As we honour Colorectal Cancer Awareness Month around the world, Cancer Grand Challenges teams are investigating novel treatments for the world’s third most common type of cancer.
Although cases of colorectal cancer have declined over the past four decades, more than 1.9 million people are still diagnosed with the disease each year, making this disease one of the leading cancer diagnoses worldwide. Puzzlingly, younger patients under 50 years old are being diagnosed more frequently than older patients, who are generally more prone to developing cancer. In the US alone, cases of young-onset colorectal cancer have doubled since the mid-1990s. Across Canada, Australia and New Zealand, and in parts of Europe and Asia, younger patients are increasingly being diagnosed with this disease.
This alarming trend has led to an urgent need to find ways to diagnose the disease earlier, when it is more treatable, and to develop novel treatments for people already diagnosed. Two Cancer Grand Challenges teams taking on our 3D Tumour Mapping and Microbiome challenges aim to create a metabolic tumour map that may reveal new therapeutic targets, and to explore how microorganisms in the gut drive cancer and influence patients’ responses to treatment, respectively.
Drugging the undruggable
The KRAS gene – historically considered ‘undruggable’ by scientists because of its molecular properties – is mutated in approximately 1 in every 4 human cancers. Cancer Grand Challenges team members Dr Andrew Campbell and Dr Johan Vande Voorde describe KRAS-mutated colorectal cancer as a “pressing clinical problem with few therapeutic options.” After being activated by mutation, KRAS drives the growth of new cells and plays a key role in altering tumour metabolism by rendering cells ‘addicted’ to the amino acid glutamine to support their proliferation.
Andrew and Johan are part of the Cancer Grand Challenges Rosetta team, taking on the 3D Tumour Mapping challenge. The team’s plan centres on developing a new way to visualise metabolites – fats, proteins and sugars produced by cellular processes – and to map their distribution in relation to individual cells’ genetics and the overarching structure of tumours. The team has developed these maps by integrating mass spectrometry imaging and other techniques to correlate the distribution of molecules, genetic information and metabolic signatures in cells.
Using mass spectrometry imaging to better understand tumour metabolism, the Rosetta team has identified a potential metabolic target, called SLC7A5, for treating KRAS-driven colorectal cancer. The findings, published in Nature Genetics in early 2021, may help patients whose tumours have become resistant to other therapies (read more in our story on the discovery).
SLC7A5 is an antiporter that ejects glutamine, a major energy source for rapidly dividing cells, while importing other essential amino acids into cells. “It’s thought that this is a means by which the cell can balance the demands for amino acids, protein synthesis and various other metabolic reactions,” says Andrew, a cancer biologist at the Cancer Research UK Beatson Institute in Scotland. Andrew, Johan and their colleagues are developing potential therapeutic antibodies against SLC7A5 and, elsewhere, small-molecule drugs targeting the antiporter are currently in phase I clinical trials.
Andrew says the collaborative nature of the team’s Cancer Grand Challenge – including analytical chemists, physicists, cancer biologists and geneticists – lends itself to this type of research. “There’s a whole range of life-sciences and physical-sciences experts converging to tackle a single, really significant problem in cancer biology; it’s a different way to think about science,” he says.
A community of bugs
Mounting evidence suggests that the microbiome, the trillion-member community of microorganisms living in our bodies, contributes to colorectal cancer development and growth. In fact, in 2021, the Cancer Grand Challenges OPTIMISTICC team identified a unique bacterial signature in patient stool samples that is associated with colorectal cancer. As part of our Microbiota challenge, the team is now delving deeper into the gut microbiome to search for innovative ways to treat and prevent the disease.
At Canada’s University of Guelph, Dr Emma Allen Vercoe was involved in the discovery of the overabundance of the bacterium Fusobacterium nucleatum in colorectal tumours. This common oral Gram-negative bacterium travels to the colon through the bloodstream and, in tandem with other microorganisms, triggers colorectal tumorigenesis.
In Emma’s lab, PhD candidate Greg Higgins is training members of a group of predatory bacteria known as Bdellovibrio and like organisms (BALOs), which are found in water and soil samples, to attack and kill cancer-causing pathogens such as F nucleatum. Preliminary data suggest that BALOs, which feed on Gram-negative bacteria, can successfully eradicate F nucleatum in mouse models. Greg is now studying whether these predatory bacteria can work in an anaerobic environment such as that in the human gut. “BALOs could provide an important opportunity, as there are no biologic therapies that target F nucleatum,” he says.
If successful, BALOs may provide a more targeted approach to eliminating F nucleatum in the gut than broad-spectrum antibiotics, which can promote antibiotic resistance and damage the microbial environment of the colon. “BALOs don’t seem to have any toxic effect on human cells,” says Emma, “so this could be a safe, selective way of removing F nucleatum.”
Stimulating an immune response
While Emma’s sub-team investigates predatory bacteria for the potential treatment of colon cancer, co-investigator Dr Rob Holt, of the BC Genome Sciences Centre in Canada, is taking a different tack by developing a vaccine that could potentially generate immunity against F nucleatum.
Previous attempts to develop an F nucleatum vaccine used intracellular proteins as the immunogen, but those proteins have limited ‘visibility’ to the immune system and are unlikely to stimulate an immune response against the most important antigens. Instead, Rob’s vaccine uses mRNA lipid nanoparticles and induces an immune response with the F nucleatum Fap2 protein. Fap2 has a dual role, both enabling F nucleatum to accumulate at tumour sites and inhibiting immune cells.
“By using Fap2 as our vaccine target, we hope to stimulate antibody responses that will block these two functions of Fap2, as well as lead to an overall reduction of extracellular F nucleatum,” says Cody Despins, a graduate student in Rob’s lab. “We also anticipate that the vaccine will induce T-cell responses, in addition to the antibody responses, to target and kill F nucleatum-invaded cells.” This approach is similar to that of the COVID-19 mRNA vaccines, which target a protein on the surface of the virus.
Rob, Cody and the team plan to first use this approach as a research tool in model systems to determine whether vaccine-mediated prevention of tumour infection leads to better outcomes with chemotherapy or decreases tumour progression. If so, they will then explore clinical testing of the vaccine, which would be used in combination with chemotherapy or after surgical removal of a tumour to maintain remission.
“In that sense,” Rob says, “it would be part therapeutic and part preventative,” and might be well suited for people at high risk of developing colorectal cancer.
Written by Scott Edwards
With thanks to Andy Campbell, Johan Vande Voorde, Emma Allen-Vercoe, Greg Higgins, Rob Holt and Cody Despins for their input.
Image: Human colon cancer cells, credit NCI
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