Often overshadowed by clinical research, scientific discovery in the lab can sometimes seem hidden behind the scenes. But this research is critical in the fight against cancer, and we at the Cancer Research Institute are determined to shine a spotlight on the discovery science.
Cancer detection science is research that aims to transform our fundamental understanding of cancer biology. It is sometimes called basic or fundamental science (although it is usually very complicated!). Discovery Science explores a vast array of topics within cancer biology – ranging from the process involved in regulating cell division to how cancer can develop and adapt, from the interactions of the immune system with cancer cells to the role of networks of chemical signals in the growth of cancer cells.
Discovery science is often done in cells or in model systems, such as yeast, fruit flies, nematode worms and mice, where scientists try to recreate the cancers found in the human body. It also includes computer science, which uses mathematical models to analyze and answer scientific questions.
Conclusions from discovery science can then, with further research, be used to translate discoveries into outcomes that directly benefit people: a process often described as going from the bench to the bedside.
Although their work is a bit far from the clinic, the discovery scientists at the ICR are determined to select areas of research that have the potential to ultimately benefit patients. They focus on finding clues to the fundamental biology of cancer that can lead to the development of promising, innovative new cancer treatments.
The ICR has hundreds of discovery science researchers, I spoke to some of them about their work and why they think discovery science deserves to be celebrated.
“Every drug discovery can be traced back to discovery research”
Professor John Pines is Head of Cancer Biology at the ICR. As a PhD student, Professor Pines worked in the laboratory of Nobel laureate Sir Tim Hunt at the University of Cambridge. John contributed to the scientific study of cyclins (proteins involved in the control of cell division cycles) in sea urchin eggs, which won Hunt the 2001 Nobel Prize in Physiology or Medicine along with Sir Paul Nurse and Leland H. Hartwell.
“There’s nothing quite like discovering the answer to something in science and realizing for a brief moment that you’re the only person in the world who knows it,” Professor Pines says. “I had that feeling when I cloned and sequenced ‘cyclin’ in Tim’s lab.”
The discovery that cyclins are key regulators of cell growth and division allowed cancer researchers to investigate whether inhibiting protein complexes containing cyclins, called cyclin-dependent kinases (CDKs), might have potential as cancer treatments. One of these CDK inhibitors, palbociclib, is now a common treatment for some types of breast cancer.
“Without the discovery science made by Tim Hunt and others, we would not have palbociclib. The origins of every drug discovery can be traced back to discovery research, and that, to me, is why we celebrate discovery science.”
Pieces of a puzzle
It can be hard to see how studying animals like sea urchins can tell us anything about human cancers. I asked Dr. Lucas Dent, a postdoctoral fellow in the Dynamic Cellular Systems Laboratory at the ICR, about the importance of cell and animal models in discovery science.
“One way to understand the complex mechanisms going on inside and between cells is to first look at cells isolated in the laboratory and simple life forms.” Dr Dent explained: “These model organisms have very similar basic biology to that of humans and may provide clues about how cancer works in humans. It is also possible to genetically modify many model organisms to study the role of certain genes and proteins.
“In our lab, we are genetically modifying fruit flies as well as using computational methods and human cells to understand more about how complex biochemical signaling networks are ‘rewired’ during cancer development.”
He continued: “However, it is important to be clear that findings in discovery science are the starting point in the process when considering future benefits for patients. Cells can behave differently when isolated in a laboratory and in animals not closely related to humans. So scientific discoveries should be seen as pieces of a puzzle, it takes many pieces of the puzzle to see the picture.
Characterization of the BRAF gene
Another great example of a scientific discovery leading to a vital new treatment for patients is the work of ICR scientists to characterize the BRAF gene and its role in cancer.
In the early 1990s, a team of ICR researchers led by Professor Chris Marshall began studying a cell signaling pathway involved in the control of cell growth. Their research looked at the role of the pathway – known as the RAS/RAF/MEK pathway – in cancer. Further work by the team suggests that a protein called BRAF may contribute to the development of cancer.
The researchers then went on to confirm mutated BRAF as an oncogene capable of promoting cancer development even in the absence of other major genetic defects.
These research findings helped pharmaceutical companies discover cancer drugs that work by inhibiting the mutated BRAF protein. These selective inhibitors of mutated BRAF include dabrafenib, which is approved for the treatment of melanoma skin cancer.
Tracking discoveries from the laboratory to benefit patients
Professor John Pines, who holds the Chris Marshall Chair in Cell Biology at the ICR, spoke to me about this work. “Chris worked at the ICR for 35 years, he was an extremely insightful and rigorous scientist. It’s fantastic to be able to follow his discovery in the lab and see it get to the point where it has a positive effect on patients’ lives.
Professor Pines continued: “There are few organizations where you can see research move from the laboratory table to the patient’s bedside as you do at the ICR, and that is quite special.”
Dabrafenib was discovered by a GlaxoSmithKline team that included Dr Olivia Rosanese – who is now Head of Cancer Therapeutics and Director of Cancer Therapeutics at the ICR. Dr. Rosanese agrees that discovery science is essential to drug discovery and development.
“What’s really important for us is to understand the underlying mechanisms and genetic changes in cancer that lead to uncontrolled tumor growth and spread,” she explains, “And when we start to understand those mechanisms, we really have a good idea of what the targets are.” of the therapists.’
The groundbreaking scientific study of the RAS/RAF/MEK pathway by Professor Marshall and others at the ICR also led to the identification of the mechanism by which mutated RAS proteins cause cells to become cancerous.
The team showed that the RAS protein activates an important signaling pathway in cells called the MAP kinase pathway. In cancer cells with a mutated RAS, the MAP kinase pathway is always on and makes the cancer grow.
Additional research found that two molecules, RAF and MEK, transmit signals from RAS to MAP kinase and are essential for cancer growth. RAF and MEK are excellent drug targets, and translational research based on ICR’s basic science led to the discovery of the MEK inhibitor trametinib. Trametinib is already licensed for use and regularly used together with dabrafenib to treat melanoma.
“Look how far we’ve come”
Someone who has directly benefited from the science at the ICR that led to the discovery of dabrafenib and trametinib is patient advocate Debbie Keynes.
Debbie was diagnosed with advanced melanoma in April 2016 and was treated with dabrafenib and trametinib for several years.
We spoke with Debbie in 2018 and she told us about her experience of being diagnosed with melanoma and being treated with dabrafenib and trametinib.
A core part of the work we do
We at ICR are extremely proud of our research findings. I spoke to ICR CEO and President Professor Christian Helin about why this part of our research is so key.
“Take the Covid-19 vaccines for example, what most people don’t realize is that there were at least 25 years of research in laboratories that allowed the vaccines to be developed and taken to clinical trials so quickly. Without discovery science, we wouldn’t have vaccines, it’s that simple.
“It’s the same for cancer – there wouldn’t be new drugs if it weren’t for the science of discovery. It is an absolutely fundamental part of the work we do at ICR.”
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