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Disease and treatment

Side-effects from cancer medicine to advance our knowledge of cardiac arrhythmias

What happens at the molecular level when the heart suddenly starts beating irregularly? A new research project at the University of Copenhagen will attempt to answer this question by studying cancer patients who experience arrhythmia as a side-effect of treatment with tyrosine kinase inhibitors. The purpose is to outline what happens at the molecular level in the heart when a person experiences arrhythmia. The scientist behind the initiative believes that a hypothesis-free and data-driven approach is key to identify novel causes of heart disease. The goal is that the insight gained will aid the identification of new strategies for treating heart disease.

Cardiac arrhythmia is a leading cause of death in the Western world. The diagnosis is a common term for disorders where the heart beats irregularly. This is often due to incorrect propagation of the electrical impulses that control the cardiac contraction. As a direct consequence of their involvement in the electrical signal propagation in hearts, we know that arrhythmias can occur if specific proteins called ion channels do not function the way they are supposed to. Yet, in the majority of cases, the molecular reason for the arrhythmia remains to be found.

Alicia Lundby, who is an Associate Professor at the University of Copenhagen, aims to change this. She and her research group are attempting to solve the heart’s molecular mysteries by harnessing the power of cardiac proteomics to study precisely which proteins are present in the heart and how they are changed in heart disease.

“One region of the heart my group has studied in great detail is the sinus node – the heart’s natural pacemaker. The first step was to very thoroughly characterize what makes this pacemaker unique at the molecular level compared with the surrounding heart tissue, and we have done that now. This has given us new insight into how this region differs from the rest of the heart,” says Alicia Lundby.

Last year, Alicia Lundby and colleagues published “Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking” in Nature Communications. The article provided unique understanding of which specific proteins contribute to the repetitive generation of electrical impulses by the sinus node that controls every heartbeat. The results are crucial for understanding how the rhythmic contraction of the heart is controlled at the molecular level.

Side-effects in cancer patients provide a new angle for research on arrhythmia

Alicia Lundby and her research group are now building on this important insight in a new project that will investigate what happens in people’s hearts when they experience arrhythmia as a result of treatment with anticancer drugs based on tyrosine kinase inhibitors.

The Novo Nordisk Foundation recently awarded a grant to Alicia Lundby for the project Unravelling Novel Molecular Mechanisms of Cardiac Arrhythmia from Onco-cardiology that will examine how the heart changes at the molecular level following treatment with tyrosine kinase inhibitors. The reason why tyrosine kinase inhibitors cause arrhythmia is a mystery – something that Alicia Lundby hopes to solve in the new project.

“In striving to understand the cause of cardiac arrhythmias, new knowledge from cancer research provides a unique opportunity to study the mechanisms of the disease from a completely new angle that neither we nor others had ever thought about. We know something about what tyrosine kinases do in heart development. However, we know virtually nothing about what tyrosine kinases do in the adult heart. Now it turns out that, if tyrosine kinases are targeted pharmaceutically, it can cause arrhythmia. My hypothesis is that the equivalent mechanism – that is, dysregulation of tyrosine kinases – may be a fundamental cause of arrhythmia. Thus, if this hypothesis holds true, we have a new class of proteins involved in the mechanisms of arrhythmia. That also means eventually identifying new pharmaceutical targets,” says Alicia Lundby, explaining the background for using the results from cancer research as an alternative approach to research on heart disease.

The main purpose of the research is to obtain new insight into the molecular mechanisms of the heart that cause arrhythmia, which will comprise the basis for new strategies for treating people with arrhythmia. The research therefore seeks to determine which specific proteins in the heart are dysregulated in arrhythmia.

“The main purpose of my research is to provide insight into the molecular mechanisms behind heart disease. I believe this insight is crucial for developing new and better types of medicine in the long term,” says Alicia Lundby.

Mechanisms activated in the heart still an open question

Arrhythmia is a relatively newly discovered side-effect of cancer treatment using tyrosine kinase inhibitors. Alicia Lundby says that, over the past year, more and more cases of this side-effect have been reported to the United States Food and Drug Administration (FDA), which has a database of side-effects for all types of drugs approved for use in the United States. This is precisely the database Alicia Lundby and her colleagues used to identify which cancer medicines the research project should focus.

“We started with a bioinformatic approach in which we investigated which cancer medicines most often cause arrhythmia as a side-effect. FDA has a huge database of reported side-effects, and we analysed their entire database of cases in which arrhythmia was reported as a side-effect. From this analysis, we identified the five drugs we will start examining,” explains Alicia Lundby.

Specifically, the aim of the project is to identify the proteins and signalling pathways that create the problematic effects of tyrosine kinase inhibitors in the heart. Which proteins are active in causing arrhythmia as a side-effect is a completely open question.

“The side-effects experienced by people with cancer indicate that manipulating tyrosine kinases can lead to arrhythmia. Currently, we do not even know which tyrosine kinases are present in the heart. We know even less about what proteins are regulated, when they are regulated. Using proteomics technologies, we will measure and quantify thousands of proteins in the heart to determine which tyrosine kinases are present in our hearts and which proteins are regulated when tyrosine kinase inhibitors affects the heart,” explains Alicia Lundby.

Data-driven approach to reduce the number of potential proteins

The first part of the research will focus on narrowing the number of potential protein candidates that may play a role in developing arrhythmia. The best way to do this, according to Alicia Lundby, is to adopt a hypothesis-free approach and let the data identify the proteins that are worth investigating.

Many protein candidates are available in the initial phase of a proteomics study. Cardiac proteomics can measure and quantify about 10,000 proteins in a microscopic heart sample. These measurements are made in human tissue, when possible, and otherwise in heart tissue from animal models.

Both diseased and healthy tissue from the same region of the heart are examined this way, enabling researchers to compare the samples and thus quantify which proteins have altered quantities in diseased versus healthy tissue – that is, how protein expression changes.

“The next step is to examine the proteins that have changed, since they are very likely the important ones. This reduces the number of candidates. If we started with 10,000 proteins, we might now have 100 or 200 whose quantity has changed. These likely comprise the new protein or proteins that are important for the disease process,” says Alicia Lundby.

Once the researchers have reduced the number of these significant proteins, they must create separate studies to investigate their function. The researchers will only begin to work purposefully with hypotheses in this part of the research.

“The data-driven approach can reveal molecular biological mechanisms that we did not know are important for how the heart functions and that we would therefore not have considered using a hypothesis-driven approach. To me, this strategy is really exciting, because every time we get new data, we get new knowledge that creates new ideas and connections. We are examining the initial data now, and we cannot help constantly forming hypotheses about what we think is happening. But we have chosen a strategy of letting the data direct us – so we are focusing on collecting data sets of the highest quality possible that we will later analyse in great detail,” explains Alicia Lundby.

In 2020, the Novo Nordisk Foundation awarded a grant under the Research Leader Programme to Alicia Lundby for the project Unravelling Novel Molecular Mechanisms of Cardiac Arrhythmia from Onco-cardiology. “Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking” was published in Nature Communications in 2019.

Alicia Lundby
Lektor
Cardiac proteomics is the merging of two scientific disciplines: molecular cardiac physiology and high resolution proteomics technology. In the interface between these two disciplines novel mechanistic insight on molecular regulatory mechanisms of the heart can be achieved. Cardiac proteomics allows for unbiased investigations of protein and signaling changes taking place in cardiac tissue, and it is a scientific field spearheaded by the Lundby group. In the Lundby group cardiac proteomics is applied to gain molecular insights into regulatory processes in the heart. The efforts undertaken aim at uncovering a deep molecular understanding of the changes in hearts exposed to various perturbations ultimately allowing us to identify novel pharmaceutical targets for cardiac disease intervention. The application of high resolution proteomics to investigate protein- and signaling regulation directly in cardiac tissue has opened a new avenue of molecular cardiac research. In recent years proteomics method developments have been achieved that allows for in-depth investigations of the cardiac protein landscape. In the Lundby group we exploit state-of-the-art proteomics technologies to pinpoint specific proteins and peptides crucial for proper cardiac function. Our proteomics based strategies allow us to address fundamental questions on protein- and signaling regulation for all cardiac proteins in single experiments.