“UNCAN.eu” refers to a collective European effort seeking to enable a leap forward in our understanding of cancer. This initiative, which includes the creation of a European cancer research data hub, will pave the way to new advances in cancer care. Starting on September 1, 2022, a 15-month coordination and support action will generate a blueprint for UNCAN.eu. Here, we summarize the cancer research issues that the blueprint will propose to tackle at the European level.

Two convergent novel initiatives of the European Union (EU)—in health, Europe's Beating Cancer Plan and, in research and innovation, the Horizon Europe Mission on Cancer (https://research-and-innovation.ec.europa.eu; ref. 1)—spurred the creation of a platform to better UNderstand CANcer (UNCAN.eu) as part of their implementation road map. Starting in September 2022, a 15-month coordination and support action (4.UNCAN.eu) will generate a blueprint for setting up UNCAN.eu. This initiative is anticipated to collect research data, patient health data, and any other relevant data at an unprecedented scale to gain a new and deeper understanding of cancer mechanisms. The global ambition of this initiative is to achieve significant new knowledge to guide improvements in cancer prevention, early diagnosis, and treatment, including prevention of treatment-related side effects, ultimately providing a basis for saving millions of lives and improving the quality of life of cancer survivors and their caretakers.

The blueprint for the UNCAN.eu platform includes two pillars (Fig. 1). One is the implementation and management of the European Cancer Research Data Hub with well-defined standardization, robust interoperability, and open access. The second is the generation of a research road map identifying ambitious international projects as use cases to feed the data hub. These projects may address research challenges that cannot be tackled properly at the level of individual EU Member States and complement the Cancer Grand Challenges launched by Cancer Research UK (CRUK) and the U.S. National Cancer Institute (NCI; ref. 2). In line with the European Commission's strategic priority on the digital transformation of health, anticipated outcomes may include artificial intelligence (AI)–powered medical decision support systems to guide personalized cancer prevention, diagnosis, or care. Importantly, use cases will be selected in close interaction with cancer patient advocacy groups to integrate the expectations of patients with cancer and their families into the proposed agenda.

Figure 1.

The two pillars of the UNCAN.eu initiative.

Figure 1.

The two pillars of the UNCAN.eu initiative.

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Although sometimes perceived to be a disease of modernity, cancer has existed since antiquity. The earliest fossil evidence for malignant neoplastic disease in the hominin record is a metatarsal osteosarcoma identified in the cave site of Swartkrans in South Africa, with the estimated age of these human remains ranging between 1.8 and 1.6 million years. The Greek physician Hippocrates (460–377 BC), who is credited with naming cancer, pioneered the knowledge of the disease, suggesting it was due to a retention of humors. This theory stood for almost 2,500 years, during which due to limited life expectancy, cancer did not represent a prominent health concern.

Starting in the middle of the 19th century, breakthroughs in cancer treatment were driven by technological projections and research advances, schematically one every 50 years. Progresses in light microscopy allowed Rudolph Virchow to formulate the cellular theory of cancer in the 1850s, and simultaneous advances in ether anesthesia by Crawford Long catalyzed development in cancer surgery. Radiotherapy was introduced at the beginning of the 20th century following discoveries by Wilhelm Röntgen and Pierre and Marie Curie, and 50 more years were needed to introduce chemotherapy, based on advances in synthesis chemistry. Finally, the development of genomic tools together with 50 years of intense investigation in cellular and molecular biology culminated in the emergence and validation of targeted therapies, starting with the 21st century. Therapeutic responses obtained with immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells, which were introduced 10 years after targeted drugs, validated a new concept—that is, cancer can be controlled not only by targeting tumor cells but also through invigorating and mobilizing host immune cells. Oncology moved from a reductionist view focused on cancer cell genetics and epigenetics to a more holistic one that includes the host.

After 170 years of intense investigation to decipher the biological bases of cancer and despite multiple initiatives to further understand and better prevent, detect, and treat this disease, cancer remains the second leading cause of death worldwide. Across the 27 EU Member States, 2.7 million people are diagnosed with cancer every year, and 1.3 million die from the disease. More than 6,000 disease victims are children, adolescents, and young adults, with cancer being the leading cause of child mortality from disease in Europe, and over half a million of European citizens are childhood cancer survivors dealing with long-term effects of the disease and its treatment (3). Cancer puts immense pressure on health systems, and this major societal challenge will be growing further due to increasing life expectancies (cancer has become the main cause of death in both males and females ages 60–79), unhealthy lifestyles, and unfavorable environmental and working conditions.

A new level of investment for a better understanding of cancer is needed to generate new thinking and hopefully new breakthroughs in our ability to prevent, diagnose, and treat this disease. To this end, Europe calls for strengthening collaboration among Member States and consolidating its stakes for data sciences to enable a leap forward in modern oncology and efficiently curtail the rise of disease burden.

Decades of cancer research have shown that cancer is a highly complex and heterogeneous disease, as no two cancers are exactly the same. Determining the right treatment strategy requires the acquisition and proper integration of a large variety of clinical and biological data. Following a variety of sophisticated technological developments, a hitherto unimaginable and exponentially growing number of data points can now be generated from each individual cancer patient and tumor. High-performance computational approaches enable us to integrate clinical information with high-resolution images and multidimensional biological information collected from large cohorts of patients (e.g., by using AI-powered tools). The expectation is that these approaches will allow us to generate a comprehensive and dynamic view of how cancers initiate, develop, and spread in the host, exposing new mechanistic insights that pave the way for novel and more effective therapeutic interventions.

Having acknowledged the utmost strategic importance of coordinated data sciences in cancer research, the implementation of the European Cancer Research Data Hub will have a pivotal role in UNCAN.eu. One of the added values of the cooperation between Member States is the opportunity to share and integrate enough information to achieve the power to reach robust conclusions, especially when dealing with cancers characterized by low incidence. The strategic interest of this approach is emphasized by the fact that multidimensional analysis stratifies most common tumors in a constellation of rare entities—each of them demanding innovative, highly individualized, and effective therapies that reduce the toll of treatment-related side effects.

The biomedical research sector is typically data-rich but information-poor, as the pace at which data are being collected and the multiplicity of siloed databases without standardization often preclude the ability of users to translate these data into knowledge (4). Exploitation of large datasets requires coherent data generation, collection, storage, and management, as well as innovative analytic approaches (data analysis and theoretical methods, mathematical modeling, and computational simulation techniques). The 4.UNCAN.eu coordination and support action (CSA) will identify, among existing European infrastructures, the best partners to build and host a rapidly effective cancer research data hub. In other words, the blueprint for UNCAN.eu will recommend taking advantage of the experience accumulated by existing infrastructures rather than creating a new one. In the context of this infrastructure, UNCAN.eu will promote the development of open science practices, encompassing the management of research software and data products, with every UNCAN.eu partner committing to findable, accessible, interoperable, and reusable (FAIR) guiding principles for scientific data collection, management, and stewardship while adhering to Europe's General Data Protection Regulation (GDRP). The 4.UNCAN.eu CSA will also cooperate with existing European Strategic Forum for Research Infrastructures (ESFRI) to identify required procedures and facilities for standardized data generation. Patients with cancer and their families, as well as European citizens, may play a facilitating role in personal data collection.

Data collected in the European Cancer Research Data Hub will include analysis of cancer models, in vitro as well as in vivo, and longitudinal data collected from patients, including medical and biological as well as other relevant data such as lifestyle and geographic information. Importantly, UNCAN.eu will not drive clinical trials by itself but rather will produce new knowledge that generates hypotheses for clinical testing. Nevertheless, clinical trials provide an excellent opportunity to collect high-quality, multidimensional data that fuel basic and translational research programs. UNCAN.eu will connect with and integrate clinical research networks as another approach to feed the data hub. Real-world data, which provide useful additional information, will be collected through hospital networks, such as that of European Comprehensive Cancer Centres, whose creation is also part of the Mission on Cancer road map and Europe's Beating Cancer Plan flagships.

The blueprint for the UNCAN.eu platform will propose a model of governance of the European Cancer Research Data Hub and develop legal, ethical, and technological frameworks for protecting personal data, regulating data sharing and use, and ensuring the education of researchers for proper use of the collected information. To initiate the process of data collection and define the best standards, the blueprint will also propose a road map to identify ambitious projects as use cases leveraging multidisciplinary resources across Member States to address challenges in cancer research in the areas described below.

Although the recent approval of many new therapies has improved the treatment of established tumors, new knowledge is required to further improve the prevention and early detection of cancers (4). Strategies have emerged to personalize early detection and introduce active surveillance, including pharmacologic prevention, in some tumor types and predisposing situations (5). Importantly, recent paradigm shifts in our understanding of cancer biology call for a deeper understanding of the earliest steps in disease onset and progression in order to refine cancer interception approaches.

One of these shifts relates to the role of somatic mutations in cancer driver genes. Improved genetic tools have revealed the presence of multiple clones defined by somatic variants in cancer driver genes in stem cells of otherwise healthy tissues (6). Some mechanisms (e.g., tissue homeostasis and architecture) limit the expansion of these clones in healthy tissues. The accumulation of clones with age, combined with other factors, such as wounding (7) or stromal cell senescence (8), promotes cancer development through diverse trajectories—that is, one of these clones toggles to a malignant tumor, or an inflammatory climate induced by these clones or environmental insults promotes the independent emergence of a cancer. A better identification of the impact of specific ecosystems on neoplastic development, either at the individual (genetic, epigenetic, metabolic, microbiome, age, and comorbidities) or at the collective (exposure to chemicals, pathogens, or radiations and socioeconomic disparities) level, could expose approaches to improve disease prevention. Rejuvenating strategies eradicating nonmalignant clones were suggested to preserve the tumor-suppressive properties of otherwise healthy tissues. However, recent analyses in mouse models suggest that mutant clones accumulating in normal epithelium could outcompete and eliminate emerging tumors rather than promote cancer (9), emphasizing the need for a better understanding of these interactions to drive appropriate interventions.

Another benefit of the improved understanding of the early steps of oncogenesis may be the timely detection of early-stage cancers. Many cancer types currently lack effective screening approaches. In other cases, the benefits from screening are marginal when weighed against the potential for harm, including the risk for overdiagnosis leading to unnecessary treatment. The computational analysis of single-cell multiomics and images collected longitudinally from patients and patient-derived experimental models during the progression from health to disease, characterizing transformed cells and their environment, could guide earlier therapeutic interventions in the course of cancer (10). Analysis of an atlas of preneoplastic and early-stage neoplastic lesions, cells, and analytes (e.g., circulating tumor DNA) could also produce innovative approaches for early diagnosis and drive an interceptive medicine to eradicate early-stage cancers before they become intractable and potentially lethal (11).

Use cases that explore tumor–patient interactions in men and women through life span will be part of the blueprint for UNCAN.eu. Pediatric cancers are typical examples in which data sharing is critical, as these diseases are fortunately rare (50–200 children/million/year worldwide, 35,000/year in Europe) and heterogeneous (60 histotypes, many subtypes through molecular characterization). In the European pediatric oncology community, strong collaborative basic and clinical research networks already exist and have successfully delivered over the past decades. Very often, driver events are conditioned by the developmental stage in which the tumor arises, linking developmental biology to cancer research and treatment—for example, how immune system development impedes anticancer therapeutic initiatives such as immunotherapy remains poorly known. Cancer predisposition syndromes account for ∼10% of childhood cancers. For 90%, the causes are unknown and the low mutational burden typically observed in these tumors should not be confused with simplicity in their underlying mechanisms. Achieving effective progress in the molecular and genomic analysis of pediatric cancers necessitates the sharing of data between institutions performing integrative analyses beyond DNA panels. Analysis of these data will guide molecular tumor boards in making decisions with the ultimate goal of maximizing the chances of cure and ensuring a long and safe life for patients (12).

Aging is both an important risk factor for many types of human cancers (i.e., most cancers arise in individuals over the age of 60, and the main molecular signature identified in cancer cells is a clockwise signature) and an impediment to various treatments. However, accumulating evidence on the complex biology of aging is rapidly giving rise to novel pharmaceutical approaches, such as senolytic drugs, to reduce aging-associated, late-onset human diseases including cancer and to strive to make people healthier longer. Elimination of cancer cells by induction of acute senescence has also emerged as a promising concept in adjuvant anticancer therapy—that is, senolytic drugs combined with senescence-inducing drugs could maximize cancer treatment efficacy. In addition, longitudinal and mechanistic studies on molecular footprints of aging including proteins, epigenetics, and metabolites provide readouts of biological, age-related decline in organ and tissue function, offering new guiding metrics of health to guide cancer prevention, diagnosis, and treatment strategies (13).

The cancer mortality rate is 25% higher for males than for females. Sex disparities are apparent across a range of nonreproductive cancers and vary by age. Furthermore, there are significant sex differences in therapeutic response and toxicity for many cancer types. Nevertheless, how differences based on sex or gender affect cancer emergence and therapeutic response is not adequately understood. Sex differences may arise due to a combination of environmental, genetic, and epigenetic factors, as well as differences in gene regulation and expression. In addition, cancer risk and outcome are poorly explored in 0.3% to 1.2% of the adult population in Europe identified as transgender or gender diverse, referring to a chosen sexual identity with associated lifestyle choices and specific risks (14). UNCAN.eu is committed to improve our understanding of the drivers of differences in cancer development based on sex and gender and their interactions with treatment.

The consequence of decreasing cancer mortality entails a rapidly increasing number of cancer survivors (and patients leaving with cancer). The needs of this population require a novel and adapted level of understanding and research. The best models for providing survivor care (including management of the adverse health effects and the emotional toll on family members, friends, and caregivers that are part of the broad definition of survivorship) remain to be defined. Survivorship encompasses multiple aspects that could benefit from basic and translational research programs. With few exceptions, there are no evidence-based guidelines for the follow-up care of cancer survivors. An emerging concept is that some cancer treatments cause premature or accelerated aging in survivors, thus already mentioned research on aging and cancer may yield innovative approaches to prevent the late effects of cancer treatment. Studies encompassing hypothesis-driven approaches that explore the predictive value of inflammatory and metabolic biomarkers, and discovery approaches identifying novel markers through harnessing genomic, proteomic, metabolomic, and imaging data will likely enhance the quality of life of cancer survivors (15).

Resistance to drugs and radiotherapy is the main limiting factor for achieving cancer cure and is observed in most metastatic cancers. Therapeutic resistance usually involves a combination of several parameters that include tumor volume and growth, tumor heterogeneity driven by the reiterative process of clonal selection and expansion, physical barriers with sanctuary sites such as the central nervous system, the tumor microenvironment affecting drug diffusion or immune cell infiltration, and interactions with distant environment such as the gut microbiota or the liver metabolic clock. To overcome resistance in hard-to-cure cancers, multiple solutions have been proposed, including earlier diagnosis of tumors, improved use of existing therapeutics, monitoring of treatment response before adapting the therapeutic intervention, and mapping actionable tumor cell dependencies. After several decades of research, cancer-resistance mechanisms remain a complex issue that precludes achieving the cure of many metastatic cancers, even with the most recently approved drugs (16). An improved understanding of cancer-resistance mechanisms could spare patients from receiving ineffective drugs and provide the rationale for administrating personalized drug combinations. The recent success of immunotherapeutic interventions and the increasing evidence that tumor cells remodel their immediate and distant environments suggest that better understanding the ecosystem formed by the tumor and the host at the local, tissue, and organismal levels might stimulate technological and pharmacologic advances to reduce the burden of hard-to-cure cancers.

The European Commission has launched a bottom-up initiative to prepare UNCAN.eu, a platform to better understand cancer. This platform will complement the U.S. Cancer Moonshot initiative and the CRUK/NCI Cancer Grand Challenges. The blueprint is expected to be delivered in November 2023. It will propose a sustainable framework for the European Cancer Research Data Hub, fed with a series of programs or use cases, mobilizing the best cancer research teams with complementary expertise across Member States to address critical issues in oncology. Such a framework could lead ultimately to the creation of a European virtual cancer institute. To derive this European strategic agenda in cancer research, a Delphi consensus process will define between 8 and 10 initial international programs in the fields of prevention and early diagnosis, cancer across ages and genders, therapeutic resistance, and survivorship. Expert researchers and patient advocates across all Member States are invited to apply to join the expert working groups that will contribute to this impactful endeavor.

E. Solary reports grants from the European Commission during the conduct of the study, as well as grants from Thermo Fisher, Stemline, Granite Bio, and the Amgen Foundation and personal fees from Novartis outside the submitted work. M. Boutros reports grants from the European Commission during the conduct of the study, as well as grants from GSK and Merck outside the submitted work. P. Nagy reports grants from the National Institute of Oncology (Országos Onkológiai Intézet) during the conduct of the study. J. Tabernero reports personal fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc., IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc, Oniria Therapeutics, Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER) outside the submitted work. No disclosures were reported by the other authors.

This work was funded by the EU. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the EU or the Health and Digital Executive Agency. Neither the EU nor the granting authority can be held responsible for them. The 4.UNCAN.eu CSA is funded by the EU. The authors gratefully acknowledge Christine Chomienne, Javier Carmona, Alexandro Piris, and Gilles Vassal for helpful comments and suggestions.

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