【癌症的里程碑】Milestones in Cancer 2000-2020.pdf

Produced by:Nature Genetics and NatureMedicineWith support from:C 2020微信扫码，免费报告轻松领微信扫码，工作轻松无忧行业资源微信群1.进群即领取群利报告与资源合编领取群利报告与资源合编，内有近百行业、上万份行研、管理及其他学习资源；2.每日学习分享最新6+份精选报告；3.群友信息交流，群主免费解答并提供相关行业报告。扫一扫二维码，添加客服微信（微信号：Teamkon3）；添加好友请备注：姓名姓名+单位单位+业务领域业务领域知识星球 行业与管理资源社群1.无限制下载行业研究报告、咨询公司管理方案，企业运营制度、科技方案与大咖报告等。2.每月同步更新3000+份最新行业资源；涵盖科技、金融、教育、互联网、房地产、生物制药、医疗健康等行研报告、科技动态、管理方案；海量资源在手 工作轻松无忧报告收集整理于网络，只用于群友学习，请勿他用Credit:S.Fenwick/Springer Nature LimitedCancerMILESTONES 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 branchedtrees S15 Undruggable?Inconceivable S16 Good bacteria make for good cancer therapy S17 The AI revolution in cancerCITING THE MILESTONESNature Milestones in Cancer includes Milestone articles written by our editors and an online Collection of previously published material.To cite the full project,please use Nature Milestones:Cancer https:/ you wish to cite any of the individual Milestones,please list Author,A.Title.Nature Milestones:Cancer (2020).For example,Milestone 1 is Valtierra,I.Routes to resistance.Nature Milestones:Cancer https:/ cite articles from the Collection,please use the original citation,which can be found online.VISIT THE SUPPLEMENT ONLINEThe Nature Milestones in Cancer supplement can be found at JOURNALSBMC Cancer,Nature,Nature Cancer,Nature Communications,Nature Genetics,Nature Medicine,Nature Reviews Cancer,NatureReviews Clinical Oncology,Nature Reviews Drug Discovery,Nature Reviews Gastroenterology&Hepatology,Nature Reviews Genetics,Nature Reviews Nephrology.SUBSCRIPTIONS AND CUSTOMER SERVICESSpringer Nature,Subscriptions,Cromwell Place,Hampshire International Business Park,Lime Tree Way,Basingstoke,Hampshire RG24 8YJ,UKTel:+44(0)1256 Customer serviCes: 2020 Springer Nature Limited.All rights reserved.NATURE MILESTONES|CANCER DECEMBER 2020|S1With 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:/ 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 are crystallizing.The adaptations used by tumour cells to breach cell-intrinsic(MILESTONES 5,6)and tissue-specific proliferative barriers,and establish malignant diaspora at secondary sites are better understood than ever before.Cancer cells can be profiled at unprecedented scale and resolution,increasingly in the context of their tissue and microbial(MILESTONE 13)microenvironments.These discoveries have propelled the development of new treatments,most notably immunotherapies(MILESTONES 8,9),which are now a crucial part of the treatment armoury,alongside surgery,chemotherapy,radiotherapy and an expanding repertoire of targeted treatments(MILESTONES 4,12).We hope that these Milestones will inspire optimism about the future of cancer research.We look forward to new approaches to tackle cancer types for which progress to date has been modest.We anticipate further improvements in the understanding of treatment resistance(MILESTONE 1)and metastasis,the process responsible for most cancer deaths.We also hope that technological innovations will drive powerful new strategies to detect and monitor cancer(MILESTONES 2,14).As treatments become more sophisticated,so too must the strategies to ensure that the benefits of research are available to everyone.The socioeconomic disparities that disproportionately limit access to care must be overcome.From prevention(MILESTONE 3)to diagnosis and treatmentwe must ensure that no patient is left behind.This project was made possible by the support of our colleagues in the Nature Editorial Cancer Community.We thank Javier Carmona and Ian Green for preparing the original proposal.In addition to the many editors who wrote these milestones,we extend our gratitude to Javier Carmona,AnnaDart,Iain Dickson,Linda Gummlich,Ulrike Harjes,Barbara Marte and Sarah Seton-Rogers for managing and editing individual milestones.We appreciate the support we have received from Rebecca Jones,Simon Fenwick,ChrisRyan and Maya Shani.Finally,we would like to thank our expert advisors and to 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 MedicineEDITORIAL OFFICESLondonSpringer NatureThe Campus,4 Crinan Street,London N1 9XW,UK Tel:[phone]Coordinating editors:Safia Danovi,Saheli SadanandCopy editor:Maya ShaniproduCtion:Simon Fenwick,Susan Gray,Nick Brunidesign&Web deveLopment:Chris Ryanmarketing:Helen Burgess,Nicole JacksonpubLishing:Rebecca Jonesvp,pubLishing:Richard Hugheseditor-in-Chief,nature pubLiCations:Magdalena Skippersponsorship:David Bagshaw,Stephen Brown,Natasha Boyd Springer Nature Limited.All rights reserved.MILESTONES ADVISORSDavid J.AdamsCatherine Alix-PanabiresRen BernardsTrever G.BivonaNavdeep S.ChandelRyan B.CorcoranSarah-Jane DawsonJulian DownwardKristian HelinJakob N.KatherChristopher A.KlebanoffCrystal L.MackallIgnacio MeleroNarges RazavianJohn T.SchillerClemens A.SchmittCharles SwantonGiorgio TrinchieriLaurence ZitvogelPRODUCED WITH SUPPORT FROM:Illumina,Johnson&JohnsonPRODUCED WITH SUPPORT OF A GRANT FROM:AstraZeneca,Boehringer Ingelheim,MSD Cover:Design by Chris Ryan.S2|DECEMBER 2020 complex II mutations found in tumours2001Mechanisms of resistance to targeted treatment(MILESTONE 1)Nobel Prize awarded for“discoveries of key regulators of the cell cycle”2003Epidemiological link between cancer and obesity2004First epigenetic drug to gain FDA approvalFirst antiangiogenic agent to gain FDA approval for cancer treatmentLiquid biopsies for non-invasive diagnosis and monitoring of patients(MILESTONE 2)HPV vaccines to prevent cervical cancer(MILESTONE 3)2005Leveraging synthetic lethality for treatment(MILESTONE 4)Oncogene-induced senescence in premalignant tissues and cancer(MILESTONE 5)2006Metabolic adaptations in cancer(MILESTONE 6)2008First interim analysis published by The Cancer Genome AtlasFirst cancer whole-genome sequence(MILESTONE 7)2009Description of colorectal cancer organoids IDH1 mutations leading to the generation of 2-hydroxyglutarate2010Immune-checkpoint inhibitors from bench to bedside(MILESTONE 8)Engineering T cells to kill cancer cells(MILESTONE 9)2011Use of screening to decrease mortality from lung cancerClearance of senescent cells by the immune system2012Epigenetic 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 cellsAnti-tumour role of metabolite depletion2013Targeting undruggable non-kinase proteins(MILESTONE 12)Gut microbiome influences on anti-tumour immune responses(MILESTONE 13)2015The Big Bang theory of cancer evolution is proposedDriver mutations found in healthy tissueFirst FDA approval for a combination of immunotherapies2016First FDA approval for an anti-PD-L1 inhibitor2017Potential of artificial intelligence in cancer diagnosis and monitoring(MILESTONE 14)First FDA approval of a treatment on the basis of tumour genomics aloneFirst inhibitor of mutant IDH2 approved for clinical use2018Nobel Prize awarded for“discovery of cancer therapy by inhibition of negative immune regulation”2019Clinical trial of CAR T cells to target BCMA in patients with multiple myelomaNobel Prize awarded for“discoveries of how cells sense and adapt to oxygen availability”2020Pan-cancer analysis of whole genomesClinical trial of CD19-targeting CARNatural Killer cells in patients with CD19+cancersMILESTONES IN CANCERCredit:Sciepro/Science Photo LibraryCredit:Juan Gaertner/Science Photo LibraryNATURE MILESTONES|CANCER DECEMBER 2020|S3By the turn of the millennium,drugs that selectively target driver genes had been devel-oped.For instance,tyrosine kinase inhibitors,such as imatinib,had been demonstrated to lead to sustained and durable remission in patients with advanced chronic myeloid leukaemia(CML)by targeting BCR-ABL,a fusion gene with constitutive tyrosine kinase activity.Furthermore,in contrast to more conventional genotoxic treatments,these drugs were believed to cause fewer adverse effects.With such precise targeted therapies,hopes were high that this new generation of drug might represent the magic bullet long sought after by patients and clinicians.Unfortunately,the reality was not so simple.Although patients(even those in advanced stages or with complex molecular alterations)initially responded to these targeted drugs,a clinical trial of imatinib reported by Druker et al.showed that in patients with acute lymphoblastic leukae-mia or with CML in lymphoid blast crisis,tumours eventually returned after daily treatment for a few weeks or months.The question of how cancer can adapt to special-ized strategies that directly target essential cancer machinery still remained.Mercedes E.Gorre,Charles Sawyers and collaborators set out to answer this question.Imatinib was known to work by binding the BCR-ABL kinase domain,thus blocking its function.Because previous work by Chinetal.had shown that cancers often require the activity of their primary oncogene,Gorreetal.wondered whether imatinib-resistant tumours might still be dependent on the BCR-ABL fusion gene.They reasoned that if the relapsed tumours were still dependent on BCR-ABL,then BCR-ABL signalling activity would be evident even after treatment.Because of the fast degradation of the BCR-ABL protein,they measured the phosphorylation of one of its downstream targets,CRKL.Indeed,in tumours from 11 patients with relapse,CRKL phosphorylation was nearly as high as that in untreated patients.The next step was to identify what allowed BCR-ABL to remain active.The authors con-cluded that a cell-intrinsic factor was respon-sible,because relapsed cells isolated from patients still showed this oncogenic activity,thus suggesting that no extrinsic factors were involved.The authors examined changes in the BCR-ABL gene itself and found two strik-ingly distinct escape mechanisms in different patients.The first resistance-related alteration could be understood as a brute-force,all-out approach to fight against the inhibitor:the tumours of three patients who relapsed had produced multiple copies of the BCR-ABL gene through gene amplification.The number of copies increased with subsequent rounds of treatment;however,in one patient,these amplifications disappeared after switching to another therapy,thus suggesting that the drug was selecting for clones bearing the amplification.In contrast,the second resistance mechanism required a single modi-fication:a point mutation changing threonine 315 of ABL1 to isoleucine was found in six patients.Because this particular amino acid is critical for imatinib binding,the mutation abrogated binding to the drug.In contrast to the wild-type BCR-ABL,this mutant retained activity in cell lines,even after exposure to the drug.This study,together with similar studies published shortly afterwardsincluding the discovery by Kobayashi et al.of EGFR mutations conferring resistance to gefitinib in lung cancerillustrates several important aspects of cancer.On the one hand,these data show that cancer is an evolutionary process:under strong selective pressure,cells with adaptations allowing them to overcome the adverse environment will dominate.Such cells may actually already be present in the initial tumoureven seemingly homogeneous cancers can harbour genetically heterogeneous populations that have an edge in the arms race against therapy,as described by Dagogo-Jack and Shaw.In addition,resistance can be achieved by markedly distinct but function-ally convergent approaches.On the other hand,these studies have also unmasked one critical feature of cancers:certain genes and mutations remain essential drivers of tumour growth and survival.Therefore,knowing and targeting these central drivers continues to be an important clinical strategy,which is being used to develop new generations of clinically effective tyrosine kinase inhibitors.Targeted therapies will remain an important part of the arsenal to combat cancers,especially when tested in different combinations that can circumvent resistance to a single drug.The roles of off-target,non-genetic mechanisms in this resistance are also starting to be acknowledged and will need to be addressed with correspondingly tailored approaches.As long as the design and use of these therapeutic strategies is guided by evolutionary principles,the hope is that drug resistance in patients will one day be predicted and sidestepped.Ilse Valtierra,Nature Communications MILESTONE 1Routes to resistanceORIGINAL ARTICLE Gorre,M.E.et al.Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.Science 293,876880(2001).FURTHER READING Please visit the online article for a full list of further reading.Credit:iStock/Getty Images PlusS4|DECEMBER 2020 have long been aware that cancer cells disseminate through the bloodstream.In the early 2000s,substantial efforts were devoted to developing techniques for the reliable and sensitive detection of cancer cells and their components in bodily fluids.As cell-detection systems were optimized,several studies aimed to determine their clinical utility.A study published by Cristofanilli et al.in 2004 was the first to use the CellSearch platform to show that the number of circulating epithelial cells in the blood is markedly higher in women with metastatic breast cancer before starting systemic therapy than in women without breast cancer or with benign breast disease.In analys-ing survival outcomes,the investiga-tors established the prognostic value of such differences:the durations of progression-free survival(PFS)and overall survival were significantly shorter in patients with cell counts above an established threshold at baseline and,more importantly,at the first follow-up visit during treatment.This study was the first to demonstrate the clinical relevance of circulating tumour cell enumeration for stratifying cancer patients