act as a reliable indicator of COPD or if it was connected in some way to the development of the disease.”

In the study, the researchers compared the microbiome and metabolite profiles of stool samples from COPD patients with healthy individuals. Revealed were significant differences between the two groups.

COPD patients exhibited increased levels of the bacteria Streptococcus and Lachnospiraceae in their stool samples. Also identified in individuals with COPD was a unique metabolite signature–formed by the chemical by-products of the metabolic process.

“Our research indicates that the gut of COPD patients is notably different from healthy individuals,” said first author on the paper Dr Kate Bowerman, University of Queensland.

“This suggests that stool sampling and analysis could be used to non-invasively diagnose and monitor for COPD,” she said.

The study’s researchers believe that the altered gut microbiome found in COPD patients could also support the gut as a potential target for new treatments.

“The ‘gut-lung axis’ describes the common immune system of the lung and gastrointestinal tract. This means that activity in the gut can impact activity in the lung. Our COPD findings suggest that the gut microbiome should now also be considered when looking for new therapeutic targets to help treat lung disease,” said Professor Hansbro.

COPD, a life threatening inflammatory disorder of the lungs, is the third most common cause of death globally. More than 3 million lives are lost every year to COPD.

Researchers involved in the study were affiliated with The University of Queensland, Hunter Medical Research Institute, University of Newcastle, The Prince Charles Hospital, Centenary Institute and University of Technology Sydney.

Publication: Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease.

Read more about our COPD related medical research here.

How the humble sea sponge helped scientists unravel a 700 million-year-old mystery of evolution

In a momentous breakthrough, Australian scientists have found that humans, and most likely the entire animal kingdom, share important genetic mechanisms with a jelly-like sea sponge that comes from the Great Barrier Reef.

Published in one of the most prestigious journals ‘Science’, the breakthrough reveals that some elements of the human genome (an organism’s complete set of DNA) are functioning in the same way as the prehistoric sea sponge. Incredibly this means it has been preserved across 700 million years of evolution. This mechanism drives gene expression, which is key to species diversity across the animal kingdom.

The findings are a fundamental discovery in evolution and the understanding of genetic diseases, and will help drive future biomedical research activities.

Read the full story here.

Pictured: Co-senior author on the paper, Associate Professor Mathias Francois from the Centenary Institute (left) and lead author, Dr Emily Wong from the Victor Chang Cardiac Research Institute (right).

Publication: Early origin and deep conservation of enhancers in animals.

New understanding of how proteins operate

A ground-breaking discovery by Centenary Institute scientists has provided new understanding as to the nature of proteins and how they exist and operate in the human body.

The key finding–the changing state of a protein’s structural bonds–is likely to have significant implications as to how proteins are targeted by medical researchers, particularly in terms of drug development and the fight against disease.

Proteins are responsible for all of life’s processes and had previously been considered to exist in an intact single state when mature. The new study however has found two human proteins involved in blood clotting and immunity existing in different and changing states.

“The most sophisticated molecules made in nature are proteins which consist of unique sequences of amino acids,” said Dr Diego Butera from the ACRF Centenary Cancer Research Centre and lead author of the study (pictured right). “Disulphide bonds link the amino acid chains together and were thought to just stabilise protein structure.”

Previously it has been believed that these disulphide bonds were fully formed in the mature and functional protein. In this study however, the researchers found that the proteins are being produced in multiple disulphide-bonded states.

“We were able to precisely measure whether the disulphide bonds in the blood proteins were formed or broken. Remarkably, we saw that the proteins were made in multiple, possibly thousands, of different disulphide-bonded states,” said Dr Butera.

Professor Philip Hogg, Head of the ACRF Centenary Cancer Research Centre and senior author of the study believes that their research will change how proteins are viewed and targeted in future drug and medical experiments.

“It’s very likely that we will find many other proteins that exist in multiple states. Crucially, a drug may bind more or less preferentially to different states, impacting the effectiveness of the drug.”

“In experimental settings, differing states of a protein should now be considered as part of the investigative medical research process,” Professor Hogg said.

The study was published in the prestigious science journal ‘Nature Communications’.

Publication: Fibrinogen function achieved through multiple covalent states.

Anti-inflammatory benefits from gut bacteria found in fish and humans

Researchers at the Centenary Institute have found that sensitivity of the immune system to ‘good’ gut bacteria is present in zebrafish, proving that the ability of an animal to benefit from good gut bugs is evolutionarily conserved whether you walk or swim.

The study, published in the science journal ‘Gut Microbes’, was an international effort led by Centenary Institute researchers with collaborators from the Duke University School of Medicine, USA and Macquarie University, Sydney.

Using transparent zebrafish embryos, the researchers found that zebrafish inflammatory immune cells are calmed by the addition of butyrate. Butyrate is an important ‘short chain fatty acid’ molecule that is produced when good bacteria ferment dietary fibre in the gut–it’s widely touted as a treatment for a range of inflammatory diseases in humans.

“We found that butyrate treatment on zebrafish reduced inflammatory markers on important immune cells called macrophages (a type of white blood cell) that are the generals of the immune system and that help fight inflammatory diseases,” said Dr Pradeep Cholan (pictured right), lead author of the study and research officer in the Immune-Vascular Interactions Laboratory in the Centenary Institute’s Tuberculosis Research Program.

“From an evolutionary perspective, the fact that zebrafish neutrophils (another type of white blood cell) use the same receptor as human neutrophils to ‘sense’ butyrate and activate anti-inflammatory benefits, is yet another example of co-evolution between animals and their gut bacteria for mutual benefit,” said senior author of the study Dr Stefan Oehlers (pictured left), Head of the Centenary Institute Immune-Vascular Interactions Laboratory and also affiliated with the Discipline of Immunology and Infectious Diseases at the University of Sydney.

This study underpins a wider body of research at the Centenary Institute using transparent zebrafish embryos to analyse the interactions between animals and their gut bacteria during inflammatory disease states.

“We have been excellent at using zebrafish to find ‘bad’ bacteria that cause or worsen diseases in people, but here we show that these tiny fish could contribute to the finding of ‘good’ bugs or prebiotics that act like a natural ibuprofen,” said Dr Oehlers.

The research was funded by the NHMRC, the NSW Health Early-Mid Career Fellowships Scheme and the University of Sydney.

Publication: Conserved anti-inflammatory effects and sensing of butyrate in zebrafish.

Read the full media release here.

Concealed cardiomyopathies revealed in cardiac arrest survivors

Centenary Institute researchers have discovered that genetic testing can identify ‘concealed cardiomyopathies’ in nearly a quarter of sudden cardiac arrest (SCA) survivors who seem to have a normal heart.

The findings will mean improved diagnosis rates and personalised care for SCA survivors as well as guide the screening of family members who may have the same underlying genetic condition.

The study, reported in the ‘International Journal of Cardiology’, undertook genetic testing and analysis of clinically-idiopathic SCA survivors (individuals where previous clinical investigations had failed to reveal a diagnosis).

The researchers identified a genetic cause of arrest in 22% of the SCA survivors studied. The majority of these newly identified cases had genetic abnormalities associated with cardiomyopathy.

“Cardiomyopathies are diseases of heart muscle. They can impair the heart’s ability to pump blood around the body, leading to heart failure but can also cause electrical changes which can lead to dangerous heart rhythms,” said lead author of the study, Dr Julia Isbister from the Centenary Institute’s Agnes Ginges Centre for Molecular Cardiology.

“These conditions are usually detected on clinical tests such as ultrasound but our findings show that state-of-the-art genetic testing may be useful in revealing cardiomyopathy before structural abnormalities are evident.”

Dr Isbister says that identifying the reason for a SCA is critical for both patients and their families.

“If the specific disease can be diagnosed we are better able to implement personalised care for the survivor. If we discover that the SCA is genetically-based we can then screen family members for similar issues. Screening of first-degree relatives is an extremely important aspect of caring for SCA families, aiming to reduce the risk of further cardiac arrests in the family,” said Dr Isbister.

Professor Christopher Semsarian AM, Head of the Centenary Institute’s Agnes Ginges Centre for Molecular Cardiology and senior author on the study says that the role of genetic testing in the management of SCA survivors requires reappraisal given the results of the team’s findings.

“Current guidelines recommend only limited genetic testing of SCA survivors when a specific genetic condition is already suspected. Genetic testing is not generally recommended for those survivors classified as clinically ‘unknown’,” he said.

“Our study has shown that advances in genetic testing technology and analysis can improve diagnosis rates by revealing heart defects that were previously hidden. A reassessment of guidelines and increased genetic testing may lead to better outcomes for survivors, their families and overall prevention of sudden cardiac death in the young.”

Publication: “Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest.