In-depth profile: Translating basic research into clinical practice
NCMM group leaders, Dr Anthony Mathelier and Marieke Kuijjer, and Professor Vessela Kristensen, head of the Cancer Genome Variation group at Oslo University Hospital (OUS) and Professor at the Department of Medical Genetics, discuss their research and how they support one another’s projects.
One of NCMM’s overall objectives is to conduct cutting edge molecular medicine research and to enable the translation of this research into clinical practice. To support this, NCMM has developed strong links to Oslo University Hospital (OUH). All NCMM Translational Research group leaders have an adjunct position in a clinical or paraclinical department at OUH. These affiliations help to facilitate these vital clinical collaborations, giving NCMM Group Leaders better access to patient materials, biobanks, and clinical trials. The collaborations are also crucial for facilitating translational research.
Dr Anthony Mathelier is Head of the Computational Biology and Gene Regulation Group at NCMM. In addition, he has an adjunct position with the Department of Medical Genetics, OUH, which allows him to collaborate closely with the Kristensen Group.
Dr Marieke Kuijjer, Head of the Computational Biology and Systems Medicine Group at NCMM, has also started working with Professor Kristensen. She was awarded funding in August 2020 as part of the Rosa Sløyfe (Pink Ribbon) campaign from the Norwegian Cancer Society.
Anthony, how would you describe the role that basic, translational research plays in treating diseases like cancer?
Basic research aims at better understanding the molecular mechanisms that drive diseases like cancer. This knowledge can then be translated into useful information that can help in finding new biomarkers or therapeutic targets for a better prognosis, stratification of patients, and treatment. Indeed, what we ideally want is to understand the biological mechanisms underlying the development of a disease. That way, we are better placed to treat it.
As an example, a molecular classification of breast cancer tumours was discovered in the early 2000s. This provides an intrinsic subtyping classification in addition to predictive and prognosis value, which can help assess treatment options. This research was paramount in highlighting the biological aspects of tumour behaviour, function, and identity; and led to the discovery of five intrinsic subtypes (luminal A and B, HER2-enriched, basal-like, and normal-like) based on gene expression profiling of 550 genes. A 50-gene classifier (PAM50) has now been approved by the US Food and Drug Administration (FDA) (Prosigna test) to assign tumours to luminal A, luminal B, HER2-enriched, or basal-like subtypes. This stratification has been useful to assess the likelihood of efficacy from neoadjuvant chemotherapy.
Vessela, what are you trying to discover with your research?
We work with germ-line genetic heritability, which is where we try to understand why some patients are predisposed to developing cancer and why others are not. We also look at the progression of disease in the patients that have received a cancer diagnosis, for example why cancer progresses so quickly in some patients but slowly in others. Ultimately, we’re trying to understand how this progression can be modified.
We also examine the bigger genetic questions related to treatment response to try to understand why some patients respond well to treatment but others are resistant.
Related to this treatment response, we also try to identify why some patients suffer badly from the side-effects caused by their treatment. If we can better understand this, we can try to make improvements to the treatment so that their quality of life is improved. Cancer survival rates are increasing but sometimes the effects of treatment are long-lasting and negatively impact the patient’s future. We, therefore, want to understand the involvement of genetics in this process.
Anthony, can you explain to me how your research at NCMM works in the context of diagnosing and treating cancer?
We can now generate a tremendous amount of molecular data from patient samples to help us better understand the biology behind their disease. This data requires dedicated computational and statistical tools to analyze it adequately. This is where computational biology comes into play. We aim at developing computational tools and resources that will help us better understand the basic molecular biology of the diseases.
Our ultimate goal is to implement basic research that will fuse experimental approaches with the parallel development of computational methods to patient samples. This then has the potential to deliver new knowledge in cancer that will be beneficial to cancer patients in the future.
We believe that improved computational biology tools will reduce healthcare costs by decreasing the number of expensive diagnostic laboratory tests needed.
Vessela, how do you see NCMM as part of Oslo’s wider healthcare and research ecosystem, and how do you see our group leaders’ supporting this in the longer term?
NCMM is quite a unique centre for Oslo. The group leaders are selected purely on their excellence and not so much because they work in a particular field.
This is a huge investment for Norway; these star scientists come from all over the world to work here in Oslo and I think this is wonderful for our research as a whole. It is so important that their talent and intellectual capacity is channelled into health or innovation or other projects that are ultimately useful to Norway.
It’s therefore vital that we introduce these young researchers to the clinical and medical environments that will benefit from their basic research. This is particularly important for when they come to the end of their 5+4 years’ contract at NCMM, as the hope is that they will find a permanent position in Norway. It can be tough to go up against local candidates who are already based within a Faculty and I know it is challenging to go from a very international environment to a very Norwegian one. They, therefore, need mentors who know the local environment and who can help give them some guidance about how to navigate this. As I am myself originally not Norwegian but have been here for over 30 years, I see myself as being in a position to provide this mentorship and support. After all, it is only a very positive thing for research, and for science in general, if we can keep these talented researchers here in Norway.
How do your research interests complement one another?
Vessela is a molecular biologist by background with strong expertise in breast cancer biology. I am a computational biologist with expertise in developing bioinformatics tools and resources with immediate application to answer biological questions. Our complementary expertise allows for the implementation of cutting-edge computational analysis of molecular data strongly grounded on the understanding of the molecular biology of breast cancer.
We partner from the very beginning of the projects to maximize the input using each group’s specific expertise throughout the progress of the research. This multidisciplinary aspect is key for the future of biology.
Anthony is extremely interested in finding new research problems and questions where he can apply his knowledge to help solve them. Having access to translational questions with a medical significance, along with a dataset that he can interrogate, is very important for both his research and mine. I also work a lot with other members of his group, for example, I was the co-supervisor of his PhD student, Marius Gheorghe, who graduated earlier in 2020. We will also share a research technologist on a future breast cancer project, which will see the wet lab work done with a PI in my lab called Xavier Tekpli, and my group at Ullevål.
We have also published papers and written grants together. Together with Xavier, both Marieke and Anthony were awarded projects from the Norwegian Cancer Society as part of the Pink Ribbon (Rosa sløfe) campaign this year based on our collaboration. I generally support all of the breast cancer grants that they are interested in. I also support Marieke in the same way and additionally I am working together with Sebastian Waszak too.
Marieke, from your point of view, how is your research and basic research in more general helping to change how we treat cancer?
Cancer is very heterogenous— there are many different types and subtypes of the disease. Despite this, cancers sometimes do have things in common. For example, there might be a mutation or regulatory alteration that’s often found in breast cancer that also happens in a small subset of sarcoma patients. Based on this, you might then be able to find a treatment that has already been tested in the clinic for one type of cancer but not the other.
This is why basic research matters so much; you can find these small subgroups of patients that might benefit from specific treatments. That’s what we hope to achieve with our network analysis tools.
Anthony, how did you come to work with Vessela, and which projects are you currently working on together?
When I interviewed for my group leader position at NCMM, I asked to meet Vessela because I was fascinated by the work developed by her group over the years. Indeed, her work is very interdisciplinary and specifically aims at better understanding the molecular mechanisms of breast cancer to lead to new successful prevention and treatment strategies. Our research goals aligned very well and our complementary expertise are very synergistic.
When possible, I attend Vessela’s weekly group meetings at Ullevål Hospital. We are currently working on several projects looking at the non-coding portion of the human genome containing regulatory regions that control when and where genes are specifically activated. We have recently started to work on a new project, where we will combine the application of state-of-the-art experimental technologies with computational approaches to identify regulatory signatures to improve breast cancer patient stratification and highlight a specific set of regulatory regions essential for breast cancer cell survival.
We hope that the knowledge derived from this basic research project will have an impact on basic research for a better understanding of breast cancer, with the mid-term objective of better stratifying patients and discovering new biomarkers and therapeutic targets.
Marieke – you are also about to start working with Vessela Kristensen. Can you explain how this collaboration has come about?
My group and I generally work with large-scale network models to study cancer. While a large part of my previous research in cancer has been focused on osteosarcoma (which is what I did my PhD on), we have recently expanded our analyses to look at alterations across a wide variety of tissues and cancer types. Tatiana Belova, a postdoc in my group, was working on a pan-cancer analysis where she was trying to understand the differences and similarities in how genes are regulated in multiple types of cancer. Ping-Han, a PhD student in my group, had developed a new tool to analyze cancer data together with clinical information. They teamed up to test this new method and decided to focus on breast cancer, the cancer type for which there was the largest amount of data available. Their analyses revealed some very nice results, which then gave us enough data with which to apply for the Pink Ribbon funding. We were, however, lacking in the necessary breast cancer expertise to fully realise the project, which is where Vessela and her group came in. We needed their expertise to help fully examine this data.
Vessela and her group also work with a lot of genome analysis in breast cancer. They have molecular biology and bioinformatics expertise and, therefore, aligned very well with my group. I had first met Vessela when I came to NCMM as part of my group leader interview process. She was very friendly and open, and I hoped that one day we might be able to work on a project together with her group, so this was the perfect opportunity.
Marieke, what will the Pink Ribbon (Rosa sløfe) project involve, and how will you work with Professor Kristensen?
The overall goal of the project is to find new regulatory subtypes in breast cancer. Regulatory subtypes can tell us how genes are being regulated and how this regulation differs in individual breast cancer patients. By analysing alterations in these subtypes, we hope to find biomarkers and targets for treatments that can then be applied to these patients.
The project officially starts in March 2021. We will mostly be collaborating with Miriam Ragle Aure, who is an expert in MicroRNAs. The project will see us use a tool that my group developed called ‘PUMA’, which models networks for MicroRNAs to identify new subtypes in breast cancer. Miriam will support this; her expertise will be able to help determine if, when we find different MicroRNAs, they then play a role in breast cancer or if they are something new. She will also be able to help us find the right datasets to include in the PUMA models.
We will also work with Xavier Tekpli, who used to work at NCMM in the Staerk group. He has a background in gene regulation, specifically in breast cancer, and has done analyses to find associations with breast cancer prognosis. He will help us put the regulatory alterations that we find through this project into the context of known and novel prognostic factors in breast cancer, and how regulatory interactions in each tumour evolve in response to breast cancer treatment.
This is just the start of what I hope will become a longer-term project.
We have these network models but there are so many other data types that we can integrate. Part of this will be done by a new method development which will form a large part of this project. There are certainly many other possibilities for what we can do together, such as using deep learning to make our network model analyses better. We, therefore, need and highly value the expertise of Vessela and her group in helping us to do this.
How important is the basic research carried out by some of the groups at NCMM for your group, Vessela?
It is extremely important! Translational medicine needs to be backed up by science and research if it is to be useful. As we come ever-closer to the patient in our research, we must remember this. The work of researchers at NCMM, like Anthony (Mathelier), Marieke (Kuijjer) and Sebastian (Waszak), is at the interface of the very latest knowledge and technology available when it comes to computational biology. The time and expertise required to convert the work of computational biologists like these NCMM researchers into treatments for cancer patients can be demanding. It can also be a challenge to explain to a medical oncologist why this basic research involving computational biology is so important. In addition to my research I, therefore, see myself as responsible for communicating and explaining the importance of this basic research to the clinic.
How important is a setting like the one of NCMM, with its links to Oslo’s hospitals, in terms of helping you to do your research?
When I started my group leader position at NCMM, I had the opportunity to complement it with a 20% co-affiliation at an OUH department. This arrangement makes it possible to be directly embedded in a hospital environment to become exposed to their ongoing research, make them aware of our research, and discuss regularly to foster collaborations. This co-affiliation was also useful as I was new to the Oslo research environment and got to network more broadly in the beginning. Biologists, clinicians, and bioinformaticians sometimes speak different languages and have complementary research expertise and culture; providing an environment promoting regular interactions is very important to maximize the synergy between the disciplines, which will ultimately benefit science and patients.
The 5+4 years model that NCMM follows is really good for starting out as a group leader; it’s not a permanent position but it gives some stability. There is a real need to perform quickly, which I think is actually a good thing! The start-up package has also been helpful; it means that I can work on crystallising some of my research ideas, rather than having to solely focus on applying for external grants. This is something that I am still doing of course, but the group's core funding has given me a bit more time and space to think about my research and to develop my own research program. It means I have been able to focus more on generating preliminary analyses, which is one of the reasons that we were awarded the pink ribbon funding. We were able to include a lot of preliminary data in the grant application which gave some real evidence of what we already had, and helped to make the case about what was possible with the right support and funding. It also has allowed us to work with Vessela and her group, which is very exciting.