Harnessing the Power of Discovery Free

The global research effort has resulted in significant advances in our understanding of the initiation, development, and progression of cancer, which in turn, have led to improvements in prevention, early detection and diagnosis, and treatment. Yet, despite the progress we as a global community have made, cancer is still the second leading cause of death worldwide, claiming nearly 10 million lives in 2020 (1).

Many unanswered research questions continue to impede progress, and their complexity and scale require us to think differently and work collaboratively if we are to solve them. Cancer Grand Challenges is an international funding initiative that aims to unite the world's best scientists to tackle these challenging questions by funding team science on a global scale.

A partnership between Cancer Research UK (CRUK) and the National Cancer Institute (NCI) in the United States, Cancer Grand Challenges empowers international research teams to cross traditional boundaries to conduct transformative research, with the ultimate aim of changing outcomes for people with cancer.

We recently announced a new set of challenges and are now inviting interdisciplinary teams to submit proposals. The challenges were identified after a global consultation with the research community and people affected by cancer, which resulted in 300 ideas being proposed. These ideas were discussed and debated by the Cancer Grand Challenges Scientific Committee, which translated them into nine challenges. Thereafter, NCI and CRUK leadership agreed upon the final challenges announced today.

Our new round of challenges addresses a broad spectrum of problems that, if solved, could transform the way we prevent, diagnose, and treat cancer. Some of the challenges, such as the “cancer cell plasticity” challenge, seek to address gaps in our understanding of fundamental cancer processes, which could help in identifying novel cancer vulnerabilities and targets. While progress against other challenges, such as the “obesity, physical activity and cancer” and “aging and cancer” challenges, holds the potential to benefit whole populations.

Below, we outline our nine new, ambitious challenges, to make progress against which will require an interdisciplinary research approach.

T cells are central players in the immune response, and harnessing their power in the development of immunotherapies has transformed the treatment landscape for some cancers. Despite the recent clinical success of immunotherapies, such as chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors, their effects are not universal across cancer types and patient subsets.

Tumor-infiltrating lymphocyte (TIL) cell therapy has shown success recently, particularly for metastatic melanoma, highlighting the ability of TILs to recognize tumor-associated antigens. While it is possible to sequence the T-cell receptors (TCR) present on the surface of these immune cells, in most cases the nature of the antigens recognized by TCRs is unknown. This lack of knowledge is impeding opportunities to potentiate immune responses against cancer cells and to develop novel advanced cellular therapies.

A more comprehensive understanding of the interactions between major histocompatibility complex–bound peptides and TCRs will improve our knowledge of the nature of the cancer antigens that are recognized by T cells. This has the potential to greatly improve the clinical effectiveness of future cancer immunotherapies, as well as improve our understanding and treatment of autoimmune and infectious diseases.

We need new approaches to make progress in this area. With technological advances in sequencing modalities and progress in machine learning/artificial intelligence, the time is ripe to tackle this important problem. The power of machine learning approaches has been demonstrated by DeepMind's AlphaFold, which has predicted full 3D protein structures from linear amino acid sequences using deep learning (2, 3). This Cancer Grand Challenge offers the opportunity to bring innovative technologies like this together with the expertise of structural biologists, immunologists, and computational biologists, which could be key to improving the success of cancer immunotherapies.

Obesity and sedentary behavior are important risk factors for cancer. Epidemiologic evidence generated over the past three decades has conclusively demonstrated the association between physical activity, sedentary behavior and obesity, and cancer incidence. Large meta-analyses have provided convincing evidence that obesity is associated with an increased risk of developing 13 different types of cancer, and physical activity is associated with reduced risk (reviewed in ref. 4). However, despite decades of research, the causative mechanisms linking obesity, sedentary behavior, and physical activity to cancer development and progression are not well understood, thus hindering the development of effective interventions.

Several biological processes have been posited as being involved. These include, perhaps unsurprisingly, metabolism, insulin resistance, and chronic low-grade inflammation, as well as overstimulation of endogenous sex hormones, oxidative stress, adiposity, changes in the microenvironment, and disruption of circadian rhythms (5).

Emerging data indicate that physical activity may impact cancer risk via epigenetic changes, including DNA methylation, alterations in chromatin structure, and miRNA expression (6). Studies have also revealed that increased physical activity can increase the concentration of neutrophils, lymphocytes, and monocytes, including natural killer cells and CD4⁺ T cells and B cells, which may help to boost immune surveillance against cancer (6).

Addressing this challenge will require a functional and mechanistic understanding of the processes underlying cancer risk, causation, and progression mediated by obesity, sedentary behavior, and physical activity. Bolstering our understanding in this area will accelerate development of interventions to reduce global cancer incidence and mortality, and prolong survival, which could have population impact worldwide.

Over the last decade, there has been a marked increase in the incidence of some cancers in adults between 20 and 50 years of age, with the mean age of diagnosis for some cancer types decreasing by up to 10 years. The incidence of early-onset cancers has increased in multiple countries, and the rise cannot be explained only by germline genetic alterations or increased screening. The changes in incidence have been observed across a variety of cancer types, including in the breast, colon, endometrium, esophagus, extrahepatic bile duct, gallbladder, head and neck, kidney, liver, bone marrow, pancreas, prostate, stomach, and thyroid. These early-onset sporadic cancers contradict the general rule of aging and cancer, and risk becoming an epidemic in the future. Further understanding the etiology and pathogenesis of early-onset cancers is key to developing preventative measures and protecting populations at risk.

Younger generations may be at greater risk of specific cancers, as the “exposome” or early-life environmental exposures (such as antibiotics, diet, smoke, pollution, alcohol, sleep deprivation, and circadian rhythm) are different from those of older generations. However, what exactly those exposures are, when during development the exposure has taken place (i.e., development in utero, childhood, or puberty), or how they increase the risk of cancer development are yet to be uncovered (7).

To address the emerging issue of early-onset cancers, we need to understand the mechanisms linking lifetime exposures in multiple cancer types to cancer initiation. For example, recent data from the Child Health and Development Studies suggest a link between maternal obesity and risk of colorectal cancer in offspring (8). Early-onset colorectal cancer represents a significant cancer burden among younger adults. However, studies thus far have failed to identify the causes of its recent rise (9).

Addressing this challenge will require a robust understanding of the mechanisms underpinning the biological and environmental causes behind the global phenomenon of early-onset cancers.

Cellular plasticity is the ability of cells to switch their identity in response to intrinsic and extrinsic stimuli and is a property of both normal and cancer cells. Cellular plasticity is important in processes such as wound repair, but in cancer cells, it can bestow stem-like properties, driving tumor heterogeneity, treatment resistance, invasion, and metastasis. Cancer cell plasticity therefore represents a huge barrier to treatment success, yet the mechanisms governing it remain poorly understood.

Each stage of cancer progression likely involves significant alterations to the epigenetic state of cells during clonal evolution. Furthermore, many cancers progress or recur despite an initial response to treatment, and the progressing or recurrent cancer is often more resistant to therapy. This increased therapeutic resistance results, in part, from the plasticity of cancer cells, which allows them to adopt new cellular programs in response to treatment (reviewed in ref. 10).

Epithelial-to-mesenchymal transition (EMT), when cells lose their epithelial phenotype and gain mesenchymal characteristics, is one of the best described examples of cell plasticity. Recent studies suggest that cancer cells can adopt a partial EMT state to migrate as clusters as they metastasize (11, 12). In addition to its role in metastasis, EMT has recently been shown to be involved in drug resistance to EGFR tyrosine kinase inhibitors (13).

Our increased understanding of cell fate determination through epigenetic reprogramming means that it is timely to study in detail how cancer cells achieve these switching processes (reviewed in ref. 14). This challenge seeks to expand our knowledge of the developmental switching programs of cancer cells, how they contribute to cancer progression, and what mechanisms, epigenetic or otherwise, govern them. An improved understanding of cancer cell plasticity could lead to new ways to regulate these programs to improve effectiveness of current therapies or offer new nontoxic alternatives, ultimately improving patient survival.

Inequities in cancer prevention, screening, and treatment lead to disparities in cancer incidence and mortality and are a major public health concern.

While most inequities are the consequence of social determinants and circumstances, such as late-stage diagnosis due to inadequate access to health care, there are emerging data suggesting that genetics and biology also play a role. Polygenic scores confer risks that vary by self-identified race and ethnicity (SIRE); genetic ancestry is correlated with cancer risk or outcomes independently of SIRE; and tumor phenotypes and mutational signatures differ by SIRE. As the relative contributions of genetic, biological, and social drivers of cancer etiology remain unclear, approaches aimed at reducing inequities remain inadequate.

Research to address cancer inequities has suffered from several limitations. First, prior approaches have been siloed within disciplines and do not leverage data addressing the multifactorial contributions of genetics, biology, demographics, social drivers and circumstances, contextual factors, and health care delivery. Second, the definitions of groups being compared in studies of cancer inequities have also been largely based on SIRE. Thoughtful consideration of the groups of interest, including definitions based on genetic ancestry or multivariate features that include social position or circumstances, may be required. Third, most of the work that has informed our understanding of cancer etiology has been undertaken in European ancestry populations. New modalities and technologies for prevention, early detection, screening, and treatment have largely not been developed or tested in diverse populations. As a result, these modalities and technologies can create or exacerbate health inequities.

Recent studies have reported that genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original genome-wide association studies (GWAS). Polygenic risk scores built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities (15). Similarly, emerging studies focused on ancestry-specific genetic architecture and mutation signatures that have involved diverse and international recruitment have demonstrated that in triple-negative breast cancer, African ancestry in African Americans and East and West Africans has been associated with immune cell trafficking and canonical cancer pathways (16). And in lung cancer, Native American ancestry among Latin Americans is associated with somatic EGFR and KRAS mutation frequencies (17).

These data suggest that a deeper understanding of SIRE and/or genetic ancestry is required to reveal mechanisms that underpin global variation in risk and tumor biology. This knowledge is needed to improve the application of risk assessment and precision medicine to tailor cancer prevention and treatment (18).

This challenge seeks to generate functional and mechanistic insights into cancer inequities by generating new transdisciplinary approaches applied in diverse populations. This should lay the groundwork for the development, evaluation, and implementation of future prevention, early detection, and treatment strategies to achieve equity in cancer outcomes for all people.

In 1950, Barbara McClintock identified genetic sequences that could move from one location of the genome to another in maize (19). Almost 80 years after this seminal discovery, the existence of mobile genetic elements in humans has been broadly established.

Transposable elements are widely dispersed throughout the genome, but their activation is often suppressed, and they are tightly controlled during normal development (20, 21). However, these genetic elements can become reactivated as part of the widespread epigenetic dysregulation that cells undergo as they transform from normal to cancer (22).

A major class of transposable elements are retrotransposons, which show RNA sequence homology with that of a retrovirus. Despite the understanding that there is a long-standing relationship between retrotransposons and the mammalian genome, little is known about the genomic organization or mechanisms that drive retrotransposable element reactivation or reintegration in cancer. A better understanding of these elements offers the potential to identify novel therapeutic vulnerabilities.

Recent studies have found that blind mole rats, which have unusually long lifespans and a strong natural resistance to tumorigenesis, express low levels of DNA methyltransferase 1 (DNMT1). DNMT1 usually acts to silence retrotransposons, but when cells proliferate rapidly, low levels of DNMT1 result in increased activity of retrotransposons. In the blind mole rat, this is advantageous as it causes subsequent activation of the immune system to kill cancer cells. Similar pathways exist in humans, but more work is needed to understand these mechanisms both in model systems and the human setting (23).

This challenge seeks to solidify our understanding of how retrotransposable elements are regulated, evolve, reactivate, and reintegrate. This could provide new therapeutic targets to maintain genome stability in cancer, prevent retroelement reactivation, or add to our understanding of their impact on the innate immune system.

Cancer remains the leading cause of death by disease in children globally. Outcomes for some pediatric cancers have not improved in more than 30 years, and progress in the treatment of children with solid tumors, including brain tumors, has largely stalled. In children who relapse, there are limited treatment options available meaning their outlook is often poor.

Despite increased understanding of the underlying biology of pediatric solid tumors, standard curative treatment regimens continue to rely on cytotoxic agents developed decades ago and often radiotherapy. Such therapies induce an alarming rate of severe late effects, including secondary malignancies; cardiac, neurologic, and skeletal toxicity; and infertility. New targeted therapeutics are urgently needed to improve outcomes for pediatric cancers.

Recent advances in harnessing the power of the immune system have shown promise for treating childhood hematologic malignancies. There are now major efforts underway to recapitulate this success in solid tumors. Indeed, one of our current Cancer Grand Challenges teams, NexTGen, is aiming to develop novel CAR T-cell therapies in this regard.

We know that tumors arising in children differ from those occurring in adults. Whereas mutant kinases commonly drive adult cancers, the oncogenic drivers in children's solid tumors are typically transcription factors and/or epigenetic, which have historically been considered “undruggable” targets.

Compounding the biological challenges, drug development in biopharma for pediatric solid tumors has often not been prioritized due to the small market size. However, new platforms show promise for targeting transcription factors and epigenetic pathways, including selective protein degraders, molecules that disrupt essential protein–protein interactions, and cell-selective delivery of oligonucleotides to modulate gene expression.

This challenge will support a disruptive, collaborative approach to employ these new technologies to target oncogenic drivers in children's solid tumors, with the aim to improve survival and diminish the lifelong toxicities experienced by survivors of these diseases.

Cancer incidence increases dramatically with age after sexual maturity, and it has been shown to be the leading cause of death in both males and females aged 60 to 79 years old (24). Aging is associated with an accumulation of somatic mutations, genome instability, epigenetic alterations, and mitochondrial dysfunction among other cellular abnormalities and tissue remodeling. Interestingly, the hallmarks of cancer overlap with the hallmarks of aging. However, it remains unclear how distinct aging processes increase cancer risk in different organs.

Aging tissues suffer from extracellular matrix (ECM) remodeling that might permit expansion of mutant clones within “normal” tissue, and an aging immune system impairs immune surveillance. The ECM varies in the different tissues in organs throughout the body depending on requirements for structure and function, and heterogeneity in ECM stiffness and elasticity is also observed. These factors change as we age (reviewed in ref. 25). Interestingly, a recent study using a system called ICE (inducible changes to the epigenome) demonstrated that erosion of the epigenetic landscape drives aging and restoring epigenome integrity reverses this (26).

However, no single aging process explains cancer risk across all tissues, suggesting that distinct cellular processes associated with aging drive cancer risk in different organs. The multifaceted impact of aging on cellular and organ function, the absence of tractable model systems that reflect human longevity and our nascent understanding of clonal evolution of normal cells in aging tissue, and the impact of aging processes on tissue architecture have together limited our understanding of how aging increases cancer risk.

This challenge aims to elucidate a deep understanding of diverse cellular, tissue, and immune aging processes and their functional consequences on organ-specific cancer risk. Identifying functional aging processes that drive organ-specific cancer risk could help us to identify new interventions that could lower cancer risk in aging populations.

Chemotherapy remains a cornerstone in the treatment of many cancers. Unfortunately, many patients with cancer receiving cytotoxic chemotherapeutic agents, including platins and taxanes, develop neurologic toxicities, which can severely impact their day-to-day functioning and health-related quality of life. Effects on the central nervous system by chemotherapy can lead to neurocognitive deficits with long-lasting consequences in some patients. This is commonly found after breast cancer treatment, for example.

Despite the prevalance of these chemotherapy-induced toxicities, there is limited understanding of why they occur. Understanding how these agents interact with the nervous system and therefore the biological mechanisms of these toxicities is crucial. Expanding our understanding of these toxicities will enable the identification of biomarkers to stratify patients at risk, aid in devising strategies to prevent their occurrence, and offer therapeutic solutions to alleviate these debilitating side effects.

Preclinical models and clinical studies have not yet led to any reliable way to predict patient groups most susceptible to these neurologic toxicities. Currently available preventative measures and treatment remedies have limited effectiveness and are not uniformly applied in the clinic. The different mechanisms of action of chemotherapies have been linked to the neuropathic symptoms they induce, and recent studies suggest there may be off-target effects that contribute to structural damage, mitochondria dysfunction, and the release of different proinflammatory cytokines (reviewed in ref. 27).

This challenge will bring together a concerted effort to maximize our understanding of the pathophysiology of chemotherapy-induced neurologic toxicities. Subsequently, this knowledge will be used to guide the development of hypothesis-driven clinical trials in the prevention and treatment of chemotherapy-induced neurologic toxicity, with the hope to bring much needed improvements for patients receiving chemotherapy.

We believe we have identified nine important and exciting cancer challenges where innovative new approaches are required if we are to make progress. We are inviting experts from a diverse range of disciplines to come together and think differently, and to apply for funding to the Cancer Grand Challenges initiative. With this round of funding, up to four international, interdisciplinary teams will each receive up to $25 million to take their ideas forward and drive progress against some of cancer's toughest challenges.

From now until June 22, 2023, we invite you to assemble your Cancer Grand Challenges team and submit applications (https://cancergrandchallenges.org/apply2023) that hold the potential to accelerate important and transformative discoveries and ultimately change outcomes for people with cancer.

No disclosures were reported.

The authors gratefully acknowledge Gemma Balmer-Kemp, Bethan Warman, Andrew Kurtz, Sean Hanlon, Tony Dickherber, and Christine Siemon for support when writing this article.