Media release

From: The University of New South Wales

For doctors in training, death becomes a familiar part of hospital life — but every so often, the loss of one patient changes everything.

Scientia Associate Professor Natalia Castaño Rodríguez was a medical intern at the Clínica San Rafael University Hospital in her native Colombia when she met a patient who was a young mother not much older than herself. Within weeks of being diagnosed with pancreatic cancer, she was dead.

“I remember that really marked me and I was like, ‘we need to do something about this – I want to be involved in cancer research’,” says A/Prof Castaño Rodríguez, now a researcher with UNSW’s School of Biotechnology and Biomolecular Sciences.

Drawing on her academic background in immunology and genetics, A/Prof. Castaño Rodríguez was determined to understand how cancers of the digestive system develop, and how they might be prevented. That led her to specialise in stomach cancer, the fourth leading cause of cancer-related deaths globally, and the leading cause of cancer deaths in Colombia.

“And unfortunately, in my home country, people present with the disease quite young,” she says.

“This is normally a type of cancer that presents in people over 50 years old, but in Colombia you see people in their early 30s already with advanced cancer.”

International study

In Australia, stomach cancer isn’t one of the most common cancers, but mortality rates are high if it’s detected late. Different dietary habits, good sanitation, access to early diagnostics and a low prevalence of Helicobacter pylori infection are all factors that keep stomach cancer incidence low, when compared with global hotspots such as South America and East Asia. However, within Australia, stomach cancer is more prevalent among disadvantaged populations lacking access to good healthcare.

A/Prof. Castaño Rodríguez recently won an NHMRC Investigator Grant to examine the intersection between microbes, genetics and the immune system.

She is collaborating with researchers in a global study involving more than 1900 participants across East Asia, the Middle East, Europe, South America and Australia. From these diverse global populations, the researchers will obtain samples and data that will enable them to analyse genetic mutations and the microbiome associated with stomach cancer risk.

“My goal is to represent the low-risk populations, medium-risk populations and high-risk populations around the world to try to create a signature for stomach cancer that is consistent across the different locations,” A/Prof. Castano Rodriguez says.

“Our research lays the groundwork for more precise ways to prevent and treat disease.”

Bacteria, genes and the microbiome

Since the early 1980s, researchers have known that the bacterium Helicobacter pylori causes gastritis and peptic ulcers, thanks to the groundbreaking work of two Nobel-winning, Australian researchers Barry Marshall and Robin Warren, and efforts from UNSW researchers to advance cures for stomach disorders. Up until then, it was believed that stomach ulcers were caused by stress or a build-up of acid.

Not long after, scientists made the link between chronic H. pylori infections and stomach cancer. But while at least half the world’s population is believed to have the H. pylori bug, only a small percentage go on to develop stomach cancer.

“Clearly something else is happening,” says A/Prof Castaño Rodríguez.

“We think development of stomach cancer actually requires a combination of factors: infection with H. pylori, genetic mutations in the patient’s stomach lining and immune cells, and changes in the stomach microbiome.”

She says chronic inflammation from H. pylori infection alters the stomach environment, allowing other bacteria – especially from the mouth – to colonize and produce lactate, which cancer uses as a tool to survive and spread.

“It’s been known for a while that lactate fuels cancer tumour growth, but nobody has really looked closely at the lactate coming from microbes,” says A/Prof. Castaño Rodríguez.

“Microbes can produce really large quantities of lactate, so we need to examine whether bacteria like Lactobacillus that are used in commercial probiotics might contribute to the progression of stomach cancer in a person already presenting with premalignant lesions in the stomach.”

However, she stresses that more research is needed to confirm whether there is any effect from probiotics.

Treatment options

While genetic mutations drive key changes in stomach cancer cells – such as uncontrolled growth – A/Prof. Castaño Rodríguez is also looking at how these cells tap into a natural survival process called autophagy, which helps them cope with stress and stay alive in tough conditions.

Blocking autophagy with existing drugs – some of which are already approved for other conditions – is emerging as a potential strategy to make stomach cancer cells more vulnerable to therapy.

Other treatment options include manipulating the microbiome to limit specific bacteria, such as lactic acid-producing bacteria, while clinical guidelines may be updated to advise caution with probiotics containing certain bacteria for patients with gastric precancerous lesions.

Since 2012, A/Prof. Castaño Rodríguez has led the development of a stomach cancer consortium that includes disadvantaged communities from Asia and South America.

“This focus is crucial as East Asians and South Americans account for 65% of worldwide gastrointestinal cancer cases,” she says.

“And Australia has a substantial migrant population from these regions.

“Identifying host and microbial risk factors in these populations is therefore a pivotal first step to tackle the global burden of disease.”

Looking ahead

A/Prof. Castaño Rodríguez says the next steps are to validate immunogenetic-microbial signatures in prospective human studies and to advance in-vitro and animal models.

“In the medium-term, we would like to initiate the first clinical trial investigating autophagy inhibitors in stomach cancer, and pre-clinical studies using lactate metabolism inhibitors,” she says.