The multifaceted approach of Cancer Grand Challenges research

24 April 2023
"I really believe the way we enable research through Cancer Grand Challenges will ultimately make a difference for people with cancer" Gemma Balmer-Kemp, head of research, Cancer Grand Challenges

Cancer Grand Challenges research covers a broad spectrum of areas and disciplines, with teams generating novel insights at each stage of the research pipeline.

Here, Gemma Balmer-Kemp, head of research at Cancer Grand Challenges, delves deeper into some of the areas of research covered by the Cancer Grand Challenges teams.

This blog was originally published in our annual progress magazine, Discover.

I really believe that the way we enable research through Cancer Grand Challenges will ultimately make a difference for people with cancer. One of the elements of Cancer Grand Challenges that I think is most powerful is the scope of research being undertaken by the teams, and the ability of teams to span the research pipeline, from discovery research to the clinic, and in reverse. Having this collective brainpower coalesce around a challenge area is hugely beneficial, because the problem can be viewed through multiple lenses, but everyone is focused on achieving the same goal.

For example, the CANCAN team, taking on the Cachexia challenge, is using Drosophila as a model to investigate this complex wasting syndrome that affects patients with advanced cancer and other chronic illnesses. Cachexia involves several organs and systems in the body. Using the Drosophila model developed by CANCAN co-investigator Norbert Perrimon (Harvard Medical School, US), the team can investigate tumour intrinsic factors and the tissues on which they act to induce wasting. The ability to dissect these intricate tissue-tissue interactions will be important to better understand these biological processes. This work will synergise with expertise in mouse models, metabolism and human metabolic disease, (neuro)endocrinology, immunology, clinical epidemiology and clinical research – bringing findings from fruit flies into the human context.

It is amazing that, by using a Drosophila model of organ wasting, pathways relevant to conditions as complex as cachexia can be probed. I’m excited to see the insights that the CANCAN team will generate by using this model, as well as the links to cachexia that will be discovered in humans. One exciting method that the team will be using is human chamber calorimeters, in which key metabolic and neural responses can be measured in human participants over the course of several days.

We have such a range of innovative models and approaches being utilised in Cancer Grand Challenges, and the scientists who invented them are often part of the research teams. For the Future Leaders and trainees within the programme, it’s a unique opportunity to really learn from the best.

Another great example of the scope of research and the range of models is the eDyNAmiC team, taking on the Extrachromosomal DNA (ecDNA) challenge. Team members will first use yeast as a model organism to interrogate the mechanisms of ecDNA generation, function and maintenance. They will then scale up from yeast to experiments using cancer cells, mouse models and patient tissue, to gain a comprehensive understanding of how ecDNA drives tumour evolution and therapy resistance. In addition, Ben Cravatt (Scripps Research Institute, US), eDyNAmiC co-investigator (and 2022 awardee of the Wolf prize, alongside Nobel prize winner and NexTGen co-investigator Carolyn Bertozzi of Stanford University, US), is already testing innovative chemical probes to pharmacologically modulate ecDNAs. The research really spans the full pipeline.

To make this range of research possible within a team, efforts on the scale of Cancer Grand Challenges are truly necessary to provide support.

Emerging research themes

As the teams progress through their programmes, we are starting to see some common themes emerging, as well as opportunities for cross-collaboration not only across disease types but also in other exciting areas. This means we have a multifaceted view of a problem, and this approach is immensely valuable when insights from different teams come together.

Colorectal cancer (CRC) is one example – we have different teams investigating different aspects of CRC development. The Mutographs team is looking at the mutational signatures present in CRC to understand what drives the development of this cancer type. The SPECIFICANCER team has generated interesting insights into how APC and KRAS mutations contribute to CRC, and why these mutations are more common in this cancer type than others. Complementing this work, the Rosetta team has identified a potential metabolic target – the glutamine-ejecting antiporter SLC7A5 – for treating KRAS-driven CRC. The STORMing Cancer team is also conducting in vitro work exploring the role of the stroma in CRC development, and the OPTIMISTICC team is examining elements of the microbiome associated with CRC development and growth. This overlapping research across teams is providing a comprehensive view across organ systems.

Another emerging theme is field cancerisation, which was first described in 1953, when pathologically abnormal cells were identified in clinically normal tissue surrounding oropharyngeal carcinomas. Many Cancer Grand Challenges teams are seeing this phenomenon in their research. The PRECISION team is examining this concept in ductal carcinoma in situ. The team’s elegant work in mouse models has shown that cells containing oncogenic mutations are spread over vast ductal areas of the breast and sensitise the epithelium to future transformation. The team is cross-validating these findings in humans by using 3D high-resolution imaging of human breasts in combination with deep sequencing to map the extent and dynamics of mutation spread, and further explore their clinical meaning.

As part of Mutographs, Peter Campbell (Wellcome Sanger Institute, UK) and his team have looked at the prevalence of oncogenic mutations in normal tissues in people with cancer. Surprisingly, normal tissue often contains cells that have oncogenic mutations yet are phenotypically normal. What happens to push these potentially ‘primed’ cells from normal to cancerous? This is the focus of the new team PROMINENT, whose work is aimed at improving understanding of cancer promotion.

Exploring the role of the tumour microenvironment (TME) is also an area of commonality among teams. Since the development of single-cell sequencing approaches, cancer cells and their intrinsic properties have become a focus, but, as many of our research teams have been showing, understanding the TME is also important.

Some teams are investigating how interactions in the TME can lead to cancer development. For example, the STORMing Cancer team is investigating how chronic inflammation affects the stroma; what happens as the tissues transition from a normal state to metaplasia, dysplasia and eventually cancer; and whether the stroma can be reprogrammed to halt or reverse cancer development.

NexTGen is working to develop chimeric antigen receptor (CAR) T-cell therapies for solid tumours in children. A key element of their programme is understanding the immunosuppressive microenvironment of paediatric solid tumours, and engineering next-generation CAR T cells that can overcome this immunosuppression to improve efficacy.

Rosetta and IMAXT – the two teams taking on the 3D Tumour Mapping challenge – have developed tools to study cancer cells in the context of their environment, in ways that were not previously possible. Using their mass spectrometry imaging platform, the Rosetta team has visualised the local distribution and metabolism of gemcitabine in tumours from mouse models of pancreatic cancer. The findings may help explain how the stroma prevents the distribution of the drug to tumour cells and leads to treatment failure.

IMAXT has built a map that gets inside tumours, providing a view of spatial information within the TME, and how TME elements affect mutational processes in the context of the actual tissue. This map has major implications for how cancer is diagnosed and treated. The IMAXT map is unique and incredibly powerful, and I’m looking forward to seeing how the research community can utilise it to drive important and impactful research.

Several themes are emerging that pull the community together, and this is great to see.