Cancer Grand Challenges awarded grants to four teams –CANCAN, PROMINENT, eDyNAmiC and NexTGen – in its third round of funding in 2022. Charles Swanton, a member of the Cancer Grand Challenges Scientific Committee, shares his reflections on the work of these teams as we look towards announcing the next round of challenges.
This article was originally published in our annual progress magazine, Discover.
The beauty of Cancer Grand Challenges is that they enable us to address really ambitious questions that have relevance to human health and to helping patients with cancer. These questions have the potential to meaningfully improve patients’ survival and quality of life. For example, the CANCAN team is taking on the Cachexia challenge, which addresses the critical problem of why patients lose weight during the course of cancer. The team is looking at the underlying mechanism of sarcopenia – muscle and fat loss in the body – and how and why it correlates with poor responses to therapy and poor outcomes.
Cachexia is an incredibly complex process – one that we know very little about, and one that requires different teams’ expertise to disentangle and interpret.
I’m excited about the synergy brought about by our teams. Take Mutographs and PROMINENT as a case in point. PROMINENT spun off from findings from the Mutographs team – namely that most environmental carcinogens are not associated with DNA mutagenesis. So how are the carcinogens causing cancer if they’re not doing so through mutations? The PROMINENT team is doing spectacular work to untangle the answer to this question.
There’s also a beautiful synergy between a 2022 article by Ludmil Alexandrov (University of California, San Diego, US), showing that the anti-viral factor APOBEC recognises and mutates extrachromosomal DNA (ecDNA), and work by the Mutographs team and eDyNAmiC, led by Paul Mischel (Stanford University, US), showing that ecDNA is a potent evolutionary force that has the potential to completely change our understanding of cancer evolution. This phenomenon will be hard to control, but we’ve got the best researchers looking at it.
NexTGen is a wonderful opportunity to improve outcomes for children with cancer. It’s a clear example of where Cancer Grand Challenges funding can support fields that are under-resourced and areas of unmet need. Clearly, paediatric malignancies are a key example of that: this set of complex diseases lacks drug targets, and we’ve got the best academic groups focusing their expertise on finding new cellsurface targets for chimeric antigen receptor T-cell therapy.
In addition to these teams, what excites me more than anything about Cancer Grand Challenges is what I’ve coined ‘embracing complexity’. I come from a background in reductionist cell biology, where there’s elegance and beauty in simplicity –controlling all parameters of an experiment in more simple model systems to understand nature’s rules. The problem is that cancer and its origins, evolution and communication with the host, are hugely complex. In addition, translational research in patient cohorts is very difficult. However, the past 10 years have seen an explosion in understanding of human physiology and pathophysiology. With modern technologies and the best minds – many trained in reductionist cell biology – we can embrace this complexity and disentangle it to make major inroads into understanding this disease, and developing new therapies to improve the outcomes and quality of life of people with cancer. We’re essentially taking the elegance of reductionist cell biology and applying the same rigor and new technologies, embracing different disease areas and medical specialties, to tackle the complexity of human cancer. That, to me, is the real excitement of Cancer Grand Challenges.
This article was original included in our annual progress magazine, Discover: a year of scientific creativity, which will be launching digitally on Wednesday 24 April.