The microbiome has been a buzzword for years because of its association with a number of diseases, from obesity to Crohn’s disease. Now researchers around the world are increasingly interested in the potential links between cancer and the microorganisms that call our body home – which, if real, would open up a host of new opportunities to understand and tackle the disease. We take a look at what’s happening in this rapidly developing field and ask some of its leading figures if they think it will live up to the hype.
In November 2016, Dr Jennifer Wargo stood in front of an audience in Liverpool to speak about two things with no immediately obvious connection – faeces and skin cancer. An Associate Professor at the University of Texas MD Anderson Cancer Center, Jennifer was closing the National Cancer Research Institute’s conference by presenting results from her study examining more than 100 faecal samples from people with advanced malignant melanoma.
Soon the connection became clear. The patients whose cancer responded well to certain new cutting-edge immunotherapies had more diverse and different types of bacteria in their gut. “Our research shows a really interesting link that may mean the immune system is aided by gut bacteria when responding to these drugs,” said Jennifer.
This is an intriguing area of research which potentially offers a lot of promise but also has many uncertainties at present. It will take innovative and multi-pronged approaches to untangle the complexities, and this is why we’ve identified it as one of the big questions in the next round of our Grand Challenge award.
Dr Iain Foulkes, Executive Director of Research & Innovation at CRUK
Jennifer’s study builds on the hypothesis that by altering gut bacteria you might improve a person’s response to immunotherapies, increasing the numbers who could potentially benefit from these new cancer drugs. Her results reinforce earlier mouse studies, although the bacteria are different. And it appears that the benefits may not be limited only to response to these drugs, with other studies showing that feeding certain bacterial species to antibiotic-treated or germ-free mice receiving treatment can also reduce a dangerous side effect from the treatment – the inflammatory bowel condition, colitis.
This research highlights a rapidly developing new avenue in cancer exploration that focuses on the human microbiome, the complex ecosystem of thousands of different microorganisms that call our bodies home. Imbalances in the microbiome (or ‘dysbioses’) have already garnered a lot of interest in the medical world as a potential player in numerous conditions, from inflammatory bowel disease to multiple scelorosis, diabetes (type 1 and type 2), allergies, asthma, obesity and even autism.
The human microbiome is composed of the trillions of bacteria, archaea, viruses and eukaryotic microbes that live in and on our bodies.
Initial estimates were that microorganisms could outnumber human cells in the body by 10 to 1, but more recent figures suggest the ratio is actually much lower – 3 to 1 or even 1 to 1.
It is calculated that there are more than 10,000 different species occupying the human ecosystem.
There is an extraordinary diversity between the healthy microbiomes of different individuals.
The microbiomes of different organs within the body are distinct.
99% of the body’s microbial mass is in the gut – which is why it’s the most well-studied.
An explosion of interest
Attention on cancer and the microbiome is coming from several directions. First, from the research community – clearly demonstrated by the fact that between 2005 and 2015 the number of published articles on the topic increased by nearly 2,000%. The media have also leapt on the bandwagon, capturing the public’s imagination with reports of its potential for preventing and treating various diseases by targeting and ‘rebalancing’ our microbiomes. And results from early studies like Jennifer’s have spurred industry to back research into live biotherapeutics (or probiotics), with several start-ups backed by heavy investment. Even some of the giants of the pharma sector, including Bristol-Myers Squibb and Roche, are moving into the microbiome immuno-oncology space.
Researchers are also actively exploring what role the microbiome might play in the development of cancer, and their early findings make interesting reading (see box below). The microbiome appears to differ between people with cancer and those without, and the disease can develop in a healthy mouse after transferring the microbiome, via a faecal transplant, from another with colorectal cancer. Several species of bacteria are also potentially connected with cancer, with researchers finding them in higher proportions in people with the disease. This opens up intriguing possibilities that a certain microbiome may be a risk factor in developing cancer or could be used as a new diagnostic tool.
Jennifer calls the science “potentially game changing” for cancer. “We have made tremendous advances in cancer treatment over the decades, with personalised medicine and immunotherapy that target components of the tumour cells. The next era we are entering is to understand not only the tumour but other parts of the individual, such as interactions with the immune system and the scaffolding in the surrounding tissues that counts towards the development of cancer and how it responds to treatment,” she says.
This is a whole new aspect of cancer therapy. Could we predict responses? Could we treat cancer more effectively by modulating the microbiome? Or prevent it altogether? That’s why it’s exciting.
Dr Jennifer Wargo
But looking behind the scenes, a number of important challenges still remain for researchers in the field – particularly around teasing out which changes to the microbiome are meaningful, if any, and distinguishing between cause and effect. The latter is indeed a very big caveat, as researchers are yet to properly establish whether changes in the microbiome contribute to cancer onset and progression, or whether the changes seen are a consequence of the disease.
Hypothetically, this perhaps isn’t such a big jump as there are already well-known microbes that can cause cancer, such as Helicobacter pylori and human papillomavirus (HPV). But as Paul O’Toole, Professor of Microbial Genomics at the APC Microbiome Institute at University College Cork, notes, the scientific community has been criticised for hype before. “It’s important to make clear that these are association studies,” Paul says. “There is no causal link. Sure some research hints at causation, but such studies have been done in mouse models, which can’t be replicated in humans.” The solution, he says, is to study people and follow their microbiome over a long time, comparing it between people who develop cancer with those who don’t.
But many others within the community are becoming more confident that there is indeed a connection. A 2013 opinion piece in Nature Reviews Cancer states: “Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis.”
And while the evidence continues to stack up, many researchers believe the potential mechanism is through our resident microbes’ influence on the immune system, with their abilities to dial up or dampen down inflammation as well as to manipulate the capabilities of our immune cells. For instance, it has been known for years that inflammation is central to the development of colorectal cancer, but there have been question marks over its source – and now fingers are pointing towards the microbiome.
But the relationship is complex, with some studies suggesting certain bacteria can promote tumour growth while others appear to inhibit it – and, in some cases, they might even switch roles in different cancers. At the moment, there are simply too many moving parts – we don’t understand enough about which species is doing what, how they change over time and how they interact to know what role they play in disease and what we might be able to target. And we need to relate any results seen in laboratory animals with what actually happens in patients. Despite the challenges, the potential is enormous and is continuing to fuel the current flurry of interest.
The microbiome is a plastic environmental factor. If it is found to be an additional determinant of cancer then we can modulate it. That’s exciting.
Professor Paul O’Toole
Some recent findings exploring the role of the microbiome in cancer
2011 – Studies identify that Fusobacterium is found more often in colon cancer tissues than healthy tissue.
2013 – University of Michigan researchers show that transferring the gut microbes from a mouse with colon cancer to those with no microbiome sees them develop two times more tumours than mice receiving microbes from a healthy mouse.
2014 – Researchers at the European Molecular Biology Laboratory predict the presence of colorectal cancer from the abundance of bacterial species in stool samples, with about the same accuracy as a blood test.
2016 – NYU Langone Medical Centre find that people whose oral microbiome includes Porphyromonas gingivalis, linked with gum disease, have a 59% greater risk of developing pancreatic cancer compared to those who do not.
2016 – Researchers from Kumamoto University in Japan find that people whose oesophageal tumours test positive for Fusobacterium nucleatum have poorer survival chances.
2016 – Researchers at the University of Texas MD Anderson Cancer Centre show that people whose malignant melanoma respond to immunotherapy have more diverse and different types of gut bacteria compared with non-responders.
Indeed, the opportunities are considerable, with the scope to change our approach to cancer treatment sparking a lot of interest. At the end of 2016, a new phase 2 clinical study started at Roswell Park Cancer Institute in the US, with backing from Merck & Co. This is one of the first human trials looking for links between the microbiome and response to immunotherapies. The team will evaluate how well 40 ovarian cancer patients respond to a combination treatment of the immunotherapy drug pembrolizumab (Keytruda®) and two other cancer drugs, bevacizumab (Avastin®) and oral cyclophosphamide (Cytoxan®). Then, the researchers will analyse their blood, tumour, stool, vaginal and skin microbiomes to identify any associations with clinical outcomes and tumour response.
“The study will extend the work that has already been carried out looking at the influence of the gut microbiome and highlights the variety of research angles being investigated to improve immune defences against cancer”, says the study’s principal investigator, Dr Emese Zsiros of Roswell Park Cancer Institute. Indeed, for scientists exploring drug responses, this opens up a possible new treatment paradigm whereby patients’ microbiomes are checked before treatment – and then modulated, if needed, to enable the best drug response.
Benefits could also come through using live medicines or probiotics to modify a person’s resident microbial communities. Uncovering this tantalising possibility, last year a team in Finland and China carried out a study feeding mice with a microbial cocktail called Prohep for a week before injecting them with liver cancer. Their results were astonishing – the weight and size of tumours in the microbially treated mice were reduced by 40% compared with control mice without the probiotic, with the team showing that it works by promoting an anti-inflammatory environment in the gut and liver. Dr Hani El-Nezami, associate professor of biological sciences at the University of Hong Kong and lead author of the study, is excited by their results. He says, “We had not expected such a significant impact and we are now exploring even better cocktails for study. We now also want to investigate how humans will respond to this bacterial cocktail.”
Start-up companies are also getting in on the microbiome immuno-oncology therapeutic opportunity. One such firm is Evelo Biosciences, which is developing the next generation of immunotherapies to treat cancer and inflammatory diseases. The company plans to begin first-in-human testing of its products – monoclonal microbials – in early 2018, says Evelo’s Chief Scientific Officer, Mark Bodmer.
The oncology products are orally-delivered single strains of microorganisms that induce a systemic anti-tumour immune response with the potential to treat to treat melanoma, non-small cell lung cancer, renal and bladder cancer. The products exert a systemic immunomodulatory effect via the lumen of the gut. This can be either alone or in combination with current immunotherapies. “What has become increasingly clear is that naturally occurring monoclonal microbial strains act through the gut to modulate systemic immunity for an anti-tumour effect,” says Mark.
It’s still early days, but the new tools and a new appreciation of the microbiome has opened up a massive area of biology with scope to develop new types of therapeutics for patients.
Dr Mark Bodmer
Meanwhile, others are spearheading early investigations into using the microbiome in cancer diagnostics. In 2014, a team at the University of Michigan found that identifying differences in gut microbiome data alongside known clinical risk factors improved their ability to differentiate between healthy people and those with colorectal adenomas and carcinomas. And a team of Canadian researchers is studying the potential of using the breast tissue microbiome as a biomarker in cancer diagnostics and in determining individual risk.
So is it really the next big thing?
From a patient’s point of view, research into the microbiome holds great promise for tackling cancer from many different angles: identifying who is at increased risk, earlier diagnosis, and new and improved treatments with fewer side effects. It could also open up simple new interventions to help prevent the disease from ever occurring, such as promoting a healthy microbiome through the diet.
But, while the excitement continues to build, we need to be mindful that research into cancer and the microbiome is very much in its early days with a host of questions that still need answering. Dr Michael Burns, an Assistant Professor at Loyola University Chicago studying the cancer microbiome, notes two phases for research: characterisation and functional testing. “We are currently in the characterisation phase. We have to determine what microbes, and how many of them, are present in cancer patients before we can try to understand exactly what these microbes are doing. Once we nail this down – and it’s by no means trivial – we’ll have targets to start investigating function. The first phase is critical to identify the differences, and the second is needed to identify which of these are actually biologically and medically relevant.”
So it’s still too early to say where the current buzz around this area will ultimately lead. But the rewards that it could open up for patients mean that it’s something to keep a close eye on – particularly if the balance of evidence confirms that a causal link does indeed exist. Achieving that, and the ability to modify one environmental risk factor, not to mention improving the efficacy of current drugs, could transform the whole approach to cancer. With 1 in 2 people in the UK now likely to develop the disease, new findings are critical. Microbiome research is turning heads but will it deliver all that it promises? Only time and research will tell.
Grand Challenge is our £20m international funding call aiming to engage and stimulate novel and ambitious proposals to tackle the toughest challenges in cancer.
In this story
Mark Bodmer, Chief Scientific Officer, Evelo Biosciences
Michael Burns, Assistant Professor, Department of Biology, Loyola University Chicago
Hani El-Nezami, Associate Professor, School of Biological Sciences, University of Hong Kong
Paul O’Toole, Professor of Microbial Genomics, APC Microbiome Institute, University College Cork
Jennifer Wargo, Associate Professor, University of Texas MD Anderson Cancer Centre
Emese Zsiros, Assistant Professor of Oncology, Roswell Park Cancer Institute