Pancreatic adenocarcinoma cells / CNIO
For decades, patients with pancreatic cancer could be offered only few clinical advances to offer. But research was making silent progress which has eventually altered that landscape: the area is now buzzing with results.
Prevention is no longer a pipe dream, and neither is early diagnosis. In treatment, new inhibitors of the KRAS oncogene are a turning point.
Pancreatic cancer is one of the biggest challenges oncology faces. It is on the rise, possibly also among young people, and its survival rate remains very low – less than 5% of patients live for five years after diagnosis. It is often detected in the advanced stage, when the tumour is no longer operable. The same, largely ineffective drugs have been used for decades now.
But the research has indeed progressed: “In the last 20 years, the progress in pancreatic cancer research has been impressive,” says Francisco X. Real, a researcher at the National Cancer Research Centre (CNIO). As a result, “it is one of the best-known tumours at the molecular level,” state his colleagues Carmen Guerra and Mariano Barbacid, researcher and head of the CNIO Experimental Oncology group, respectively.”
To mark this year’s World Pancreatic Cancer Day, here are the main findings made by CNIO in relation to this tumour.
- Prevention: an ‘app’ that estimates personal risk?
Until recently, this would have been considered “an impossible dream” because pancreatic cancer is not associated with a specific habit, such as smoking in lung cancer, or with genetic alterations that greatly increase the risk. This cancer is the combined effect of numerous factors, some of which are still unknown.
But researchers now know enough for Núria Malats, head of the CNIO Genetic and Molecular Epidemiology Group, to be developing an individualised ‘app’ that estimates personalised risk.
The tool will consider whether there is obesity, diabetes or pancreatitis in the person’s medical history, whether they are a smoker or consume alcohol, and will integrate this information “with genetic variation biomarkers that, although only increasing the risk slightly, are still there; we also use markers of methylation, microbiome, metabolome… We are working on it.”
A recent finding from the group led by Francisco X. Real may make a contribution in this regard: it explains how a genetic variant in a specific gene, CTRB2, increases the risk of developing the tumour. The variant is present in 17% of the population; the increased risk it confers by itself is not high, but “when it appears alongside other factors, such as diabetes or pancreatitis, the risk could increase,” explains Real.
- Early diagnosis: towards liquid biopsy
Nowadays, there are no techniques to detect pancreatic cancer before it becomes incurable; developing such techniques is one of the most pressing goals. Malats and her colleague Héctor Peinado are leading CNIO’s participation in PANCAID, which stands for PANcreatic CAncer Initial Detection via liquid biopsy, an international consortium of eight countries. They are looking to develop a blood test that can detect the tumour in its early stages.
PANCAID will end in 2027. After analysing blood samples from patients and at-risk individuals, it will use artificial intelligence to determine the best markers and their combinations. Afterwards, they will test the effectiveness of this test.
- Is it operable? Avoiding harmful surgeries
20% of patients can undergo surgery to cure the disease. But in the vast majority of cases, the cancer is only detected once it has already spread to other organs – when it has metastasised – and at that point surgery is no longer advisable. The problem is that, in pancreatic cancer, determining the presence of metastasis can be difficult; in fact, a significant number of patients undergo surgery that does not benefit them, because the metastasis was not detected in time.
The group led by Malats has developed an algorithm that predicts the existence of metastasis from images of the primary tumour. The system, which uses artificial intelligence, could “help surgeons and doctors to detect metastasis,” which will directly impact patients’ quality of life.
- Treatment: finally, some progress
In pancreatic cancer, personalised therapies or immunotherapy have not yet been approved. But, after half a century with no new therapeutic strategies, the landscape is starting to change. The first drugs targeting the KRAS oncogene, mutated in 90% of patients with the most common type of pancreatic cancer, have begun to be tested. Their effectiveness is modest, but they pave a valuable path for progress.
The Experimental Oncology Group at CNIO primarily investigates “specific targets for pancreatic tumours that are effective and non-toxic,” explains Carmen Guerra. “KRAS inhibitors are yielding better results than chemotherapy, but ultimately resistance appears. That’s why we are investigating the molecular mechanism of these resistances, to learn how we can overcome them.”
Guerra’s group has played a key role in the development of animal models for pancreatic cancer, essential for the advancement of research in this area.
- Paving new paths: interrupting the conversation with the tumour
At CNIO, the Metabolism and Cellular Signalling Group, led by Alejo Efeyan, is seeking to disrupt communication between the tumour and the surrounding tissue in order to block the support that the cancer receives. Pancreatic cancer cells are surrounded by multiple non-cancerous cells: support cells, blood vessels, nerves, immune cells… To weaken pancreatic cancer, we need to decipher the messages between all these cells and intercept the support that the cancer cell receives. And then, strike with force through improved therapeutic efficacy.
Efeyan is investigating the relationship between obesity and pancreatic cancer: “This association involves abnormal communication between immune cells called macrophages and cancer cells; we are close to deciphering, and then interrupting, the chemical communication pathways.” It is one of the most promising pathways currently being explored.
• From discouragement to revitalisation: the rejuvenation of research
For decades, the lack of clinical advances to offer patients meant that few young people chose pancreatic cancer as a research area (“It was seen as an insurmountable challenge, too difficult,” says one researcher). That is also changing.
The improvements in animal models of pancreatic cancer, among other advances, have attracted “a generation of young, particularly bright individuals in Spain, who are fully committed to combining basic and translational research for the benefit of patients,” says Real, president of the ALIPANC alliance of pancreatic cancer researchers, launched through CNIO, which encompasses around 60 groups throughout Spain.
It is important because, as the entire research community usually claims, “the only way to make progress in one of the most complex challenges of current medicine is to keep on researching”.
Francisco X. Real: “This is the least bitter moment in the history of pancreatic cancer.” – CNIO
CNIO opens up an avenue to pancreatic cancer prevention – CNIO
About the National Cancer Research Centre (CNIO)
The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.