CNIO Friends Newsletter 42

Nature Medicine. Researchers at the CNIO found a way to increase the efficacy of radiotherapy against brain metastasis. A team of CNIO researchers headed by the Leader of the Brain Metastasis Group at the CNIO, Manuel Valiente, has found that a simple blood test can be used to identify patients with radioresistance (before they undergo radiotherapy) and that a drug might reverse it. A multi-centre clinical study is now under way to validate the predictive potential of this biomarker through the National Brain Metastasis Network (RENACER).

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Gut. An international study suggests that stool tests can detect early-stage pancreatic cancer. The study was conducted by a team of researchers led by Nuria Malats, Leader of the Genetic & Molecular Epidemiology Group, and Peer Bork from EMBL in Heidelberg. They have found a genetic signature of 27 microorganisms in stool samples that could predict whether patients are at high risk of pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, and even allow for the diagnosis of patients in the early stages of the disease. It is the most comprehensive study of the influence of this microbiome on pancreatic cancer to date.

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EMBO Molecular Medicine. CNIO researchers design a drug screening platform compatible with patient biopsies to fight metastasis. It is estimated that about one out of four cancer patients is at risk of brain metastasis. To address this situation, the team led by Manuel Valiente, Head of the Brain Metastasis Group at the CNIO, designed METPlatform, which will enable researchers to test drugs that could be used against brain metastasis.

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Journal of Hepatology. CNIO researchers identify a mechanism that causes liver cirrhosis. Liver cirrhosis is a deadly disease that is still poorly understood, in part due to the lack of animal models to study it. The Growth Factors, Nutrients and Cancer Group at the CNIO, led by Nabil Djouder, has created the first genetically modified mouse that develops liver cirrhosis comparable to human cirrhosis and has thus managed to identify the molecular mechanisms underlying this disease.

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Nucleic Acids Research. CNIO researchers led by Oscar Llorca, Director of the Structural Biology Programme and Leader of the Macromolecular Complexes in DNA Damage Response Group, have shed light on a cellular process involved in certain types of cancer, in particular, the role of proteins RUVBL1 y RUVBL2.

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In the early months of this year, we organised a number of events aimed at deepening and sharing knowledge with scientists in relevant fields and presenting our work in various activities and through different channels.

The latest event was Molecular, Cellular and Organismal Drivers of Aging, as part of the CNIO-CaixaResearch Frontiers Meetings. These meetings, held twice a year, were cancelled in the past two years due to the COVID-19 pandemic. They are leading international conferences on the latest advances in cancer research, where about twenty speakers from different countries present their recent findings. Additionally, there is a selection of posters or brief oral presentations by about a hundred other researchers.

Furthermore, we organised outreach activities like the 7^th edition of CNIO Arte, plus special campaigns on World Cancer Day, the International Day of Women and Girls in Science and International Women’s Day. In addition to the presentation of the latest CNIO ARTE, we organised the 3^rd Art and Science Symposium, where artists and scientists discussed the impact of major pandemics on art throughout history. Art historian and critic Carlos Jimenez; virologist and coronavirus expert Luis Enjuanes from the National Centre for Biotechnology (CNB); writer and journalist Ruth Toledano; and artist Ana Matey took part in the event.

A team of researchers from CNIO’s Genomic Instability Group, led by Oscar Fernandez-Capetillo, identified drugs that could reduce mortality triggered by SARS-CoV-2 infection. Fernandez-Capetillo tells us how this study was conducted during the COVID-19 confinement.

What was the starting point of your research?

SARS-CoV-2 infection can trigger excessive inflammatory responses – a process known as cytokine storm, which may be the real cause of fatality instead of the virus itself.

What is a “cytokine storm”?

The term “cytokine storm” refers to an aggressive immune response in which too many cytokines are released into the blood at once, which can be harmful. This reaction can occur in patients with severe COVID-19. Using IT tools, we tried to predict which drugs could control the excessive immune response in COVID-19 patients.

¿Why did you decide to carry out a study that moved away from the usual lines of research in your lab?

We started off during the tight COVID-19 lockdown in Madrid, when you had to stay home and could only go out to perform essential tasks. Laura Sanchez Burgos, a student from our lab, had designed a bioinformatics approach to drug effectiveness against diseases. We applied it using the databases developed in Harvard, Boston, which contain thousands of drugs. They are a sort of catalogue where each drug is assigned a code. If you define a code for a given disease, you can look in the database for an “antidote” whose code is the opposite of that of the disease.

And what were your findings?

Our strategy enabled us to identify some drugs that were presumed or known to counteract an inflammatory response. Our results also suggested that some compounds used to treat cancer could be used to control COVID-19-related inflammatory responses. Some of those compounds were validated later and some are still undergoing clinical trials. What is more, our study helps understand gender differences in COVID-19 mortality. We believe they are partly caused by the anti-inflammatory effect of female sex hormones. This study was the result of our need to feel we were doing something useful during the COVID-19 pandemic. Given the lockdown, the only way we could help was through IT tools, so we applied what we already knew about drug response predictions in cancer treatment to COVID-19.

Pedro Alonso (Madrid, 1959) was the star scientist of CNIO Arte earlier this year. A medical epidemiologist, he served as Director of the WHO Global Malaria Programme in Geneva, Switzerland, for eight years. The Global Malaria Programme is responsible for coordinating WHO’s global efforts to control and eliminate malaria; it sets and disseminates global guidance and policies, and supports countries affected by malaria worldwide.

When he joined WHO, Alonso was serving as General Director of Instituto de Salud Global de Barcelona (ISGlobal), was Professor of Global Health at the Medical School of the University of Barcelona, and was Chairperson of the Board of Trustees at Fundação Manhiça and the Manhiça Health Research Centre in Mozambique.

At present, Alonso is Professor of Global Health at the Medical School of the University of Barcelona. Since 2014, he has served as Director of the WHO Global Malaria Programme in Geneva. His first big achievement, on the efficacy of insecticide-treated bed nets (ITNs), was published in The Lancet in 1991. The use of such nets was controversial at the time, but Alonso’s team in Gambia carried out a study whose results were subsequently confirmed by other research teams. More than a thousand million ITNs have been distributed over the past decade, as they are now considered “a key tool in the fight against malaria.” In Alonso’s own words, “ITNs are an effective low-cost, high-impact means to control malaria.” The use of ITNs is recognized as one of the most effective ways to reduce malaria mortality, with an estimated six million lives saved so far, especially young children in Africa.

Alonso also contributed to demonstrate the efficacy of malaria vaccines, something that was not so obvious at the time when he conducted his studies, given the complexity of the malaria parasite. More recently, he took part in the development and assessment of a new, ground-breaking malaria vaccine (RTS,S), whose use in pilot programmes WHO recommended for Sub-Saharan Africa as of 2018.

Throughout his career, Alonso has published more than 300 articles in international science journals, mostly on malaria prevention and control, as well as on vaccine trials. He has been a member of a number of national and international expert committees.