www.nature.com/collections/cancer-milestones December 2020

Cancer

Produced by: With support from: Nature Genetics and Nature Medicine Cancer MILESTONES S2 Foreword S3 Timeline S4 Routes to resistance S5 Tracking cancer in liquid biopsies S6 When cancer prevention went viral S7 A licence to kill S8 Sitting on the fence S9 Not a simple switch S10 Sequencing the secrets of the cancer genome S11 Unleashing the immune system against cancer S12 Engineering armed T cells for the fight S13 Oncohistones: epigenetic drivers of cancer S14 Tumour evolution: from linear paths to branched trees S15 Undruggable? Inconceivable S16 Good bacteria make for good cancer therapy S17 The AI revolution in cancer

Credit: S.Fenwick/Springer Nature Limited

CITING THE MILESTONES VISIT THE SUPPLEMENT ONLINE SUBSCRIPTIONS AND CUSTOMER SERVICES Nature Milestones in Cancer includes Milestone articles written The Nature Milestones in Cancer supplement can be found at Springer Nature, Subscriptions, by our editors and an online Collection of previously published www.nature.com/collections/cancer-milestones Cromwell Place, Hampshire International Business Park, material. To cite the full project, please use Nature Milestones: Lime Tree Way, Basingstoke, Cancer https://www.nature.com/collections/cancer-milestones CONTRIBUTING JOURNALS Hampshire RG24 8YJ, UK (2020). Should you wish to cite any of the individual Milestones, BMC Cancer, Nature, Nature Cancer, Nature Communications, Tel: +44 (0) 1256 329242 please list Author, A. Title. Nature Milestones: Cancer

Nature Genetics, Nature Medicine, Nature Reviews Cancer, [email protected] (2020). For example, Milestone 1 is Valtierra, I. Routes to resistance. Nature Reviews Clinical Oncology, Nature Reviews Drug Discovery, Customer Services: www.nature.com/help Nature Milestones: Cancer https://www.nature.com/articles/ Nature Reviews Gastroenterology & Hepatology, d42859-020-00069-6 (2020). To cite articles from the Collection, Nature Reviews Genetics, Nature Reviews Nephrology. © 2020 Springer Nature Limited. All rights reserved. please use the original citation, which can be found online.

NATURE MILESTONES | CANCER DECEMBER 2020 | S1 ith little regard for borders, age, wealth or ethnicity, cancer has swept through human history and remains one of our biggest killers. In curating this Milestone collection, our aim was to pick up where our last Milestone project (https://www.nature.com/milestones/milecancer/timeline.html)W left off and to showcase major advances in the understanding of cancer and the development of novel therapies that are improving patient survival. Although we have done our best to be comprehensive, we recognize that our list is by no means exhaustive. In recent decades, understanding of the disease has developed at an astonishing pace. Our catalogues of the genetic (MILESTONES 7,11) and epigenetic (MILESTONE 10) aberrations underpinning tumour development ▶ cover: Design by Chris Ryan. are crystallizing. The adaptations used by tumour cells to breach EDITORIAL OFFICES cell-intrinsic (MILESTONES 5,6) and tissue-specific proliferative barriers, and London Springer Nature establish malignant diaspora at secondary sites are better understood The Campus, 4 Crinan Street, London N1 9XW, UK Tel: +44 (0)20 7833 4000 than ever before. Cancer cells can be profiled at unprecedented scale Coordinating editors: Safia Danovi, Saheli Sadanand Copy editor: Maya Shani and resolution, increasingly in the context of their tissue and microbial Production: Simon Fenwick, Susan Gray, Nick Bruni (MILESTONE 13) Design & Web Development: Chris Ryan microenvironments. marketing: Helen Burgess, Nicole Jackson publishing: Rebecca Jones These discoveries have propelled the development of new treatments, most VP, Publishing: Richard Hughes editor-in-chief, Nature Publications: notably immunotherapies (MILESTONES 8,9), which are now a crucial part of Magdalena Skipper Sponsorship: David Bagshaw, Stephen Brown, the treatment armoury, alongside surgery, chemotherapy, radiotherapy and Natasha Boyd an expanding repertoire of targeted treatments (MILESTONES 4,12). © Springer Nature Limited. All rights reserved. We hope that these Milestones will inspire optimism about the future MILESTONES ADVISORS of cancer research. We look forward to new approaches to tackle cancer David J. Adams Catherine Alix-Panabières types for which progress to date has been modest. We anticipate further René Bernards improvements in the understanding of treatment resistance (MILESTONE 1) Trever G. Bivona and metastasis, the process responsible for most cancer deaths. We also Navdeep S. Chandel Ryan B. Corcoran hope that technological innovations will drive powerful new strategies to Sarah-Jane Dawson detect and monitor cancer (MILESTONES 2,14). Julian Downward As treatments become more sophisticated, so too must the strategies Kristian Helin Jakob N. Kather to ensure that the benefits of research are available to everyone. The Christopher A. Klebanoff socioeconomic disparities that disproportionately limit access to care must Crystal L. Mackall be overcome. From prevention (MILESTONE 3) to diagnosis and treatment— Ignacio Melero Narges Razavian we must ensure that no patient is left behind. John T. Schiller This project was made possible by the support of our colleagues in the Clemens A. Schmitt Nature Editorial Cancer Community. We thank Javier Carmona and Ian Green Charles Swanton Giorgio Trinchieri for preparing the original proposal. In addition to the many editors who wrote Laurence Zitvogel these milestones, we extend our gratitude to Javier Carmona, Anna Dart, Iain Dickson, Linda Gummlich, Ulrike Harjes, Barbara Marte and Sarah PRODUCED WITH SUPPORT FROM: Seton-Rogers for managing and editing individual milestones. We appreciate Illumina, Johnson & Johnson the support we have received from Rebecca Jones, Simon Fenwick, Chris Ryan PRODUCED WITH SUPPORT OF A GRANT FROM: and Maya Shani. Finally, we would like to thank our expert advisors and to AstraZeneca, Boehringer Ingelheim, MSD acknowledge support from our sponsors and grant funders (AstraZeneca, Boehringer Ingelheim, Illumina, Johnson & Johnson and MSD). As always, Springer Nature takes complete responsibility for the editorial content. Safia Danovi, Senior Editor, Nature Genetics Saheli Sadanand, Senior Editor, Nature Medicine

S2 | DECEMBER 2020 www.nature.com/collections/cancer-milestones MILESTONES IN CANCER 2000 Mitochondrial complex II mutations found in tumours 2001 Mechanisms of resistance to targeted treatment (MILESTONE 1) Nobel Prize awarded for “discoveries of key regulators of the cell cycle” 2003 Epidemiological link between cancer and obesity 2004 First epigenetic drug to gain FDA approval First antiangiogenic agent to gain FDA approval for cancer treatment Credit: Sciepro/Science Photo Library Sciepro/Science Credit: Liquid biopsies for non-invasive diagnosis and monitoring of patients (MILESTONE 2)

HPV vaccines to prevent cervical cancer (MILESTONE 3)

2005 Leveraging synthetic lethality for treatment (MILESTONE 4)

Oncogene-induced senescence in premalignant tissues and cancer (MILESTONE 5)

2006 Metabolic adaptations in cancer (MILESTONE 6) 2008 First interim analysis published by The Cancer Genome Atlas

First cancer whole-genome sequence (MILESTONE 7) 2009 Description of colorectal cancer organoids IDH1 mutations leading to the generation of 2-hydroxyglutarate

2010 Immune-checkpoint inhibitors from bench to bedside (MILESTONE 8)

Engineering T cells to kill cancer cells (MILESTONE 9) 2011 Use of screening to decrease mortality from lung cancer Clearance of senescent cells by the immune system

2012 Epigenetic drivers of tumour initiation and progression (MILESTONE 10) Clonal diversity of tumour cells as a basis for cancer progression and treatment resistance (MILESTONE 11) Full-length single-cell mRNA sequencing of individual tumour cells Anti-tumour role of metabolite depletion

2013 Targeting ‘undruggable’ non-kinase proteins (MILESTONE 12)

Gut microbiome influences on anti-tumour immune responses(MILESTONE 13) 2015 The Big Bang theory of cancer evolution is proposed Driver mutations found in healthy tissue First FDA approval for a combination of immunotherapies 2016 First FDA approval for an anti-PD-L1 inhibitor 2017 Potential of artificial intelligence in cancer diagnosis and monitoring(MILESTONE 14) First FDA approval of a treatment on the basis of tumour genomics alone First inhibitor of mutant IDH2 approved for clinical use 2018 Nobel Prize awarded for “discovery of cancer therapy by inhibition of negative immune regulation” 2019 Clinical trial of CAR T cells to target BCMA in patients with multiple myeloma Nobel Prize awarded for “discoveries of how cells sense and adapt to oxygen availability” 2020 Pan-cancer analysis of whole genomes Clinical trial of CD19-targeting CAR–Natural Killer cells in patients with CD19+ cancers Credit: Juan Gaertner/Science Photo Library Credit:

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Credit: iStock / Getty Images Plus

MILESTONE 1 This study, together with similar studies published shortly afterwards—including the discovery by Kobayashi et al. of EGFR mutations conferring resistance to gefitinib Routes to resistance in lung cancer—illustrates several important aspects of cancer. On the one hand, these data By the turn of the millennium, drugs that then BCR-ABL signalling activity would be show that cancer is an evolutionary process: selectively target driver genes had been devel- evident even after treatment. Because of the under strong selective pressure, cells with oped. For instance, tyrosine kinase inhibitors, fast degradation of the BCR-ABL protein, adaptations allowing them to overcome the such as imatinib, had been demonstrated they measured the phosphorylation of one adverse environment will dominate. Such to lead to sustained and durable remission of its downstream targets, CRKL. Indeed, in cells may actually already be present in the in patients with advanced chronic myeloid tumours from 11 patients with relapse, CRKL initial tumour—even seemingly homogeneous leukaemia (CML) by targeting BCR-ABL, a phosphorylation was nearly as high as that in cancers can harbour genetically heterogeneous fusion gene with constitutive tyrosine kinase untreated patients. populations that have an edge in the ‘arms race’ activity. Furthermore, in contrast to more The next step was to identify what allowed against therapy, as described by Dagogo-Jack conventional genotoxic treatments, these BCR-ABL to remain active. The authors con- and Shaw. In addition, resistance can be drugs were believed to cause fewer adverse cluded that a cell-intrinsic factor was respon- achieved by markedly distinct but function- effects. With such precise targeted therapies, sible, because relapsed cells isolated from ally convergent approaches. On the other hopes were high that this new generation of patients still showed this oncogenic activity, hand, these studies have also unmasked one drug might represent the ‘magic bullet’ long thus suggesting that no extrinsic factors were critical feature of cancers: certain genes and sought after by patients and clinicians. involved. The authors examined changes in mutations remain essential drivers of tumour Unfortunately, the reality was not so the BCR-ABL gene itself and found two strik- growth and survival. Therefore, knowing and simple. Although patients (even those in ingly distinct escape mechanisms in different targeting these central drivers continues to be advanced stages or with complex molecular patients. an important clinical strategy, which is being alterations) initially responded to these The first resistance-related alteration used to develop new generations of clinically targeted drugs, a clinical trial of imatinib could be understood as a brute-force, all-out effective tyrosine kinase inhibitors. reported by Druker et al. showed that in approach to fight against the inhibitor: the Targeted therapies will remain an patients with acute lymphoblastic leukae- tumours of three patients who relapsed had important part of the arsenal to combat mia or with CML in lymphoid blast crisis, produced multiple copies of the BCR-ABL cancers, especially when tested in different tumours eventually returned after daily gene through gene amplification. The combinations that can circumvent resistance treatment for a few weeks or months. The number of copies increased with subsequent to a single drug. The roles of off-target, question of how cancer can adapt to special- rounds of treatment; however, in one patient, non-genetic mechanisms in this resistance ized strategies that directly target essential these amplifications disappeared after are also starting to be acknowledged and will cancer machinery still remained. switching to another therapy, thus suggesting need to be addressed with correspondingly Mercedes E. Gorre, Charles Sawyers and that the drug was selecting for clones bearing tailored approaches. As long as the design and collaborators set out to answer this question. the amplification. In contrast, the second use of these therapeutic strategies is guided Imatinib was known to work by binding the resistance mechanism required a single modi- by evolutionary principles, the hope is that BCR-ABL kinase domain, thus blocking its fication: a point mutation changing threonine drug resistance in patients will one day be function. Because previous work by Chin et al. 315 of ABL1 to isoleucine was found in six predicted and sidestepped. had shown that cancers often require the patients. Because this particular amino acid Ilse Valtierra, Nature Communications activity of their primary oncogene, Gorre et al. is critical for imatinib binding, the mutation ORIGINAL ARTICLE Gorre, M. E. et al. Clinical resistance to wondered whether imatinib-resistant tumours abrogated binding to the drug. In contrast to STI-571 cancer therapy caused by BCR-ABL gene mutation or might still be dependent on the BCR-ABL the wild-type BCR-ABL, this mutant retained amplification. Science 293, 876–880 (2001). fusion gene. They reasoned that if the relapsed activity in cell lines, even after exposure to FURTHER READING Please visit the online article for a full list of further reading. tumours were still dependent on BCR-ABL, the drug.

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MILESTONE 2 that ctDNA has superior sensitivity to that of CTCs as a cancer biomarker and, crucially, changes in ctDNA Tracking cancer in liquid biopsies levels closely paralleled treatment responses: increased ctDNA levels were seen in 89% of the women with Oncologists have long been aware progressive disease. that cancer cells disseminate through The results of another necessary the bloodstream. In the early 2000s, comparison were published a year substantial efforts were devoted to later by Bettegowda et al. Analysis developing techniques for the reliable of patients with cancers across 14 and sensitive detection of cancer different tissues of origin revealed that cells and their components in bodily ctDNA can be detected in the blood fluids. As cell-detection systems were of most patients with solid tumours optimized, several studies aimed to outside the brain. For some malignan- determine their clinical utility. A cies studied, the percentage of patients study published by Cristofanilli et with detectable ctDNA was low, thus al. in 2004 was the first to use the underscoring the need for developing CellSearch platform to show that the comprehensive gene panels for number of circulating epithelial cells liquid-biopsy assays. Expectedly, most in the blood is markedly higher in patients with metastatic disease had women with metastatic breast cancer detectable ctDNA; however, ctDNA before starting systemic therapy than was also found in a substantial pro- in women without breast cancer or portion of patients with localized can- with benign breast disease. In analys- cers. This observation confirmed that ing survival outcomes, the investiga- cancer cells and cancer-derived DNA tors established the prognostic value can enter the bloodstream at any stage of such differences: the durations of of disease progression, as had already progression-free survival (PFS) and sorbetto Credit: been proposed, thus drawing new overall survival were significantly attention to a role for liquid biopsies shorter in patients with cell counts detection of tumour mutations in in enabling early cancer detection. above an established threshold at a cohort of patients with colorectal The encouraging initial results baseline and, more importantly, cancer, pioneering work by Diehl et One of from these and other studies are now prompting clinicians to increasingly at the first follow-up visit during al. has shown an abrupt decrease in the next treatment. This study was the first to circulating tumour DNA (ctDNA) use liquid biopsies for a range of demonstrate the clinical relevance of levels in blood samples from patients challenges clinical applications, including pre- circulating tumour cell enumeration who had undergone complete in this field dicting the risk of disease recurrence, for stratifying cancer patients. surgical resection or chemotherapy. will be as reported by Tie et al., matching Subsequent studies explored Moreover, the disease recurrence patients to treatments while mini- more specific approaches to identify rates were significantly lower in incorporating mizing surgical procedures to obtain the presence of tumour-derived patients with undetectable rather liquid biopsies tissue biopsies, and tracking the pres- material in blood, such as detecting than detectable levels of ctDNA, into routine ence of resistance-related mutations. tumour-related mutations in circulat- thus providing the first evidence of cancer One of the next challenges in this field ing tumour cells (CTCs). In patients the potential value of using ctDNA will be incorporating liquid biopsies with EGFR-mutated non-small-cell analysis as a tumour biomarker. screening into routine cancer screening proto- lung cancer, Maheswaran et al. The diverse clinical applications protocols cols to facilitate early cancer diagno- have demonstrated the feasibility of that derived from analysis of circu- to facilitate sis. The feasibility of this approach has using DNA extracted from CTCs for already been demonstrated in a pilot lating tumour material eventually early cancer non-invasive monitoring of patients led to the coining of the term ‘liquid intervention by Chan et al. focused on under therapy. Among patients biopsy’ by Pantel and Alix-Panabières diagnosis the detection of Epstein–Barr virus– in this study who received EGFR in 2010. In subsequent investigations, related nasopharyngeal carcinoma, tyrosine-kinase inhibitors, the PFS researchers assessed the potential of and in a pan-cancer study by Lennon duration was shorter in those carry- liquid-biopsy tools for non-invasive et al. combining positron emission ing the resistance-related EGFRT790M monitoring of response to therapy in tomography–computed tomography alteration. patients with cancer. In a landmark with the detection of biomarkers in To overcome the technical study by Dawson et al. in 2013, serial blood (including ctDNA). challenges associated with purifying blood samples from women with Diana Romero, DNA from CTCs, several groups metastatic breast cancer undergoing Nature Reviews Clinical Oncology have focused on refining the detec- treatment were collected, and CTC tion of somatic mutations in DNA quantification and ctDNA analysis ORIGINAL ARTICLE Cristofanilli, M. et al. Circulating tumor cells, disease progression, extracted from the cell-free fraction were compared side by side for dis- and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004). FURTHER READING Please visit the online article for a full list of further reading. of human blood. Through sensitive ease monitoring. This work showed

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HPV vaccination of males serves two purposes: vaccinated men are presumably less likely to transmit HPV to any sexual partners, and furthermore, vaccination is likely to confer some protection against other HPV-positive cancers, including those of the penis, oropharynx, oral cavity/larynx and anus. The latter possibility is supported by prospec- tive data: Gardasil approximately halved the risk of grade 2 or 3 vaccine

Credit: KATERYNA KON/SCIENCE PHOTO LIBRARY KON/SCIENCE PHOTO KATERYNA Credit: type HPV-related anal intraepithelial neoplasia in a cohort of men who have sex with men, a population known to have a particularly high risk of anal infections and cancers. The long latency period between MILESTONE 3 initial HPV infection and cervical cancer makes any reduction in cancer risk difficult to assess directly. Nonetheless, a registry study from When cancer prevention Sweden, where HPV vaccines have been available since 2006, has revealed that the incidence of invasive went viral cervical cancer among vaccinated women was approximately half that of Cancer prevention strategies are Another trial, by Harper et al., nonvaccinated women. The incidence theoretically appealing although published in November 2004, pro- was 88% lower for those vaccinated often difficult to implement, owing vided the first evidence that HPV Despite these below 17 years of age. Despite these to the multifactorial pathogenesis vaccination might reduce cervical apparent apparent successes, the potential of of most cancers. The possibility of cancer risk: Cervarix, a bivalent vac- HPV vaccination is only beginning a notable exception first emerged cine for HPVs 16 and 18, was found successes, to be realized. Many economically in 1983, when Harald zur Hausen to reduce the risk of associated cervi- the potential developed countries continue to and others confirmed the presence cal abnormalities from 4.9% to 0.4%. of HPV lack universal HPV vaccination pro- of a specific human papillomavirus A total of seven women had cervical vaccination is grammes, and vaccine availability is (HPV) subtype (HPV-16) in biopsy intraepithelial neoplasia, including often limited to health centres, rather samples from several cohorts of one in the vaccine group, who was only beginning than schools and other community patients with genital cancers. later found to have a persistent to be realized. settings. Increasing public mistrust Further research followed, and in HPV-51 infection. This experience in vaccines might pose further 1999, HPV was confirmed as being highlighted the potential advantage challenges to implementation. Other not only present and involved in the of a vaccine covering a broader range challenges include the development aetiology, but also a necessary cause of HPV subtypes. of HPV vaccination programs for less of virtually all cervical cancers. By Subsequent trials further con- economically developed countries, that time, attempts to develop an firmed the efficacy of HPV vaccina- where cervical cancer is often the HPV vaccine were already underway, tion, including that with Gardasil, a most common cause of cancer mor- and several technical hurdles had quadrivalent vaccine targeting HPVs tality. The emergence of generic HPV been overcome, including the availa- 6, 11, 16 and 18. Gardasil later became vaccines and the incidental finding bility of ‘virus-like particles’ (VLPs), the first HPV vaccine to receive reg- that even single-dose vaccination pro- which safely and efficiently induced ulatory approval, by the US Food and vides some protection against HPV infection-preventing antibody Drug administration (FDA) in June infection will hopefully enable wider responses in animal studies. 2006, for use in girls and women 9–26 implementation and might assist in Results from the first clinical years of age. A second approval fol- addressing these challenges. trial of an HPV vaccine, involving lowed, this time of Cervarix from the Peter Sidaway, a VLP-derived vaccine targeting European Medicines Agency (EMA), Nature Reviews Clinical Oncology HPV-16, were published in 2002. which included vaccination for the The efficacy results were deemed prevention of anal cancer in males ORIGINAL ARTICLE Harper, D. M. et al. Efficacy unequivocal by most experts: all in the same age group. The FDA of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus 41 cases of persistent HPV-16 and EMA subsequently authorized types 16 and 18 in young women: a randomised infections in a cohort of 2,392 Gardasil-9, which provides immunity controlled trial. Lancet 364, 1757–1765 (2004). 18–23-year-old women were against nine HPV strains, in 2014 and FURTHER READING Please visit the online article for a full list of further reading. observed in the placebo group. 2015, respectively.

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focusing on defects in DNA-repair other malignancies, some with loss of and cell-cycle genes. Indeed, some BRCA1/2 function (breast, pancre- chemotherapeutic drugs selectively atic and prostate cancer). killed cells with specific genetic Beyond associations with specific mutations. genetic mutations, drugs may syn- Credit: Richard Drury Richard Credit: Building on these findings, two ergize, such that treatment with one landmark studies in 2005 by Alan cancer drug exposes a vulnerability to Ashworth’s group in collaboration a second drug. In 2012, René Bernards with KuDOS Pharmaceuticals Ltd. and colleagues studied why melanoma and the groups of Thomas Helleday cells with the activating V600E altera- and Nicola Curtin demonstrated that tion in the kinase BRAF are sensitive human cancer cells with mutations in to BRAF inhibitors, but colorectal the DNA-repair tumour-suppressor cancer cells with the same mutation genes BRCA1 and BRCA2 are selec- are not. In a synthetic-lethality tively sensitive to PARP inhibitors. screen, BRAF inhibition in colorectal Loss of the base-excision-repair cancer cells exposed a sensitivity to enzyme PARP1 increases DNA the concomitant loss or inhibition lesions, such as collapsed replication of the receptor tyrosine kinase MILESTONE 4 forks, which can normally be repaired EGFR, both in vitro and in vivo. This through homologous recombination synergy arose from rapid feedback (HR). Therefore, the teams reasoned activation of EGFR signalling after A licence to kill that defects in BRCA1 or BRCA2, BRAF-inhibitor treatment. In con- which participate in HR, might be trast, melanoma cells express little synthetically lethal with the loss of EGFR; therefore, BRAF inhibitors Synthetic lethality, a term coined by PARP1 or PARP inhibition. Indeed, did not stimulate EGFR activation. Theodore Dobzhansky in 1946, arises cells with deletion of BRCA1 or These findings led to the 2020 EMA when co-occurring mutations in two BRCA2 (or other HR genes) were and FDA approval of combination genes kill cells, whereas mutation viable but died after PARP-inhibitor treatment with the BRAF inhibitor of either gene alone does not and treatment. The results strikingly encorafenib and the EGFR-targeting may elicit a milder phenotype. This revealed a large therapeutic window antibody cetuximab for BRAF-mutant phenomenon was first described by (or index) both in vitro and in mice. metastatic colorectal cancers. Calvin Bridges in 1922 in genetic The findings were notable because Examples of cancer-specific experiments in Drosophila mela- people with BRCA1 or BRCA2 synthetic-lethal relationships in nogaster. Mechanisms underlying germline mutations are predisposed mammalian cells and strategies to synthetic lethality are now known to breast, ovarian and prostate cancer, systematically discover and exploit to include genetic and non-genetic and the tumours that develop exhibit synthetic-lethal interactions for redundancies, buffers and adaptation. loss of BRCA function and impaired cancer therapy were discussed A few decades later, the concept HR. Subsequent observations from in an influential 2005 review by of synthetic lethality was applied to the groups of Alan Ashworth and William Kaelin, and many still hold cancer research, ultimately leading to Toshiyasu Taniguchi showed that true. The application of synthetic the approval of new therapies. Rapidly resistance to PARP inhibitors or lethality has rapidly advanced, and dividing cells had long been known platinum (which also targets HR) can sophisticated, high-throughput to be susceptible to drug-induced arise due to unexpected secondary genetic and drug screens, and more DNA damage, suggesting that DNA- function-restoring alterations in recently CRISPR–Cas9 technology repair inhibitors might selectively kill BRCA2 providing further evidence of are often used. Drugs have been cancer cells. By the 1980s, inhibitors a synthetic-lethal relationship. approved for more indications, and of the DNA-repair poly(ADP)–ribose As a direct result of this work, in many more clinical trials based on polymerase (PARP) enzymes had 2014, the PARP inhibitor olaparib the principles of synthetic lethality been shown to kill cancer cells more became the first targeted therapy are underway. Current areas of The results efficiently in concert with DNA- for the treatment of patients with exploration include cell-intrinsic strikingly damaging agents than as single agents. ovarian cancer with germline mechanisms, such as the BRCA– Then, in a seminal 1997 article, BRCA1/2 mutations to be approved PARP and BRAF–EGFR interactions, revealed Leland Hartwell, Stephen Friend and by the European Medicines Agency and vulnerabilities mediated by the a large colleagues suggested that synthetic- (EMA) and US Food and Drug tumour microenvironment, such as therapeutic lethality relationships could lead to Administration (FDA). Olaparib combinations of targeted drugs with new anticancer drug targets, and and three other PARP inhibitors immunotherapies. window (or genetics might therefore offer a have since been approved for several Barbara Marte, Nature index) both rational approach to drug discovery. ORIGINAL ARTICLES Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of in vitro and Because genetic and drug screens poly(ADP-ribose) polymerase. Nature. 434, 913–917 (2005) | Farmer, H. et al. Targeting the DNA repair defect in in mice. were then largely limited to model BRCA mutant cells as a therapeutic strategy. Nature. 434, 917–921 (2005) | Prahallad, A. et al. Unresponsiveness organisms, the researchers used a of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 483, 100–103 (2012). FURTHER READING Please visit the online article for a full list of further reading. Saccharomyces cerevisiae screen,

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methyltransferase SUV39H1 and the MILESTONE 5 tumour suppressor RB, which jointly promote DNA compaction mediated by methylation of histone H3 Lys 9 Sitting on the fence (H3K9me); this process is crucial for triggering H3K9me-mediated senescent growth arrest and thus pro- Picture this: an unattended stew is into the molecular groundwork. viding an initial barrier to lymphoma boiling over and splatters every- Although unified in their finding development. where. What could we do? We could that OIS is tumour suppressive, these Research Do senescence triggers interact? put on a lid, remove the pot from the studies demonstrated that pathways in the past Two subsequent studies in 2006 heat, and leave it to cool. Similarly, underlying OIS are dependent on the provided robust evidence that OIS primary mammalian cells appear tumour tissue and oncogenic insult. decade has (induced via the oncoproteins to have found ways to handle their Until 2005, senescence-associated exposed the HRAS-V12, MOS, CDC6 or own undesirable spread. Cellular β-galactosidase was the ‘gold stand- multifaceted cyclin E) is associated with signs senescence can serve as a break in ard’ in vivo marker for senescence. and highly of DNA-replication stress, thereby excessive proliferation, providing Collado et al. identified a small set of establishing that OIS is a direct an initial barrier, and eventually genes with expression profiles corre- dynamic consequence of a vigorous DNA- protection, against tumorigenesis. lating with the KRAS-V12-induced nature of damage-checkpoint response, after Cellular senescence is provoked senescence phenotype and used these senescence DNA hyper-replication and the by either an intrinsic mitotic counter to show that senescent cells exist and its star formation of double-strand breaks. (replicative senescence) or extrinsic among premalignant adenomas but In addition, inflammatory mediators factors, such as oxidative stress or not malignant adenocarcinomas in players appear to be a crucial aspect in the DNA damage at any point in the lung, skin and pancreatic tissues. barrier network. Cells undergoing cell’s replicative history (premature Confirming the discoveries in OIS exhibit a senescence-associated senescence). The latter can also be preneoplasia, Michaloglou et al. secretory phenotype (SASP). In 2008, driven by activated oncogenes, such characterized the telomere- and the secretion of multiple chemokines as those in the RAS family, and is p53-independent BRAF-V600E- and interleukins (including IL-6 and better known as oncogene-induced induced senescence observed in skin IL-8) was found to maintain growth senescence (OIS). In the late 1990s, moles (nevi) but not melanoma cells. arrest, thereby stabilizing the system, findings from cultured cells linked In contrast, Chen et al. showed that whereas SASP factors may act as OIS to two major cell-signalling p53 is crucial for OIS in premalig- growth promoters in other settings. pathways that are often disrupted in nant prostate tissue in vitro and in Is the induction of senescence the cancer: INK4A–RB and ARF–p53. vivo when the tumour suppressor long-awaited tool for cancer therapy? However, at that point, whether OIS PTEN is lost. Loss of p53 and PTEN Sadly, life is rarely that simple, and was an authentic anticancer process inhibits any protection from prostate research in the past decade has or an artefact of imposed oncogene cancer development, but this type of exposed the multifaceted and highly expression in cells experiencing induced senescence is reversed by dynamic nature of senescence and ‘culture shock’ was unclear. deletion of p53 regulators. its star players. Although therapy- In 2005, four groups reported Senescent cells often show unu- induced senescence can improve remarkable in vivo evidence of the sual chromatin foci of tightly packed long-term outcomes, it has also been existence of OIS in several mouse and DNA. Braig et al. researched the epi- found to cause relapse, enhanced human premalignant tissues. They genetic contributions and found that self-renewal and adverse reactions presented a novel set of senescence NRAS-induced lymphocyte senes- to cancer treatment. Consequently, markers and provided a sneak peek cence is dependent on the histone the elimination of senescent cells has recently emerged as a sensible therapeutic strategy. Current investi- gations are underway to explore the clinical potential and benefits for cancer patients. Linda Gummlich, BMC Cancer

ORIGINAL ARTICLES Collado, M. et al. Senescence in premalignant tumours. Nature 436, 642 (2005). | Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). | Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). | Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005). FURTHER READING Please visit the online article for a full list of further reading. Credit: Khoon Lay Gan / Alamy Stock Vector Credit:

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MILESTONE 6 Moreover, glucose metabolism in the pentose- phosphate pathway (PPP) was found to be crucial for oncogenic KRAS-induced growth, through generating nucleotide precursors as Not a simple switch well as NADPH. PPP-derived antioxidants are also linked to promoting cancer cell survival, as shown by Joan Brugge’s group, thus highlighting the importance of antioxidant defence in cancer growth. Research in the 2010s led the field further away from Warburg’s path, showing substantial heterogeneity in cancer metabolism, and high- lighting the oncogenotype and tissue environ- ment as key determinants. Eileen White’s and Alec Kimmelman’s groups revealed that onco- genic KRAS-driven cancer cells depend on autophagy, a catabolic pathway that degrades intracellular organelles and macromolecules. Autophagy maintains mitochondrial metab- olism and redox control, and allows cancer cells to maintain growth in nutrient-scarce

Credit: peepo Credit: environments. David M. Sabatini’s and Cantley’s groups have reported amplification of Cells respire—they consume oxygen and The link of cancer-driving gene mutations the gene encoding the rate-limiting enzyme in glucose to produce energy in the form of to the Warburg effect was corroborated on the serine synthesis pathway in certain cancer ATP. When oxygen is not available, cells in the level of tumour suppressors. Cellular res- types, thus making the growth of these cancers differentiated tissues break glucose down piration relies on the tricarboxylic acid (TCA) dependent on serine and glycine metabolism. into lactate (through glycolysis) for energy cycle as well as the electron-transport chain Crucially, J. Michael Bishop’s group has shown production. The ‘Warburg effect’ describes (ETC) coupled to oxidative phosphorylation in mice that metabolism in MYC-driven liver Otto Warburg’s observations in the 1920s (OXPHOS) in the mitochondria. Indeed, the cancer not only differs from metabolism in that malignant tumour cells mainly perform tumour-suppressor protein p53 was found to MYC-driven lung cancer, but also differs from glycolysis even in the presence of oxygen participate in controlling the balance between metabolism in liver cancer driven by the onco- (aerobic glycolysis), thus resulting in high glycolysis and OXPHOS, as reported by Paul protein MET. In humans, Ralph J. DeBerardinis lactate secretion. These observations led him M. Hwang’s and Karen Vousden’s groups in and colleagues have observed metabolic to believe that during malignant transforma- 2006 (See Mitochondrial complex II mutations heterogeneity among tumours across patients tion, initial irreversible damage in respiration found in tumours on the interactive timeline). and within the same patient as well as among was followed by upregulation of glycolysis The TCA cycle also generates molecules regions within the same tumour. to replace the loss of respiration energy. needed for biomass production. Considering This complexity signifies that the cancer According to Warburg, the origin of cancer that glycolysis is a relatively inefficient way to metabolism field has long outgrown the con- was purely based on metabolic alterations. produce energy, Craig B. Thompson’s group, fines of the hypothesis that Warburg proposed We know today that Warburg was not quite in one of the first cancer metabolism studies nearly a century ago. Since then, seminal right: oncogenic signalling fundamentally to use carbon-13 isotope tracing, explored the findings have been reported by many groups. contributes to malignant transformation, metabolic underpinnings of the Warburg effect. Although research in the past two decades partly by regulating metabolism. They found that cancer cells use glucose- has largely focused on primary tumours, By the 1990s, the presence of aerobic derived TCA-cycle intermediates in synthetic insights into metabolism during metastasis, glycolysis in some tumours had been clinically pathways (particularly fatty acid synthesis). in the tumour microenvironment, and in the exploited for cancer detection through fluoro- Cells also require continuous replenishment systemic context, are rapidly advancing. To deoxyglucose–PET imaging. Yet the molecular of the TCA cycle with a non-glucose carbon date, only a limited number of agents targeting basis of the Warburg effect remained ill-de- source—a process achieved through uptake cancer metabolism have been successfully fined. In 1997, Chi V. Dang and colleagues and metabolism of the amino acid glutamine. applied in the clinic (See IDH1 mutations lead reported that the glycolytic enzyme lactate These and other data led Matt G. Vander to the generation of 2-hydroxyglutarate and dehydrogenase A (LDHA), which catalyses Heiden, Lewis C. Cantley and Thompson FDA approval of enasidenib for acute myeloid the final step of glycolysis, is a transcriptional to propose a model in which metabolism in leukaemia on the interactive timeline), but this target of the oncoprotein MYC. They showed cancer cells is adapted to optimize access to is likely to change in the future. that overexpression of MYC or LDHA resulted nutrients and their incorporation into biomass, Ulrike Harjes, Nature Reviews Cancer in greater aerobic lactate production in cul- thereby generating a growth advantage. ORIGINAL ARTICLES Shim, H. et al. c-Myc transactivation of tured fibroblasts. LDHA was also necessary Further shaking Warburg’s hypothesis of LDH-A: implications for tumor metabolism and growth. Proc. for MYC-induced anchorage-independent cell irreversibly damaged mitochondria in cancer, Natl Acad. Sci. USA 94, 6658–6636 (1997) | Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 growth. These findings provided a molecular Navdeep S. Chandel’s group showed that (2006) | Bensaad, K. et al. TIGAR, a p53-inducible regulator of basis for the Warburg effect, which, contrary mitochondrial metabolism and ETC function glycolysis and apoptosis. Cell 126, 107–120 (2006). to Warburg’s hypothesis, involved an oncogene are required for cancer cell growth induced FURTHER READING Please visit the online article for a full list of further reading. frequently altered in cancer. by the oncoprotein KRAS in vitro and in vivo.

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MILESTONE 7 metastatic melanoma cell lines were pub- lished. These were distinctly different from the AML results in terms of the number Sequencing the secrets of of somatic mutations observed: 32 in breast cancer, and 33,345 and 22,910 in the melanoma and lung cell lines, respectively. the cancer genome Notably, the mutations identified in the breast tumour were largely mutually exclu- The advent of next-generation sequencing SNVs were identified in the tumour sample, sive from those found in an extended series (NGS) in the first decade of the twenty-first of which 2.6 million also occurred in the of 192 tumours, as observed for the AML century heralded a major change in cancer skin and were thus categorized as germline genome. The mutational signatures of expo- research. Similarly to how electronic min- variants. After further filtering, a total of sure to tobacco smoke (C>A) and ultraviolet iaturization transformed computers from eight SNVs were validated as novel somatic light (C>T) were detected in the lung and room-sized appliances into smartphones variants with a predicted effect on gene melanoma genomes, respectively. that fit in the palm of a hand, the progress function. These eight genes had roles in Together, these four studies suggested from low-throughput Sanger sequencing functionally relevant pathways—cellular that cancers have substantial genetic hetero- to high-throughput NGS allowed an entire signalling (PTPRT, KNDC1, ADGRA1, geneity, both within and between individual genome to be sequenced by an individual GPR183 and GCOM2), cell adhesion tumour entities. Most importantly, these find- research group, in contrast to the globe- (CDH24 and CDHR2) and transmembrane ings suggested a clear path for future research: spanning industrial effort required by transport (SLC15A1)—thus demonstrating whole-genome sequencing, and related the Human Genome Project only a few that genome sequencing can identify novel techniques that profile transcriptomes and years earlier. By that time, cancer’s status candidate cancer genes within key, potentially epigenomes, would need to be applied at scale as a genetic disease was well established, therapeutically targetable tumourigenic to gain a better understanding of cancer’s and catalogues of oncogenes and tumour pathways. Most intriguingly, none of these complex genetic basis and to provide insights suppressors were available. However, the eight somatic SNVs were observed in any of a into how these genetic discoveries might be number of mutations in any given tumour, cohort of 187 AML tumours, thus suggesting clinically applied. as well as the full extent of the ‘cancer-gene substantial heterogeneity in genes affected by Large-scale studies such as The Cancer census’, remained unknown; these and other mutation in a tumour type. Genome Atlas (TCGA) and the Pan-Cancer questions could finally be answered with the Beyond identifying a set of novel candi- Analysis of Whole Genomes (PCAWG) have newly developed sequencing technologies. date cancer genes, this study attempted to now sequenced tens of thousands of cancer The first cancer whole-genome sequence, track cancer evolution by comparing variant genomes across a wide variety of tumour of an acute myeloid leukaemia (AML) from allele frequencies in amplicon sequencing types. The insights gained from these large a woman in her mid-50s, was published in data for ten somatic mutations (the eight cohorts include the identification of many 2008 by Ley et al. This karyotypically normal, SNVs, an FLT3 internal tandem duplication more cancer genes associated with previously highly pure case was carefully selected to and an NPM1 insertion) in primary and unanticipated cellular processes such as ensure adequate input material for sequenc- post-relapse samples. This analysis suggested metabolism (IDH1 and IDH2) and epigenetic ing and to facilitate interpretation of the that nine of ten mutations were heterozygous regulation (EZH2 and PBRM1), and the results. Two samples from this patient were in all tumour cells, but the last mutation—the confirmation that most somatic mutations in sequenced with Solexa technology on an FLT3 internal tandem duplication—appeared tumours are not highly recurrent (the ‘long Illumina Genome Analyzer: primary tumour to be subclonal and was suggested to be the tail’ of mutation frequency). They have ignited and normal skin tissue. most recent mutation. the study of cancer evolution (MILESTONE 11), Single-nucleotide variant (SNV) analysis In the following year, three additional based on phylogenies of somatic mutations demonstrated the importance of including cancer genomes from a metastatic breast inferred through sequencing, which has shed the matched normal sample: 3.8 million tumour, and from lung and light on the complex dynamics of tumour- igenesis. Finally, the analysis of mutational signatures has identified many previously known and novel mutagenic processes, as well as the genomic signatures of prior exposures. Credit: zmeel Credit: Although the past decade has unequivocally demonstrated the value of genome sequencing in basic cancer research, clinical use remains restricted to well-resourced institutions equipped with the expertise to generate and interpret genomic data, thus suggesting that, at least for patients, the greatest impact of sequencing may be yet to come. Michael Fletcher, Nature Genetics

ORIGINAL ARTICLE Ley, T. et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456, 66–72 (2008). FURTHER READING Please visit the online article for a full list of further reading.

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had been approved in the frontline setting after superiority over ipilimumab was demonstrated in phase III trials. Remarkably, the median OS of patients treated with the combination was >5 years, emphasizing the unprecedented potential of ICIs to induce durable remission of metastatic cancers. 2015 also marked the start of a rapid expan- sion in approvals of PD-1 inhibitors to other tumour types, starting with non-small-cell lung cancer (NSCLC)—another malignancy in which ICIs have dramatically reduced mortality. In 2016, atezolizumab became the first anti-PD-L1 antibody to join the arsenal of ICIs, with demonstrated activity against urothelial carcinoma. ICIs have now entered

Credit: S. Fenwick / Springer Nature Limited / Springer Nature S. Fenwick Credit: the treatment armamentarium for at least 17 MILESTONE 8 advanced-stage malignancies, in many cases bringing the possibility of long-term survival and perhaps even cure for a subset of patients. Unleashing the immune system ICIs are, however, not a panacea. Although generally better tolerated than other anti- neoplastic agents, ICIs come with a risk of against cancer diverse and potentially serious immune-related adverse events (irAEs). Moreover, in almost Efforts to harness the immune system for the PD-1–PD-L1 axis. In 2010, the first-in-hu- all cancers, responses are limited in frequency cancer therapy can be traced back over man study of nivolumab, an antibody to PD-1, and duration. Initial studies revealed aberra- 100 years; however, cancers develop under revealed durable regressions of several tumour tions affecting interferon signalling (JAK1/2 constant immunosurveillance and therefore types as well as a correlation between respon- mutations) and/or the antigen-presentation evolve diverse mechanisms of immuno- siveness and tumoural expression of PD-L1, machinery (B2M mutation) as mechanisms suppression, which have proven difficult to which eventually proved to be a useful, albeit of resistance. By contrast, cancers with certain overcome. A breakthrough that eventually led imprecise, predictive biomarker of response. mutational signatures generate large numbers to the establishment of immunotherapy as a 2010 witnessed a second landmark in of non-self epitopes (neoantigens) and are new pillar of cancer care was made in 1996, the development of ICIs when ipilimumab therefore particularly sensitive to ICIs. This when James Allison and colleagues demon- became the first agent shown to prolong over- concept was illustrated by the approval of strated that antagonistic antibodies targeting all survival (OS) in patients with advanced- pembrolizumab for microsatellite instability- CTLA-4, a receptor known to suppress T cell stage melanoma (to 10 months from a median high/mismatch-repair-deficient cancers activation, could induce tumour rejection in of approximately 6 months). Accordingly, in regardless of histology—the first tissue- mice. This finding revealed the contribution March 2011, ipilimumab made history as the agnostic approval—in 2017 and for cancers of ‘immune checkpoints’ with physiological first ICI to be approved by the US FDA, thus with a high mutational burden in 2020. roles in self-tolerance to cancer immune validating the approach to immunotherapy Undoubtedly, ICIs have revolutionized can- evasion and simultaneously illuminated the originally proposed by Allison. cer therapy, as reflected in the awarding of the therapeutic potential of immune-checkpoint As a clearly immunogenic tumour type, 2018 Nobel Prize in Physiology or Medicine inhibitors (ICIs). In 2003, Allison and melanoma became a key focus for the devel- to Allison and Honjo. To further exploit the collaborators provided clinical proof of this opment of ICIs, resulting in rapid clinical therapeutic potential of ICIs, these agents therapeutic concept in a first-in-human study advances. In 2013, objective response rates are being explored for earlier-stage cancers, of ipilimumab, an antibody to CTLA-4, in of up to 52% were achieved in a phase I with approved adjuvant and consolidative patients with melanoma or ovarian cancer. trial of pembrolizumab, an antibody to indications following definitive local therapy Around the same time, preclinical work PD-1. Responses were observed regardless for melanoma and NSCLC, respectively. These by Lieping Chen, Tasuku Honjo, Gordon of prior exposure to ipilimumab, hinting at agents are also being combined with various Freeman, Arlene Sharpe and others charac- distinct—and therefore potentially comple- other treatments, resulting in approvals involv- terized a different immune-checkpoint ligand, mentary—mechanisms of action. In fact, ing chemotherapies and anti-angiogenics. PD-L1, which can be found on cancer cells co-treatment with ipilimumab and nivolumab However, important issues must be addressed themselves (unlike CTLA-4 ligands, which are was already being tested and, in 2013, a phase I to further improve patient outcomes, particu- restricted to professional antigen-presenting trial revealed that 53% of patients treated at larly by improving on the currently suboptimal cells). Furthermore, Chen and Honjo demon- the maximum doses had ≥80% tumour reduc- predictive biomarkers and by mitigating irAEs. strated that PD-L1 has a direct role in tumour tions. In 2014, pembrolizumab became the David Killock, Nature Reviews Clinical Oncology immune evasion and can be targeted thera- first approved PD-1 inhibitor, for ipilimum- ORIGINAL ARTICLE Hodi, F. S. et al. Improved survival with peutically with antibodies. Previously, Honjo ab-refractory melanoma, followed by approval ipilimumab in patients with metastatic melanoma. N. Engl. J. had also identified PD-1, the receptor for of nivolumab in this setting less than 4 months Med. 363, 711–723 (2010). PD-L1, on T cells. These advances spurred the later. Within a year, both pembrolizumab and FURTHER READING Please visit the online article for a full list of further reading. development of a new class of ICIs targeting the ipilimumab plus nivolumab combination

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leukaemia and lymphoma. Later that year, MILESTONE 9 CD19 CAR T cells received US FDA approval for the treatment of children with ALL and Engineering armed T cells for the fight adults with aggressive lymphomas. Another ACT developed in parallel to CAR T cells is engineering T cells to express TCRs that recognize tumour-associated antigens. This approach offers the advantage of targeting antigens not present on the cell surface. In 2006, Rosenberg and colleagues transferred TCR T cells specifically recog- nizing the melanoma antigen MART-1 in 15 patients, two of whom achieved regression and still showed high levels of engineered cells in circulation one year after the infusion. This was the first clinical use of TCR T cell therapy, and although initial studies had demonstrated the feasibility and safety of introducing engineered T cells in patients, this trial also showed their remarkable effi- ciency. Other successful studies quickly fol- lowed, such as those demonstrating sustained Credit: S. Fenwick / Springer Nature Limited / Springer Nature S. Fenwick Credit: complete and partial responses in patients with melanoma and treatment of synovial T cells, which can efficiently identify and Physiologic recognition of tumour antigens cell sarcoma with TCR T cells against the kill infected cells, can also kill cancer cells if by T cells is mediated by the TCR–CD3 com- NY-ESO-1 antigen. they recognize them. Adoptive cell therapies plex. However, this complex alone is insuffi- Despite the success of T cell immuno­ (ACT) leverage this cytotoxic capacity of cient to trigger productive T cell responses, therapies, important roadblocks remain. T cells to eradicate tumours. which require the concomitant engagement Disease relapse and acquired resistance to The first successful clinical applications of co-stimulatory receptors. In 2002, Michel CD19 CAR T cell therapy due to antigen of ACT for cancer treatment occurred in the Sadelain and colleagues optimized CAR loss can occur after initial responses. Toxic 1980s. In these pioneering studies by Steven design by integrating the intracellular effects—such as cytokine-release syndrome Rosenberg, tumour-infiltrating lymphocytes domains of TCR and the key co-stimulatory or immune effector cell-associated neuro­ (TILs) were isolated from patients with receptor CD28 within a single molecule to toxicity syndrome—are also an important melanoma, then activated and expanded help sustain T cell expansion, function and hurdle, and biomarkers of response and before reinfusion into the patients. In the first persistence. Other similar second-generation toxicity are urgently needed. Novel CAR published gene therapy clinical trial, TILs CARs subsequently emerged, incorporating constructs are being developed to address engineered to express a foreign gene with a different co-stimulatory domains, such as these limitations, including multiple-antigen- retrovirus to mark the infused cells were safely 4-1BB, which Crystal Mackall and colleagues targeting CARs, inclusion of cytokines to transferred to patients. This study also showed showed can decrease the T cell exhaustion improve efficacy and conditional expression that modified T cells could persist for months induced by continuous CAR signalling, of CARs to regulate CAR activity and safety. after transfer—a key requisite for future ACT. thereby improving antitumour efficacy. Advances in cell engineering are enabling However, although treatment with TILs was In 2010, James Kochenderfer and col- the use of CARs with other immune cells effective in some tumours (such as mela- leagues achieved a breakthrough with a CAR such as natural killer cells, and gene-editing noma), the lack of specificity and the difficulty T cell therapy, reporting tumour regression in techniques such as CRISPR-Cas9 could in recruiting TILs from most other cancer a patient with advanced follicular lymphoma, address limitations related to the complexity types compromised the therapeutic potential. who received two infusions of autologous of CAR designs and the cost of manufactur- In 1989, Zelig Eshhar and colleagues real- T cells genetically engineered to express a ing. Collectively, these new approaches could ized that the inability of T cells to recognize CAR specifically recognizing the antigen extend these revolutionary ‘living drugs’ to surface tumour antigens could be overcome CD19 expressed on B cells. The finding that many more patients in the future. by replacing domains of the T cell receptor CAR T cells had activity in patients advanced M. Teresa Villanueva, (TCR) with antibody parts with specificity the field of ACT, which saw dramatic progress Nature Reviews Drug Discovery towards proteins on these cells. They com- in the following years and remarkable results ORIGINAL ARTICLES Maher, J. et al. Human T-lymphocyte bined the variable region of an antibody with in B-cell malignancies, including paediatric cytotoxicity and proliferation directed by a single chimeric the constant regions of the TCR chains, thus and adult acute lymphoblastic leukaemia TCRζ/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002) | producing chimeric antigen receptors (CARs) (ALL), aggressive B cell lymphomas, chronic Kochenderfer, J. N. et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous that provided T cells with antibody-type lymphocytic leukaemia and multiple mye- T cells genetically engineered to recognize CD19. Blood 116, specificity. The T cells expressing CARs loma treated with CD19 CAR T cells. In 2017, 4099–4102 (2010) | Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma recognized and eliminated target cells, and two studies—the phase II ZUMA-1 trial led using genetically engineered lymphocytes reactive with produced interleukin 2 in the presence of the by Sattva Neelapu and a case-series study led NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011). antigen, providing a proof of concept that this by Carl June—validated the efficacy of CD19 FURTHER READING Please visit the online article for a full list of further reading. approach triggers a cellular immune response. CAR T cells in patients with refractory B-cell

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MILESTONE 10 thalamus, G34 alterations are usually found in tumours that develop in the cerebral hemi- spheres. Moreover, despite the overall decrease Oncohistones: epigenetic in methylated K27 in tumours with K27M alterations, a 2017 report suggested that some loci (such as CDKN2A) retain H3K27me3, drivers of cancer thereby leading to a selective gene-silencing programme that promotes oncogenesis while Oncogenesis is often a slow process associated and progression by interfering with the retaining the identity of the tumour cell of ori- with the progressive accumulation of a com- regulation of transcription through changes gin. Anatomical specificity might be explained plex network of genetic alterations, which, over in chromatin remodelling and accessibility. by the differential gene expression patterns time, dysregulate cellular proliferation and In 2013, multiple studies reported that the of canonical and variant H3 genes across dif- function. However, this aetiology is not the H3 K27M oncohistone leads to a decrease ferent cell types. The expression of canonical case for paediatric cancers—the discovery of in trimethylated H3K27 (H3K27me3)—a histones is restricted to the DNA-replication recurrent histone mutations in children with transcriptional repressor—by inhibiting the phase of the cell cycle, whereas histone vari- cancer revealed that ‘oncohistones’ can have methyltransferase EZH2, the catalytic subunit ants can be expressed throughout any phase vast effects on gene expression and are the root of Polycomb enzyme repressive complex 2 of the cell cycle and progressively accumulate causes of many aggressive paediatric cancers. (PRC2). Interestingly, residual PRC2 activity in long-lived cells. In addition, canonical As essential components of chromatin, the is required for tumour proliferation, and H3.1 is dispersed through the genome, core histones H2A, H2B, H3 and H4 not only EZH2 inhibition has therefore been proposed whereas the H3.3 variant is incorporated create a structural backbone for eukaryotic as a therapeutic target. The loss of H3K27me3 into distinct genomic regions, such as areas DNA packaging, but are also crucial to the has been associated with the upregulation of active transcription or regulatory regions. regulation of RNA replication, transcription of many genes involved in developmental Interestingly, a recent study of patient-derived and repair. The roles of histones in these cel- neurogenesis. glioma cell lines has suggested that H3 lular processes are regulated by their patterns In 2012, H3 G34R substitutions were K27M-mediated loss of H3K27me3 might of post-translational modifications, such as also identified as recurrent GBM altera- occur only when oncohistones are incorpo- methylation or acetylation, and therefore tions. A subsequent study suggested that rated into the chromatin of dividing cells. depend on the activity of histone-modifying these oncohistones alter the interaction of A 2019 report suggested that oncohis- and chromatin-remodelling enzymes. H3K36me3 with its binding partners, thus tones might not be restricted to gliomas and In 2012, two seminal studies revealed leading to the upregulation of the MYCN sarcomas. Somatic alterations in all core the presence of high-frequency somatic oncogene, and G34R inhibition of KDM4 histones have been identified in diverse alterations in paediatric high-grade gliomas, demethylases has also been reported. tumour types. Whether these are driver or including glioblastomas (GBMs). These Moreover, H3 K36M alterations, which passenger mutations remains uncertain, but mutations mainly affected the histone H3 have been identified in chrondroblastomas the locations of the affected residues indicate genes H3-3A (encoding the histone variant and sarcomas, can inhibit several H3K36 that, similarly to the first-identified GBM H3 H3.3) and H3C2 (encoding the canonical methyltransferases. The consequent decrease oncohistones, these mutations may have the histone H3.1). Further studies confirmed in H3K36me was associated with an increase potential to substantially override normal that certain paediatric tumours often contain in H3K27me, which affected the activity of patterns of gene expression by interfering heterozygous missense mutations in H3 genes PRC1 complexes and led to the expression with post-translational histone modifica- that do not cause early protein termination of genes known to block mesenchymal dif- tions and chromatin remodelling. Further and loss, but instead result in gain-of- ferentiation, thus potentially contributing to downstream, these changes are associated function changes that drive oncogenesis. sarcoma development. with alterations in kinase signalling and These amino acid substitutions often occur in Notably, these different sets of oncohistone cellular metabolism, although the underlying the highly conserved amino terminus of H3, amino acid substitutions and the genes mechanisms remain unclear. specifically at amino acids K27, K36 and G34, that they affect are specifically associated These advances in understanding the which are associated with post-translational with distinct tumour types and anatomical roles of oncohistones in cancer have revealed modification of H3. These findings suggest locations. For example, whereas tumours with new therapeutic targets, and several histone that oncohistones promote tumour initiation K27 alterations often occur in the pons and deacetylase inhibitors and tyrosine kinase inhibitors are currently being tested in clinical trials. New precision medicine efforts, which assign therapeutic interventions in clinical tri- als according to genetic screening of tumours, should improve the chances of success. Monica Wang, Nature Reviews Nephrology

ORIGINAL ARTICLES Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012) | Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012). FURTHER READING Please visit the online article for a full list of further reading. Credit: Science Photo Library / Alamy Stock Photo Science Photo Library Credit:

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aberration analysis and ploidy profiling to primary renal carcinoma and associated metastasis samples obtained from four patients before and after treatment. Strikingly, no two samples from the same patient were genetically identical, and phy- logenetic analyses revealed a branch- ing pattern rather than linear tumour evolution. This study drove the shift Credit: Zoonar GmbH / Alamy Stock Photo Credit: in thinking of tumours in Darwinian terms—from linear to tree-like MILESTONE 11 cancer evolution. The evolutionary forces of mutation, genetic drift and selection act on billions of cancer Tumour evolution: from linear cells and their microenvironment, thus giving rise to tumours’ emer- gent behaviours. New mutations paths to branched trees and selection acting on mutations beneficial to the tumour drive the expansion of subclones; subse- The advent of next-generation sequentially dominant clones under- quently, cell division and continuing sequencing technologies enabled lying disease progression. The idea acquisition of mutations generate the characterization of cancer that tumour genetic heterogeneity Mutation, the genetic heterogeneity needed for genomes at unprecedented resolution fuels therapeutic resistance was sub- genetic drift evolutionary adaptation. (MILESTONE 7). Billions of sequencing sequently taken up by James Goldie and selection Genomic data have enabled infer- reads—representing genomes from and Andrew Coldman, who posited ences regarding the evolutionary a random subset of individual cells that clonal heterogeneity of tumours give rise to forces that act on cancer clones as contained in a tumour sample—were is the predominant factor underlying a tumour’s they evolve, yielding insights into used to build detailed catalogues of evolutionary changes resulting from emergent the generation of genetic variation somatic mutations by comparing cancer treatment. behaviour and the order, rate and mechanisms patients’ cancer DNA to their In the 2000s, several studies through which this evolution occurs. germline DNA. emerged characterizing the genetic Since the work by Gerlinger et al., Insights into the genomic land- basis for disease progression, metas- new approaches to target cancer evo- scapes of some cancers promised tasis, resistance and relapse in both lution have emerged, and focus has to move cancer treatment towards haematological and solid cancers. shifted to dissecting how subclonal genotype-guided approaches. These studies demonstrated the populations might interact (antago- However, most cancers, even highly complexity of clonal evolution and nizing or synergizing) to evolve and drug-sensitive tumours with pro- supported a model in which clonal affect clinical outcomes. Interactions nounced initial responses, develop diversity underlies disease progres- between clonal driver mutations resistance to targeted molecular sion and resistance to therapy. (those within the phylogenetic tree’s therapies (MILESTONE 1). In 2012, In 2011, Anderson et al. and Notta ‘trunk’) and subclonal driver muta- Gerlinger et al. confirmed what et al. tracked the evolutionary paths tions (those within a phylogenetic had long been suspected: cancers taken by different subclones during branch) and competition among are highly dynamic evolutionary progression of acute lymphoblastic subclones define the clonal archi- entities presenting major challenges leukaemia. Both studies showed that tecture of individual cancers. This to personalized medicine. The cancer the degree of genetic heterogeneity dynamic is shaped by the pressures genome is characterized by extreme in the leukaemia-initiating cell exerted by the environment, such as heterogeneity not only across tumour subpopulation was similar to that drug treatment. types, primary and secondary in the population of leukaemia cells Genetic heterogeneity fuels ther- tumours or individuals with the same in the sample. Moreover, branching apeutic resistance. A comprehensive histological tumour type, but also evolutionary trajectories did not fit understanding of the dynamics of within individual tumours. the linear clonal succession model of cancer evolution and assessment The notion of cancer as an cancer evolution, whereby cancers of tumour heterogeneity will therefore evolutionary process was introduced progress through single-cell clone be essential for prognostication, drug in 1976 by Peter Nowell, who bottlenecks. development and therapy. hypothesized that natural selection Gerlinger et al. then provided Linda Koch, acting on tumours in the form of a direct demonstration of multiple Nature Reviews Genetics clonal selection continuously drives genetically related subclones within a evolutionary adaption. Nowell’s solid tumour and their phylogenetic ORIGINAL ARTICLE Gerlinger, M. et al. Intratumor heterogeneity and branched original evolutionary model reflected relationships. The team applied evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012). FURTHER READING Please visit the online article for a full list of further reading. an essentially linear path with exome sequencing, chromosome

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MILESTONE 12 design to identify compounds that inhibit these interactions and thus downstream signalling. Indeed, the Undruggable? Inconceivable Boehringer Ingelheim compound also decreases the growth of NSCLC cells with RAS mutations. In the cult-classic film The Princess In mouse models of cancers Compounds that inhibit multiple Bride, every time the Man in Black driven by KRAS-G12C, these forms of RAS could have toxic, (the good guy) overcomes an agents induce tumour regression as on-target effects in non-cancerous insurmountable obstacle, monotherapies. Their anticancer cells. Evidence from preclinical Vizzini (the bad guy) exclaims, activity is enhanced when they studies, however, suggests that differ- “Inconceivable!” This happens are combined with other ences in affinity for wild-type versus repeatedly, until eventually chemotherapeutic agents mutant RAS could provide a thera- Vizzini’s companion tells him, in (particularly those that peutic window for these compounds. a moment of comedic perfection, inhibit kinases downstream Compounds targeting KRAS “You keep using that word. I do of RAS) isoforms other than G12C that are not think it means what you think or, for commonly found in NCSLC, pan- it means.” sotorasib, creatic cancer and colorectal cancer So it was with ‘undruggable’ RAS. with check- are also in development. These In the early 2000s, when dozens of point inhibitors. compounds may avoid the toxicities kinase inhibitors were In the phase I trial of AMG510, that could arise from pan-mutation heading to the clinic, no dose-limiting toxic effects or RAS inhibitors. comparatively little treatment-related deaths were Efforts to find inhibitors for progress was being observed. In patients with NSCLC other non-kinase targets have had made on key or colorectal cancer, disease control less success than those for RAS. p53, non-kinase (stable disease or an objective another lucrative anticancer target, targets in response) occurred in 88% or 74% remains clinically untamed. Indeed, oncology. respectively, of this small patient the nutlins, a much-lauded group of RAS, a small group. The extent of efficacy of potential p53-inhibitory compounds GTPase, is one of MRTX849 and AMG510 will be from Roche, failed in a phase III the most frequently determined in ongoing and future trial in acute myeloid leukaemia altered proteins in cancer larger clinical trials. in mid-2020. MYC, also high on and was therefore pur- Credit: Lobo36 RAS cycles between GTP- the list of cancer targets, remains sued with particular fervour. bound and GDP-bound states. undrugged. The lack of success in identifying Unexpectedly, the G12C inhibitors Targeted degradation could be RAS inhibitors led many to call it bind the GDP-bound, inactive state, useful for these other undruggable undruggable. thus demonstrating that KRAS G12C proteins. Proteolysis-targeting Then, in 2013, Kevin Shokat’s lab is not constitutively active (as previ- chimeras (PROTACs) serve as developed a groundbreaking inhibi- ously thought) but is hyperexcitable. synthetic E3 ligases, which bind tor of the KRAS G12C mutant, one of This key insight into RAS biology was target proteins and mark them for the most prevalent RAS alterations in enabled by the covalent inhibitors and ubiquitin-mediated degradation. non–small cell lung cancer (NSCLC). spurred investigations into state- Originally conceived in Craig Crews’s Shokat’s compound forms a covalent specific RAS-binding compounds. lab in 2001, the first PROTAC, which bond with the inherently reactive Not all RAS alterations are G12C, induces degradation of the androgen cysteine residue at position 12 in In 2013, Kevin and efforts are underway to find receptor, successfully completed a the altered form of RAS, whereas Shokat’s lab compounds that inhibit non-G12C phase I trial in 2020, showing some wild-type RAS has a glycine in this developed RAS alterations. Different tumour signs of antitumour efficacy. position and does not react with types tend to have different RAS Although many non-kinase Shokat’s compound. a ground- mutations—although nearly half the cancer targets remain undrugged, the This discovery formed the basis breaking RAS alterations found in lung cancer success of covalent KRAS inhibitors of Wellspring Biosciences, which inhibitor of the are G12C, the G12D alteration is and PROTACs demonstrates that turned the compound into a more KRAS-G12C more prevalent in pancreatic and developing therapeutic compounds drug-like molecule, ARS-1620. From colon cancers. that target these proteins may be not this growing field of covalent RAS mutant, one One of the more promising only conceivable but also well within inhibitors, two drugs have since of the most pan-mutation approaches is to target the range of current possibilities. been developed and shown signs of prevalent RAS the interactions between RAS and Megan Cully, efficacy in early-stage clinical trials: either its downstream effectors or Nature Reviews Drug Discovery Amgen’s sotorasib (AMG510) and mutations in SOS, a guanine-nucleotide-exchange non-small-cell ORIGINAL ARTICLE Ostrem, J. et al. K-Ras(G12C) Mirati’s MRTX849. factor that activates RAS. Genentech, inhibitors allosterically control GTP affinity and Both sotorasib and MRTX849 lung cancer Boehringer Ingelheim and academic effector interactions. Nature 503, 548–551 (2013). form covalent bonds with the researchers including Terence FURTHER READING Please visit the online article for a full list of further reading. reactive cysteine in KRAS-G12C. Rabbitts have used structure-based

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decreased in germ-free or antibiotic-treated MILESTONE 13 mice is restored after oral gavage with specific Bacteroides spp., particularly B. fragilis. Until that point, most of the important Good bacteria make for initial insights into how the gut microbiota sets the inflammatory tone during therapy good cancer therapy had come from preclinical mouse models. Consequently, growing impetus prompted researchers to evaluate whether similar observations could be made in patient cohorts. These efforts culminated in the 2018 publication of three parallel studies led by Zitvogel, Gajewski and Jennifer Wargo, which used metagenomic shotgun sequencing of patient stool samples to demonstrate that the efficacy of anti-PD-1 ICIs in people with melanoma and epithelial tumours is shaped by gut commensal bacteria. Compositional differences in the gut microbiota were associated with clinical

Credit: nobeastsofierce Science / Alamy Stock Photo nobeastsofierce Credit: responses to ICIs. Importantly, reconstituting germ-free mice with faecal transplants from The commensal bacteria that colonize the cyclophosphamide (CTX) displayed com- non-responding patients blunts the antitu- gastrointestinal mucosa profoundly affect positional changes in the small intestinal mour effects of PD-1 blockade by restraining host physiological functions including metab- microbiota and accompanying disruption local and systemic immunity, thus suggesting olism, cellular proliferation, inflammation of the intestinal barrier, thus leading to the that the composition of the gut microbiome and immunity. These effects are driven by translocation of select Gram-positive bacte- might be one factor accounting for primary the ability of resident bacteria to produce rial species into secondary lymphoid organs. resistance to ICIs. Unexpectedly, across small molecules and metabolites as well as to Once in the spleen, the commensal bacteria these studies, little overlap was found in the coordinate cross-talk with host immune cells induced a robust adaptive immune response specific bacterial taxa or species correlating

both at the intestinal barrier and systemically. characterized by type 17 helper T cells (TH17) with successful response, thus prompting Many current cancer therapies rely on stimu- and memory type 1 helper T cells. Indeed, the researchers to speculate on the variables lation of antitumour immune responses, but the therapeutic effect of CTX on tumours was that might account for these differences, such whether the gut microbiota might influence mitigated in germ-free or antibiotic-treated as the techniques used to analyse patient host responses to cancer therapeutics via the mice, and was partly reinstated with the samples, geographical diversity, and diet and

immune system was largely unknown. adoptive transfer of TH17 cells, thus under- lifestyle factors. In 2013, two seminal studies from the scoring the profound effect of the microbiota Confirmation that gut microbial com- groups of Laurence Zitvogel and Giorgio in treatment outcomes. munities are an influential force mediating Trinchieri shed light on this idea. In In 2015, two studies went further and pin- responses to a range of therapeutic modalities tumour-bearing mice that lacked microbiota, pointed distinct bacterial species responsible has raised the intriguing possibility that either through treatment with antibiotics for the modulation of antitumour immune microbe-based therapies could eventually be or using germ-free animals, the authors responses under therapeutic pressure. Efforts implemented in clinical settings. For example, demonstrated that priming of both the innate from the groups of Thomas Gajewski and manipulating the human gut microbiota and adaptive immune system by an intact gut Zitvogel aimed at exploring the effects of the could take the form of dietary interventions microbiota is crucial for the effectiveness of gut microbiota specifically in the context and prebiotic supplementation, faecal micro- three anticancer regimens. Iida et al. showed of immune-checkpoint inhibitors (ICIs), biota transplantations, and administration of that the responses to CpG oligodeoxynucle- which elicit T cell responses to tumours. bacterial consortia or probiotics. However, otide (ODN), oxaliplatin chemotherapy and Comparing genetically similar mice pur- before these possibilities can come to fruition blockade of the interleukin receptor IL-10R chased from two different companies known in treating patients, more work is needed are attenuated in tumour-bearing mice lacking to have varying compositions of commensal to identify and validate reliable predictive gut microbiota. Mechanistically, in the case of microbiota, Sivan et al. revealed differences microbiome biomarkers and to fundamen- CpG ODN, this effect is the result of decreased in subcutaneous melanoma outgrowth that tally define what truly constitutes a favourable tumour necrosis brought about by decreased are attributable to tumour-specific T cell microbiome that can drive effective cancer production of inflammatory cytokines from responses. Subsequently, Bifidobacterium therapy responses. insufficiently primed tumour-infiltrating innate spp. were identified by profiling the gut Anna Dart, Nature Reviews Cancer myeloid cells. In the case of oxaliplatin, a lack of microbiome through sequencing of 16S production of reactive oxygen species by non- ribosomal RNA and were found to be ORIGINAL ARTICLES Iida, N. et al. Commensal bacteria primed myeloid cells is partially accountable associated with both delayed tumour growth control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013) | Viaud, S. et al. for the lower genotoxicity of the chemothera- and optimal responses to an anti-PD-L1 The intestinal microbiota modulates the anticancer immune peutic drug in the absence of a gut microbiota. ICI in mice. Similarly, Vétizou et al. found effects of cyclophosphamide. Science 342, 971–976 (2013). In a study by Viaud et al., naive mice that the immunostimulatory activity and FURTHER READING Please visit the online article for a full list of further reading. treated with the chemotherapeutic drug tumour control of CTLA-4 blockade that is

S16 | DECEMBER 2020 www.nature.com/collections/cancer-milestones MILESTONES

MILESTONE 14 by Hollon et al. has shown that an AI-powered system can deliver accurate diagnoses for patients undergoing surgery for brain cancer, The AI revolution in cancer thus underscoring the potential of these models to increase the speed Histopathology is the current ‘gold and accuracy of clinical decisions. standard’ for establishing cancer Future studies are needed to diagnosis. Whereas the interpre- ensure that this level of augmented tation of tissue slides is subjective, perception is not available only to the advent of clinical genomics has institutions that can afford expensive contributed to refining patient strati- medical appliances and software. fication and clinical decision-making Esteva et al. paved the way to afforda- through the identification of ble access to AI-assisted differential actionable tumour vulnerabilities. classification of skin lesions through However, both histological assess- the use of regular cell-phone cameras. ment and sequencing approaches Other efforts by Chen et al. have ena- are time consuming and costly, and bled real-time integration through they often yield inconsistent results augmented-reality approaches which, across institutions. Enter big data and through overlaying an AI system with artificial intelligence (AI), with the a microscope field of view, facilitate premise that, if enough information automated histological annotation is available, predictive models can be in places lacking access to trained generated that achieve clinical-grade pathologists. These methods have automated diagnoses and facilitate extended the real-world applications clinicians’ workflows for accurate of AI a step further in the diagnosis diagnosis. for prostate cancer, and they may be The past decade has witnessed a Media AS / Alamy Stock Vector YAY Credit: expanded to other tumour types and surge in the amount of digitalized diseases that often require specialized clinical data, including electronic easily conducted visually by trained histological evaluation. health records, genomics and digital pathologists—could be ascertained Most studies to date have been biomedical images. Perhaps because The most from histological patterns. Proof- correlative and based on retrospec- of its standardized high-quality relevant of-concept work by Coudray et al. tive analysis of controlled data sets. data-collection protocols and fewer provided the first solid evidence that These have provided the foundations inherent missing-data challenges functionality deep learning on tumour histology for AI in healthcare applications and than in other clinical data types, of AI in cancer slides can predict driver mutations have illustrated new possibilities medical imaging has emerged as a histopathology and classify tumour subtypes. for enhancing the performance of frontier of success for AI in medicine. Follow-up work by Campanella et al. trained pathologists. To fully realize Computer vision has enabled some of is its demonstrated that high diagnostic their potential, AI systems must the most striking studies predicting integration accuracy can be achieved without a crucially be tested in controlled pro- molecular and pathological cues in clinical need for prior data curation, if the spective studies to accurately evaluate from digitalized images. The level workflows for datasets are sufficiently large, and their clinical value—a setting for of information that can be retrieved studies by Fu et al. and Kather et al. which specific guidelines have been from digital images surpasses human improving expanded the breadth of applicability elaborated upon by Liu et al. capacity in terms of speed as well as patient of these algorithms in detecting Computer vision and digital the ability to infer and detect subtle management. molecular footprints and prognostic pathology are only the beginning, traits hidden to human perception. correlates across multiple cancers. and AI systems are being explored In 2017, Esteva et al. published Perhaps the most relevant in multiple additional settings. The a landmark study in the field of functionality of AI in cancer histo- convergence of big data and AI in computer vision applied to cancer pathology is its integration in clinical oncology provides a unique interface detection. The authors used a large workflows for improving patient to explore the full capabilities of these dataset of digital images of skin management. For example, pioneer- approaches for the benefit of patients. conditions to train and validate a ing work by Bejnordi et al. exploring We look forward to the next 10 years deep convolutional neural network the clinical value of AI showed that of groundbreaking discoveries in this able to discriminate between benign deep-learning models can achieve exciting area of research. and malignant lesions with accuracy accurate detection of lymph node Miguel Foronda, Nature Cancer similar to that of trained dermatolo- metastases in breast cancer, rivalling gists. These findings sparked further human performance. Another prag- ORIGINAL ARTICLE Esteva, A. et al. Dermatologist-level classification of skin cancer studies aimed at understanding matic clinical application of medical with deep neural networks. Nature 542, 115–118 whether additional features beyond AI has enabled near-real-time diag- (2017). the classification of tumour versus nosis of patients in the operating FURTHER READING Please visit the online article for a full list of further reading. normal tissue—a task that can be room. A prospective clinical trial

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