Base funding 101: Oncode promotes the innovative potential of its research community by providing its investigators with base funds. Oncode base funds are unrestricted but are meant to promote innovative basic and pre-clinical research lines of high quality (high-risk/high-gain), or for OIs to apply their expertise in new research fields. Typically, these research lines are difficult to finance in the standard funding landscape due to a lack of preliminary data or track record. Of equal importance, the base funds provide OIs with the financial capability and flexibility to accelerate research lines, change the scope of research programs or quickly terminate non-successful projects. The impact of Oncode’s base funds can be seen on a multitude of levels, of which three - publications, new funding opportunities, and the ability to venture into new research and collaborations - are highlighted below. 
 
Publications: In 2020, Oncode investigators collectively published 375 publications, ten of which were in the journals Nature, Cell or Science. Of these publications, 67% were Open Access publications and ~15% lead-authored by an Oncode OI were co-authored with at least one other Oncode OI. Although not all these publications can be attributed to Oncode’s efforts, Oncode is now seeing the first publications for which the availability of Oncode base funding was vital. Additionally, despite Oncode only having been operational for 3 years, the quality of its research received international recognition in 2020. Nature Index included Oncode Institute in its Top 50 NPO/NGO institutions in cancer research worldwide. Several notable examples of key publications from the Oncode community are listed below. 

• Pleguezuelos-Manzano et al., Nature 580 (2020). Study by the Clevers, Cuppen and van Boxtel groups showing how genotoxic E. coli strains cause oncogenic mutations in colorectal cancer.  
• Hodskinson et al., Nature 579 (2020). Study by the Knipscheer and Kind groups on the discovery of two mechanisms of repair of alcohol-derived DNA cross-links. 
• Bartok et al., Nature 590 (2020). Study by the Agami and Peeper groups showing how anti-tumour immunity induces aberrant peptide presentation in melanoma. 
• Spit et al., EMBO journal 39 (2020). Study by the Maurice, JP Medema and M Vermeulen groups elucidating the role of RNF43 truncations to trap CK1 to drive niche‐independent self‐renewal in cancer.  
• Boersma et al., Cell 183 (2020). Study by the Tanenbaum and Clevers groups providing new insights in the Translation and Replication Dynamics of Single RNA Viruses. 

Rebekka Schneider (Erasmus MC): “The publication “Leimkühler, Gleitz…and Schneider, Cell Stem Cell 2020” would not have been possible without funding from Oncode, which we used to pay the sequencing costs. We now can even sequence bigger patient cohorts, which will provide unprecedented insights into mechanisms in the human disease. This would not be possible with most other research funding, which is rather conservative.”

Reuven Agami (NKI): “It is only because of Oncode that we could advance our research and connect amino acid metabolism, diet and anti-tumour immunity. This has led to novel findings published recently in Nature.

New funding opportunities: Oncode base funds provide OIs with the ability to quickly adapt their approach and allocate funds towards promising new findings. This agility advantage is often praised by investigators as one of the many impacts Oncode has on their research, as can be seen in the many testimonials from OIs. The preliminary data created by these base fund projects have already led to many successful national and international grant applications. Our investigators have reported 21 awarded grant applications with a total budget of €15.3M, with additional grant applications still pending a decision. Notable grant applications include those by:

• Michiel Vermeulen (Radboud University) – NWO ENW-Klein grant, €750K
• Jop Kind and Puck Knipscheer (Hubrecht Institute) – both ERC Consolidator grants, €2M each
• Edwin Cuppen (UMC Utrecht) – Hannarth Foundation, €235K
• Wilbert Zwart (NKI) – KWF grant, €544K

Wouter de Laat (Hubrecht Institute): “Oncode enabled novel high-risk, high gain projects that have laid a solid foundation for exciting future follow-up research […]. We could not have secured KWF funding to study the role of CTCF in endometrial cancer without collecting preliminary data using our Oncode funding.”

Peter ten Dijke (LUMC): “Base funding has enabled the generation of preliminary data for a patent application, Biotech support funding, and grant applications, and allowed significant progress to be made […] that would otherwise have been difficult to fund owing to their [the projects’] highly ambitious nature.”

Jurgen Marteijn (Erasmus MC): “The flexibility of the Oncode base funding allowed me to quickly expand promising research projects. For example, after our initial finding that Elof1 plays an important role in TC-NER, I could relatively easily let additional scientists embark on this project, which resulted in the full disclosure of the mechanism of Elof1 during the DNA damage response. Importantly, these findings will be the basis of future grant applications.”

Venturing into new research areas: Traditional research funding mechanisms predominately fund subject matter experts, largely precluding investigators from venturing into research areas outside of their own field of expertise. Oncode base funds allow OIs to break new ground in order to tackle scientific challenges. Multiple investigators have indicated the value of this in the testimonials below.

Lodewijk Wessels (NKI): “This project would have been virtually impossible to fund via regular channels as my group is primarily focused on computational sciences and has no track record in experimental (‘wet-lab’) approaches. Experimental protocols closely integrated with computational modelling would greatly enhance the impact of our work.”

Hugo Snippert (UMC Utrecht): “Along the lines of Oncode and SU2C philosophy, I aim to create more clinical impact with my basic-oriented studies. As such, I started vital collaborations with clinicians to obtain access to highly unique tumour resection material of early-stage colon cancers.”

Karin de Visser (NKI): “This Oncode project has triggered a shift in how my lab operates; from being a 100% fundamental research lab, we now pursue a mixture of fundamental and translational research, which is very inspiring.”

Technologies & Infrastructure 101: In addition to base funding, Oncode provides the Oncode community with access to state-of-the-art technologies, infrastructures, and facilities via its Infrastructure and Technologies (I&T) programme. The programme has so far allowed Oncode to fund 10 infrastructure projects and set up 7 state-0f-the-art research facilities for the Oncode and wider Dutch research community, thereby supporting broader access to key scientific capabilities that are more cost effective when shared. To ensure optimal exposure and usage of these infrastructure projects and research facilities, Oncode frequently organizes technical masterclasses and workshops. 
 
In 2020, Oncode funded 3 new facilities with a total budget of ~€2M. These included the GPU (Graphics Processing Unit) Artificial Intelligence (AI) and machine learning facility, for which Oncode offered a series of technical masterclasses co-created with GPU facility researchers. The combination of high-end facilities and tailor-made masterclasses enables the Oncode community to optimally use the scientific and technical capabilities present in Oncode to answer scientific questions.   

Sarah Derks (Amsterdam UMC): “Another example is the Oncode core facilities. I collaborate with Geert Kops to make single-cell DNA sequencing possible and get help from Jan Paul Medema to get Nanostring analyses started in the Netherlands.”

Boudewijn Burgering (UMC Utrecht): “The different Institutes/UMCs operate differently when it comes to investments in technology. So often it is a long and painstaking procedure to acquire machines and technology that can make your research cutting-edge. The proactive and positive attitude of Oncode towards supporting technology development, therefore, is not only unique but also a big help in driving our research.”

Oncode Single-Cell Core genome sequencing facility: Launched in September 2020, the single-cell genome sequencing facility is built on novel sequencing technologies established in the research groups of Alexander van Oudenaarden and Geert Kops (both Hubrecht Institute). This facility offers a series of state-of-the-art single-cell genome sequencing technologies (scWGS, scChIC-seq, scTAPS-seq and scKaryo-seq) with dedicated support for experimental design and data analysis. The Single-Cell Core facility lowers the barrier for researchers to perform sequencing-based experiments, which require a very high level of technical expertise. This facility enables researchers from Oncode and throughout the national and international research community to access (epi)genomic detection in single cells.

Oncode GPU infrastructure: AI and Deep Learning (DL) are revolutionizing the way we process complex, large-scale datasets. While applications of AI and DL for cancer research are at different levels of maturity, it is clear that these new technologies can and will revolutionize the field. Both technologies leverage the high-speed processing capabilities of GPUs. The Oncode GPU infrastructure consists of a GPU cluster distributed amongst 3 Oncode partner institutes. Spearheaded by Anastassis Perrakis (NKI), Jeroen de Ridder (UMC Utrecht), and Mario van der Stelt (Leiden University), the GPU cluster enables Oncode researchers to apply AI and DL applications in Cancer Genomics, Proteomics, and Structural Cell Biology with hands-on support provided by AI and DL experts.

Oncode platform for clinical colorectal cancer (CRC) samples: Initiated during an Oncode clinical workshop by Louis Vermeulen (Amsterdam UMC) and Mirjam Koopmans (UMC Utrecht), the platform was funded by Oncode in 2019 and set up to provide a comprehensive overview of available biomaterials and -omics data within clinical studies for CRC. Its aim is to connect fundamental and clinical research, and accelerate access to clinical samples (tissue, blood, rest materials) for proof-of-concept and validation studies. In 2020, the platform launched version 1.0 of the platform with the Dutch Prospective Colorectal Cancer Cohort at its core. The Prospective Colorectal Cancer Cohort is a pre-existing infrastructure that has now been extended with an additional 17 clinical studies and cohorts encompassing >20,000 biological samples from CRC patients. The newly-created platform is available to the entire Dutch research community through a collaboration with the Dutch arm of the pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI).

Oncode strives to create an environment in which Oncode researchers can reach their maximum innovation potential. To that end, we use our base fund to enable each of our investigators to pursue innovative research in uncharted areas of cancer biology. Each year, our 42 Senior Oncode Investigators receive €250k, and our 19 Junior Oncode Researchers receive €150k from our base fund.

These funds provide them with the opportunity to pursue leads that are typically outside their own scientific expertise, initiate research that may be difficult to finance due to the lack of preliminary data, or conduct research that requires access to specialized and expensive technologies. In this way, Oncode offers its investigators the financial capability and flexibility to accelerate research lines, change the scope of existing research programmes, or terminate unsuccessful projects.

The approach is valued by our scientific community and has led to several tangible results in 2019:

“I initiated a new research line in which we aim to investigate how inherited mutations in the LKB1 gene mediate predisposition to the development of gastrointestinal cancer in Peutz-Jeghers Syndrome (PJS) patients. Without Oncode support, it would be difficult to obtain funding for this research line because the work is entirely new to my lab and funding schemes commonly require a track record in the field.”

Madelon Maurice, UMCU

“Oncode base funding allowed me to hire a chemist with whom we are developing novel probes. These probes could potentially act as inhibitors of a family of enzymes for which inhibition might benefit (current) treatment of cancers like breast cancer and multiple myeloma. This collaboration allowed us to apply for TKI-Public Private Partnership funding which was awarded. The model for jumpstarting this industry collaboration was very useful.”

 Titia Sixma, NKI

“We use single molecule imaging to study virus replication in mammalian cells. Oncode funding gave me the opportunity to start studying oncolytic viruses, but since my lab has no previous experience in this area, and we have no preliminary data to support this project, traditional grant applications would not have been successful. However, using my Oncode base-funding, I have been able to initiate this highly successful project, and using the preliminary data generated as a result of the Oncode base funding, I have now submitted a grant proposal for traditional funding.”

Marvin Tanenbaum, Hubrecht Institute

Link to the clinic 101: Oncode aims to accelerate the translation of academic research findings into better diagnostics and better treatments for cancer patients. To that end, it focuses on de-risking innovations at an early stage. Oncode has a dedicated fund (total €10M) to invest in (pre)clinical proof-of-concept studies to demonstrate the potential diagnostic or therapeutic value of a research finding. Oncode’s team of experts provides guidance and advice to all OIs applying for Clinical Proof-of-Concept (CPoC) funding. In 2020, Oncode financed 4 projects with a total budget of €2.86M. The first 2 CPoC projects funded since the establishment of Oncode in 2017 were completed in 2020. To increase the interaction between basic scientists and clinicians, Oncode organizes clinical workshops that aim to facilitate a dialogue about clinical challenges and how scientific insights can contribute to solving them. In 2020, one such clinical workshop on breast cancer was organized, hosted by researcher Jos Jonkers (NKI) and clinician Agnes Jager (Erasmus MC). This attracted 65 participants from basic and translation science, clinical researchers, clinicians, and industry representatives. After onset of the COVID-19 pandemic, no similar events were organized in 2020.   
 
The impact of Oncode expert teams: To ensure the quality of Oncode (pre)clinical projects, Oncode is supported by 2 expert teams; the Oncode Exploratory Development Expert Support (OEDES) team and the Clinical Advisory Board (CAB). The OEDES team consists of experts in pre-clinical and clinical development, with experience in academic, industry and clinical settings. They help to define the goals of a study in relation to the overall development trajectory and can support researchers by giving them specific advice on their proposals to maximize the value of results. The CAB, comprising 8 clinical experts and 3 patient representatives, reviews CPoC proposals and offers advice to Oncode researchers about how to increase the likelihood that their research will result in successful clinical developments. 
  
In 2020, Oncode organized 2 OEDES workshops and, in collaboration with the OEDES team, also prepared various educational online tutorials about clinical research, defining a target product profile, pre-clinical requirements, and the development of a biomarker or biomarker assay. Both OIs and their clinical collaborators have praised the value of these OEDES workshops and tutorials.  

Hans Hofland (Collaborating MD, Erasmus MC): “The support given by the OEDES team for our PRRT-PARPi study was thorough and very insightful. It helped us to improve our study design. Normally, funding agencies either reject or approve research grants. It is clear that Oncode wants to change this paradigm and is committed to proactively improve research proposals.”

Sjoerd van der Burg (LUMC): “Oncode’s Business Development team and Exploratory Development Expert Support team were instrumental in the preparation of a clinical development plan for our TEIPP immunotherapy platform. It changed the way of thinking on what sort of information was required, the way we could approach our challenges, […]. This allowed us to rapidly prepare for a first-in-man clinical trial.”

Joost Gribnau (Erasmus MC): “The input of the OEDES team has been very important in shaping and improving this proposal/plan, providing valuable advice from experts in their respective fields.”

First CPoC projects completed: After initiation of Oncode in 2017, the CPoC programme was one of the first to be launched, leading to the approval of 8 CPoC projects in 2018. The first 2 of these projects were completed in 2020. One is the project of Prof. Jan Paul Medema (Amsterdam UMC) and his clinical collaborator Prof. Henk Verheul (Radboud MC) titled Pulsatile high dose Sunitinib as a specific drug for (a subset of) metastatic mesenchymal CRCs. This CPoC project has provided essential preliminary results for the follow-up Sunrise Study, a larger phase II clinical study within the Oncode-ZonMw Affordable Healthcare programme (see section 3.3.4). The CPoC project led by Prof. Wilbert Zwart (NKI) was also completed in 2020. In his study, Prof. Zwart and his clinical collaborator Dr. Bergman aimed to validate a novel gene-classifier to guide adjuvant treatment for prostate cancer. The work resulted in a robust novel gene classifier that enables the stratification of primary prostate cancer patients on metastasis-free survival, which was successfully validated in additional large cohorts. With the help of the Oncode Valorization team, Prof. Zwart is now exploring patentability of the new prognostic classifier, called PROPREDICT, and preparing outreach to molecular diagnostics companies for potential licensing of the tool. Both studies contribute to Oncode’s goal of achieving impact for patient benefit while simultaneously contributing to the affordable healthcare goals of Oncode.

Wilbert Zwart (NKI): “The CPoC fills a clear gap in the Dutch funding landscape, as it’s classically very challenging to find financial support for translating research towards clinical implementation. Yet this transition of our findings is tremendously important and critical for improving patient care, and a key feature of the societal responsibility we have as scientists.”

Steppingstone towards international collaborations: The CPoC programme is set up to promote collaborations between basic and clinical researchers. In 2020, the impact of the programme extended beyond the borders of the Netherlands in an international partnership to address unmet medical needs.

Prof. Den Boer (PMC) is driven to improve the clinical outcome for children with hematological malignancies and reduce side-effects of current treatment options. Patients are currently treated according to standardized protocols, and while optimizations in treatment protocols have improved outcomes over the past decades, relapses still occur in 15% of all cases with the outcome after relapse often being poor. Furthermore, personalized treatment options are required for children with relapses to reduce side-effects and mistreatment. Initially Prof. Den Boer proposed a CPoC project focused on patients in the Netherlands. However, after discussion with colleagues during an international meeting it became clear that the project needed to be set up in a European context. The study aims to determine actionable lesions in a uniform way by a group of experts and to advise treating physicians about trials that are open in order to facilitate enrolment of the right patient in the right early clinical trial.

Monique den Boer (PMC): “Receiving the Oncode CPoC grant for the international leukemia board has placed us in a unique position in Europe. We are currently in full swing to set up the protocols, screens, and infrastructure, including getting all European experts (and beyond) on board, to truly impact lives, not only of Dutch children but also a major part of Europe’s children.”

Oncode brings basic research and clinical practice closer together to enable the effective translation of promising research into novel clinical treatment strategies. To support this goal, Oncode created its Clinical Proof-of-Concept (CPoC) Programme, with an earmarked budget of €10M for pre-clinical and early clinical studies based on findings from Oncode research labs.

Via a rolling call, Oncode Investigators, together with clinicians, can submit proposals to start (pre-)clinical projects. To support the development of proposals, Oncode installed the Oncode Exploratory Development Expert Support (OEDES) Team. The team comprises experts in pre-clinical and clinical development with experience in academic, industry and clinical settings.

In 2019, three projects were approved with a total budget of ~€1.8M. A team led by Roland Kanaar will investigate the use of a functional repair capacity test in the selection of advanced breast cancer patients who may benefit from carboplatin treatment, Jan Paul Medema will lead a project investigating stromal activation to guide gastrointestinal cancer therapy, and Sjoerd van der burg has started a project into TEIPP-targeting immunotherapy to potentially overcome immune escape in tumours.

Clinical workshops
To facilitate connections between the basic science, clinical researcher and clinician communities, we organize regular clinical workshops each dealing with a specific tumour type. Two workshops were organized in 2019, one on Colorectal Cancer (CRC) and the other on Glioblastoma. Each of these workshops included between 50-60 attendees and stimulated fruitful discussions about unmet clinical needs, trends in basic research and challenges in the clinic. 

“For me, the CRC workshop showcased not only the clinical challenges but also the available material and ongoing studies that researchers could use to help attack those challenges. After the CRC workshop, we started collaborating with a clinical research group at NKI on the origins and impact of chromosomal instability in early adenomas.”

Geert Kops, Hubrecht Institute