“My group’s research is a mix of hard-core fundamental science and strongly translational research. One of our main questions is: ‘When and how do mutations in intestinal stem cells lead to colorectal cancer?’ To answer that question we study patients with a hereditary predisposition to colorectal cancer. One of the copies of a tumour suppressor gene is defect in their cells. The first step in the series of molecular events leading to tumour formation usually is the loss of the other copy. Such doubly mutated cells will have to compete with the healthy cells at the bottom of the intestinal crypt. This is a race against the clock because the complete intestinal wall is renewed every week or so. We are exploring methods to tip the balance in favour of the healthy cells by giving the doubly mutated cells a slight disadvantage. Our hope is that these fundamental studies will result in applicable therapies that may prevent cancer in these patients.”

“Another main research question for our group is: ‘Which molecular subtypes of colorectal cancer can be detected?’ Colorectal tumours are highly heterogeneous: one colorectal tumour may differ more from another than from a tumour in the breast. They just happen to occur in the same organ. This has implications for therapy efficacy. Using gene expression studies, we have identified four subtypes of colorectal cancer that differ in molecular, cell biological and clinical characteristics. For example, patients with tumours with high fibroblast numbers respond poorly to the standard treatment regimen. We are now investigating which molecular pathways are activated in tumours of this subtype, in order to identify novel drug targets. In addition, we are exploring options to adjust the existing treatment regimen for this."

“Yes, indeed there is a lot of research into that subject. Actually, another highlight of my group’s work in 2020 was the work done by Dr. Daniel Miedema on that topic. Investigating more than 8000 tumours from a variety of organs, we discovered a robust association between high intra-tumour molecular heterogeneity and poor prognosis. The degree of intra-tumour heterogeneity thus has diagnostic value."

Until now, multiple biopsies were needed to determine this type of heterogeneity. Biopsies are invasive procedures, so it is better to take as few biopsies as possible. Daniel has developed a clever technology to determine intra-tumour heterogeneity using just a single tissue sample. Together with Oncode business developers he has filed a patent for the technology to further develop this. An additional benefit of this work is that it is also advantageous for retrospective scientific studies on the relationship between intra-tumour heterogeneity and patient outcomes, because these studies usually have access to only one tissue sample per patient.”

“With regard to that specific example, we would like to develop a molecular diagnostic platform for colorectal cancer that can distinguish the four subtypes. There are a number of hurdles to overcome before we can implement this into the routine diagnostic workflow. The methodology first needs to be validated. And it is important that the methodology and the procedures are harmonized at a national level. We therefore need to align many different stakeholders and obtain the necessary financial investments. We also need to overcome a number of technical challenges. For example, many pathologists use paraffin-embedded samples. It is technically challenging to perform gene expression studies on these, so we are developing protocols for this in collaboration with the Prospective Dutch Colorectal Cancer Cohort."

“Being in the Oncode network helps in multiple ways. In 2020, we have initiated a nation-wide consortium called ‘PREDICATE’ to improve molecular diagnostics for colorectal cancer. It consists of a large number of treatment centres and academic hospitals, patients and professional organisations, as well as various pharma and R&D companies. Oncode Institute has provided funding for this initiative and has helped us to obtain co-funding from industry partners. They brought us into contact with pharmaceutical companies and diagnostic companies.”

“Another example is the establishment of the ‘Colorectal Cancer Research Platform’ in 2020. This platform connects researchers and clinicians by facilitating the sharing of clinical samples to exploit available patient data to its full potential. This idea actually started during an Oncode clinical workshop, a meeting in which clinicians and researcher are brought together around a specific topic, in this case colorectal cancer. This meeting sparked a collaboration with fellow clinician Miriam Koopman at UMC Utrecht. Although I already knew her, this meeting accelerated a collaborative effort to setup the platform. In the follow up, Oncode financed setting up this platform which is now integrated into the larger BBMRI biobanking platform."

“I enjoy working with industry. In general, they tend to have a very pragmatic approach. They are posing clear black-or-white questions rather than complex greyscale questions with ‘more research is needed’ answers. They just want to find out if a certain product works or not. Oncode has the appropriate expertise regarding IP protection, business development, and so on. The majority of researchers are not really experienced in these topics, so it is good that we receive high-quality support from Oncode in our attempts to translate our research into clinical benefit for cancer patients.”

“A nice example is our collaboration with Lead Pharma, a clinical-stage pharmaceutical research and development company. They develop innovative small-molecule therapies to treat autoimmune diseases and cancer. We will jointly study the efficacy and mechanism-of-action of one of their promising compounds under development for cancer. We aim to discover the potential of this compound to treat gastrointestinal malignancies using our wide collection of disease models.”