LINK LUDWIG MARCH 2019 1 Joint conference looks 16 |Diet and IN THIS ISSUE cancer preventioncancer and cancer and nutrition between links at

LIFE-CHANGING SCIENCE 18 | fiction writers Why scientists should Bert VogelsteinBert think like science Q&A with Q&A

LUDWIG LINK | MARCH 2019 2

LUDWIG LINK | MARCH 2019 Vice President for Communications President Vice Rachel Reinhardt Year! New you all aHappy Wishing 23. page on thoughts their share They care. and research of cancer world likely the to alter genre—is of the staple intelligence—a artificial how on in to weigh researchers Ludwig we askedsome fiction, of science Speaking fans. fiction like science think and inhibitions their shed should scientists believes why he things, other among out, Find genomics. of cancer field the in Vogelstein, agiant Bert Co-director Hopkins Johns 18) Ludwig is with (page issue this in Q&A Our prevention. cancer of dietary science to improve the best how on focused that UK, Research Cancer and Foundation London, co-sponsored by Ludwig, the Conrad Hilton N. in conference 16) aDecember on (page We report also you’ll research Ludwig exciting discover here. the way, by the all that, aslice of is just And cancers. various accessible to the cell’s gene reading drive machinery (which genome of the is to say, 98% of it) are also that parts noncoding the in mutations how detailed that study multi-institutional ofambitious, an results the about and response immune of the fury cells the dull melanoma helps You’llenzyme it. to treat how metabolic how a out find possibly, by chemotherapy—and, caused often mind-fog malfunctions that underpin “chemo brain”—an enduring LETTER

figured out the cellular cellular the out figured of researchers ateam how pages you’ll these in and on learn Read Link. of Ludwig issue this in abounds they’re succeeding discovery. that Proof of scientific scientists to push the boundaries of Ludwig business It is the 3 Conference in London (see page 16). (see page London in Conference Nutrition and Prevention Cancer at the Institute Ludwig of the Strausberg Bob and Health, of Public School T.H. Chan Harvard of the Walter Willett of Cambridge, Kay-Tee cover: From the left, On University of the Khaw LUDWIG LINK LUDWIG ludwigcancerresearch.org response risis source og News roundup or melding therapies checkpoints immune elucidating or tumors up cold firing or crosstalk malignant capturing or Awards and distinctions Required reading Required ascientist Ask Vogelstein with Bert Q&A prevention cancer eimagining dietary eventSpecial package timulus Clinical trials ignature analysis operation switch ne again off ets control uality of resistance rograms misfits the ourcing ancer’s noncoding genome gnals intelligence egarding micromanagement debate splice and ice TABLE CONTENTS OF A malignant diversity A malignant For probing chromosomal aberrations A versatile A versatile C F F F F F R S S O B Q P S C Si R D STING

MARCH 2019 MARCH

1 2 1 2 1 12 1 1 1 1 1 1 10 1 1 5 3 8 6 5 6 4 6 5 1 1 8 4 9 9 8 7 6 5 5 4 6 4 3 2 0

LUDWIG LINK | MARCH 2019 Awards and distinctions Ludwig Stanford Michelle Monje Ludwig MIT

FOR CAPTURING MALIGNANT CROSSTALK MALIGNANT FOR CAPTURING Michelle and her team discovered that a that discovered team her and Michelle the goal of enhancing human health.” biomedical or behavioral sciences towards the in challenges to major approaches innovative and potentially transformative highly propose who creativity exceptional of scientists individual “supports October. award Award in The Pioneer a2018 Director’s NIH received Monje Michelle investigator Stanford Ludwig chromosomes extra how detailed has She health. cellular on of aneuploidy among other things, the consequences explored, has research Angelika’s cancers. advanced many with associated aphenomenon cells, in of chromosomes or the presence of an abnormal number aneuploidy, on work forher recognized life.” human was She extending and toward understanding living systems which honors “transformative advances Sciences, Life Prize in Breakthrough a 2019 received who ofscientists five one is MIT of Ludwig Amon Angelika FOR PROBING CHROMOSOMAL ABERRATIONS 4 to improve treatment outcomes. that might manipulated therapeutically be activity specific identify and cells brain healthy with interact cells glioma how explore to further team her and Michelle award enable will The to progress. neurons healthy from signals on depend cells cancerous their that and activity, system to nervous response in grow partly gliomas called tumors brain of aggressive group discussing her work here of Angelika video Watch ashort California. Valley, Silicon in center research NASA a at hosted November in a ceremony at presented was and $3 million with award comes The therapies. of cancer development forthe exploited be can that cells cancer in vulnerabilities expose and evolution of cancer understanding to our contribute will work her that hope expressed Angelika award, her receiving In stability. disrupt and genomic metabolism alter provoke responses, that stress expression gene in imbalances cause .

LUDWIG LINK | MARCH 2019 Awards and distinctions are frequently hijacked by tumor cells cells by tumor hijacked frequently are These mechanisms autoimmune cascades. deadly prevent potentially help which pathways, checkpoint of immune complexities the unravel and discover to scientists first the among was She activation. Tcell modulate that pathways understanding of the immunoregulatory for her contributions landmark to our was Arlene recognizedimmunologist, October. in Arenowned of Medicine Academy National US to the elected was Sharpe Arlene Harvard’s Ludwig UCP2 inducing studies, mouse In not. do ones cold while UCP2, named protein of levels ametabolic high to express tend robust anti-cancer immune responses elicit that tumors “hot” that found They susceptible to immunotherapies. these made be “cold” tumors—may called often blockade— to checkpoint to respond fail that melanomas by which mechanism acellular uncovered recently colleagues his and He immunometabolomics. as known afield metabolism, cell immune and cell of cancer interplay the on focuses October. Award in research His Bridge Swiss the received who researchers of two one was Lausanne of Ho Ludwig Ping-Chih FOR ELUCIDATING IMMUNE CHECKPOINTS FOR FIRING UP COLD TUMORS commitment to service. professionaloutstanding achievement and whoindividuals have demonstrated fields ofhealthmedicine, and recognizes among the highest of honors in the Academy, considered to the Election care. cancer revolutionizing today are and tumors on attack immune the unleash help development of checkpoint inhibitors that to the led PD-1/PD-L14 and pathways, CTLA- of the elucidation her especially findings, Arlene’s attack. Tcell to evade Europe. in research cancer supports that Control and the Union for International Cancer foundation Research Cancer Swiss the League, Cancer Swiss the with associated foundation aprivate is Bridge Swiss tumors will respond to immunotherapy. whether to determine atest devising and evaluating the strategy in clinical trials confirming their results with the aim of now are team his and Ping-Chih survival. extended that responses immune tumor anti- robust elicited PD1 blockade with up following and drug diabetes existing an using tumors melanoma cold in expression 5 Ludwig Lausanne Ludwig Ho Ping-Chih Ludwig Harvard Arlene Sharpe

LUDWIG LINK | MARCH 2019 Awards and distinctions News roundup Ludwig Stanford Michelle Monje Ludwig Chicago Ralph Weichselbaum

inhibits the ability of precursor cells cells of precursor ability the inhibits the researchers found that chemotherapy tissue from mouse models and humans, brain Examining cells. immune resident brain’s the microglia, and supply; blood to their them link and neurons connect help and support which astrocytes, fibers; of nerve insulation the myelin, produce which oligodendrocytes, cells: of brain types major three affects methotrexate thatreport the chemotherapy drug colleagues her and Michelle condition. this behind mechanisms cellular the of one discovered January in Cell in published and Stanford of Ludwig Monje treatment. A cancer after long last can that brain the brain”, “chemo of afogging experience survivors of cancer half than More radiotherapy with cured be can that and oligometastasis named they that disease of metastatic stage intermediate an defining in Hellman Samuel member with former Ludwig Board in partnership work forhis known best is . Ralph contributions tooutstanding radiation have made who members on bestowed is the organization’s highest honor, October. in It Medal Gold Oncology forRadiation Society American 2018 the received Weichselbaum Ralph Co-director Chicago Ludwig FOG SOURCE FOR MELDING THERAPIES study led by Michelle by Michelle led 6 disrupted by chemotherapy. are that cells affected the between examining the precise signaling circuits now are colleagues her and Michelle myelin. and astrocytes in observed abnormalities the as well as brain chemo of symptoms cognitive of the many mice selectively depletes microglia reversed in that trials clinical in currently a drug astrocyte dysfunction. Administering in administration. That, turn,its causes after months six least for at microglia studies revealed, persistently activates their methotrexate, drug chemo The by chemotherapy. induced are that brain’s environment the in by changes caused is this that and plasticity, neural and homeostasis forboth important oligodendrocytes new to generate approaches to helping patients. new enabling are disease systemic in therapy of role radiation the and response his insights on the biology of the radiation that observed and amentor as kindness and Ralph’s noted dedication Society to therapy. The resistance confer tumors human in expression of gene patterns how explore and disease systemic widespread treat to better immunotherapy and focuses on combining radiation therapy His researchtherapies. today increasingly or other localized metastasis-directed

LUDWIG LINK | MARCH 2019 News roundup by a generating self-amplifying loop they found, drive immune dysfunction known as Catecholamines, macrophages. cells immune myeloid including cells, immune many and glands adrenal the by produced like adrenaline, hormones, levels of circulating catecholamines— the by CRS reducing from mice protect can heart, by the secreted a hormone (ANP), peptide natriuretic atrial that found researchers The occurs. it by which in reported colleagues and Verena Staedtke Vogelstein,Hopkins’ Bert Zhou, Shibin Johns cancer.treat by Ludwig led Ateam to used immunotherapies new several of acomplication and system immune life-threatening of hyperactivation the (CRS) a is syndrome release Cytokine Ludwig Johns Hopkins Shibin Zhou CRISIS RESPONSE Nature in December a novel mechanism anovel mechanism December in

Ludwig Johns Hopkins VogelsteinBert

impairing therapeutic responses. therapeutic impairing without CRS to controlling approach a rapidly implementable study suggests clinical use for the other indications, for approved already are metyrosine and ANP both CAR-T Because cells. and therapies T-cell activating bacteria, immunotherapies such as tumor-targeting by induced CRS the from mice protect could drugs same The mice. in mortality reduced and by infections induced release cytokine excessive prevented anti-hypertension metyrosine, drug withcatecholamines or ANP with the inhibited this circuit. Blocking catecholamines, forproducing necessary tyrosine hydroxylase,enzyme an enzyme of the Deletion macrophages. these in 7 Ludwig Johns Hopkins Verena Staedtke

LUDWIG LINK | MARCH 2019 DIVERSITY A MALIGNANT News roundup heterogeneity in drug resistance. drug in heterogeneity of cellular importance the underscore published in December in even revive ER findings, Their signaling. can that changes epigenetic via acquired is to KDM5 inhibitors resistance while populations, cell pre-existing for distinct to endocrine therapy arises from selection resistance that show researchers The cells. tumor by different expressed of genes ER signaling decreasing and the diversity tosensitivity anti-estrogens by modulating or inhibition of increases KDM5 activity cancer. breast Conversely, positive loss (ER)- receptor estrogen in prognoses patient worse with associated is and cells cancer of breast diversity phenotypic the increases oflevel KDM5B expression ahigh that found Michor Franziska and Polyak Kornelia Harvard’s by Ludwig led unclear. been Astudy long precisely, has cancer. why, breast in But therapies including resistance to endocrine resistance, drug with associated also They function. important are, however, this perform that enzymes express of genes family 4demethylase H3 lysine KDM5 histone The of cells. all phenotype, the molecular identity,establishing or to are central modifications epigenetic Such levels. what at and cell, agiven in forexpression available are genes which to control sites specific at chromosomes tag chemically enzymes Epigenetic

Cancer Cell,

Michal Bassani-Sternberg Kornelia Polyak Ludwig Harvard Franziska Michor Ludwig Harvard Ludwig Lausanne Ludwig 8

DEBATE DICE AND SPLICE peptides. spliced as considered be potentially to 2% 4%—could percentage—just small the original Science in used data of the own analysis their that reported of Bioinformatics Institute Swiss the from Müller Markus with collaboration in Bassani-Sternberg Michal Lausanne’s paper, December a In of others. by acouple contradicted then but study one by confirmed was finding That spliced. be might molecules I class by HLA presented peptides the Sciencein A2016 paper design. vaccine for cancer immunotherapy research, particularly in also therefore and immunology, in question important an is and debate of some asubject remains happens this body. commonly the How in protein any of those match don’t sequences peptide their that so proteasome, the spliced—by rearranged—or and cut are proteins by HLA presented peptides the cases, some in that, shown been has It HLA. or proteins called human antigens, leukocyte of by afamily done is presentation This against tumors and infectious agents. responses Tcell killer elicit antigens—that of proteins—peptide fragments small of repertoire alarge display Cells researchers led by Ludwig by Ludwig led researchers concluded that up to 30% up of that concluded Proteomics &Cellular Molecular study suggests only a

LUDWIG LINK | MARCH 2019 News roundup Ludwig Oxford Colin Goding by Alexander led scientists MSK Ludwig paper October an In they’re expressed. which in type cell by the determined is activity regulatory has, however, been unclear whether their It disorders. inflammatory and cancer impaired in many including diseases, is function or expression MicroRNA proteins. formaking instructions the messenger RNA transcripts that carry the degrading and binding specifically by so do They tissues. various body’s the differentiation that constantly replenishes cell stem the and control cell-cycle response, immune the in role acritical play and expression gene regulate MicroRNAs REGARDING MICROMANAGEMENT

in Nature Immunology in issue of the Proceedings of the issue of the National They melanoma. cancer skin the in role acentral plays and pigment-making their identity melanocytes (MITF)—which givesfactor the skin’s microphthalmia-associated transcription expression—the of gene regulator master fora accomplished is this how examined Goding Colin Oxford’s by Ludwig led team A research. of area intensive an TFs remains control of the to fine-tune integrated are signals multiple how But of genes. suites of select expression the direct can which so through transcription (TFs), factors do They expression. gene by influencing of stimuli to manner all responses cellular Biochemical signaling pathways induce SIGNALS INTELLIGENCESIGNALS , biomedical researchbiomedical community. to the use of considerable be should which cells, immune in networks 155 regulatory provides comprehensive maps of miR- also study The context. by cellular shaped indeed is expression of gene regulation showingthem, that this microRNA’s expressing is cell which on depending miR-155 by bound differentially are that targets mRNA many identified team The Bcells. Tand and cells dendritic in the immune system’s macrophages, mRNAs of cancers—targets avariety in implicated been has and immunity in role miR-155—whichnamed plays an important amicroRNA how explored Rudensky described in a September 9 drugs to treat melanoma. of development the and biology melanocyte have implications for our understanding of findings The genes. target away its from nucleus, the from MITF, expulsion its causing on code export nuclear unknown hitherto a one—exposes just phosphates—not both of addition The pathways. WNT and kinase which GSK3, named is inhibited by the PI3 by enzyme an one of another addition the for MITF primes activation BRAF/MAPK to to due MITF of aphosphate addition The activity. MITF to control integrated BRAF/MAP kinase-mediated pathway are the via dispatched those and pathways WNT and PI3 kinase the both through of Sciences Academy Ludwig MSK Alexander Rudensky how signals sent sent signals how

LUDWIG LINK | MARCH 2019 News roundup A VERSATILE STING was exacerbated by ionizing radiation. by ionizing exacerbated was increased , which and synthesis of DNA onset early the prompted of STING loss The division. 1(CDK1), toward cells kinase pushes which premature activation of cyclin-dependent to the led and proliferation their boosted cells cancer in depletion Its genome. of its toward division the maintains and integrity cell’s the progression regulates also STING cancer. in that show STING They Diana Ranoa reported additional roles for Co-director Ralph Weichselbaum and Research paper aNovember in But DNA. following radiotherapy, which damages especially that, to do seems certainly it compromising anti-tumor immunity—and by growth tumor promotes cells cancer in of STING loss the that supposed been long has It cells. cancerous and infected attack that Tcells instances, some in and, system a role the innate in activating immune production of interferon, which plays the body. STING signaling leads to the that comprise the frontline defenses of factors and cells response—the immune role up in the innate sparking important an plays that fragments of DNA sensor a is Genes) of INterferon (STimulator STING as known complex A protein , a team led by Ludwig Chicago Chicago by Ludwig led , ateam Cancer Cancer in Ralph Weichselbaum Ludwig Chicago Diana Ranoa Ludwig Chicago Ludwig Stanford Howard Chang 10

paper additionally reported in their October They gene. of that expression aberrant regulatory element that promotes the accessible anewly create can a gene away from of bases thousands sequences in mutations how show researchers The genes. of specific expression the regulate map of noncoding DNA sequences that asprawling to produce of cancer types in 410 tumor representing samples 23 genomes surveyed Greenleaf William University, Stanford and geneticist of Cancer Genomics at Stanford LudwigChang, Virginia and D.K. Professor multi-institutional study led by Howard to cancer. contribute A sequences these of the how genome—or mutations in for98% account sequences—which however, about these regions’ noncoding known, was Very little type. cell each read unique subsets of creating genes, to machinery that permits which of cells, types different in vary regions Accessible that protein reads genes. machinery to the accessible are of DNA stretches certain only aresult, As chromatin. as known structure into athreadlike wound around proteins and packaged tightly is acell’s nucleus within DNA The DNA can predispose people to cancer. people predispose can DNA variations in DNA sequence in noncoding also findings light shed on how inherited The evasion. immune tumor and cancer in role important an to play known genes and of DNA elements regulatory between of likely interactions of thousands tens NONCODING GENOME CANCER’S in Science in the identification of

LUDWIG LINK | MARCH 2019 News roundup precancerous tissue. precancerous that might prove the useful in identifying colon the and esophagus of Barrett’s cells of goblet precursors in found ITLN1, SPINK4and markers, two identified also not The study gastrointestinal immigrants. are and organ the within from arise they suggesting cells, gastric or intestinal with not but esophagus of walls the the in cells gland with profiles expression gene share esophagus Barrett’s in cells abnormal that the pathologists’ theory. They indicate Nature in Communications October normal esophagi. Their results and esophagus Barrett’s from biopsies patient multiple on sequencing RNA cell Oxford Director Xin Lu single- performed by Ludwig led of researchers a team humans, in apply might which determine To evidence. pathological on solely based is theory other the but models mouse by supported are of Four these theories. five competing currently are there and proved difficult itself—has esophagus the within arise or elsewhere from in travel they origins of these abnormal cells—whether cellular the Untangling intestine. or stomach the in found ordinarily are of which many of cells, types of other assortment a weird Furthermore, Barrett’s esophagus contains tract. digestive of the rest of the most known as columnar which epithelium, lines type by atissue replaced is this esophagus with epithelium in but Barrett’s squamous lined is esophagus normal The disease. reflux acid chronic with associated frequently condition aprecancerous is stomach, to the adjacent esophagus lower the in found often esophagus, Barrett’s SOURCING THE MISFITS , published in in , published , support , support Ludwig Oxford Xin Lu Xin

11 Ludwig Harvard Benjamin Izar Ludwig MIT Regev Aviv

already available. are drugs required the since trials, relatively quickly in examined clinical be could that possibility program—a resistance immune the repress partially could drugs, of cancer class existing that CDK4/6report an inhibitors, to immunotherapy. The researchers exposure upon up ramped was program anti-PD-1 revealed antibodies that the with treated cohort patient second of a Analysis patients. of melanoma PD-1 therapy in an independent cohort predicted clinical responses to anti- program of this detection that show The researcherscheckpoint inhibitors. of immune activity potential the reduce thereby and immunity, evade directly or tumor of the out T cells exclude may cells cancer by which The program captures mechanisms blockade. to checkpoint resistance predicts that program expression gene a identified they it, resisted who others who responded to immunotherapy and patients from obtained cells melanoma expressed of in thousands individual genes the Profiling others. not but responses in patients melanoma some checkpoint inhibitors produce durable why immune explored colleagues Cell in astudy In atime. at cell one melanoma MIT, on Ludwig taking are researchers at Ludwig and Harvard Aviv Regev, Izar and Benjamin OF RESISTANCE PROGRAMS in November, they and their

reported

LUDWIG LINK | MARCH 2019 News roundup paper October an In begins. process mitotic the before low at levels produced also MCC is signal, this to generate chance have the chromosomes the before exit Tocell. mitotic prevent apremature daughter to each for delivery positioned successfully been has chromosome every until division cell in steps later blocks that forme” signal a“wait as acts (MCC) that complex checkpoint amitotic assemble cells dividing process, this in errors cancer. in To compromised often prevent cells—a capability daughter of their to each equal complement of normal chromosomes an bequeath they divide, cells healthy When inactivation. of MCC pathways both blocking by simultaneously growth cell cancer inhibit to strategy of atherapeutic development enables discovery This MCC disrupted. is of the assembly the even when mitosis, of exiting incapable completely become cells hindered, are MCC disassembly to approaches both When end. to that synergistically act normally enzymes two the that and exit, mitotic MCC to permit separatelycan the cause disassembly of APC15, enzyme, distinct functionally alternative, an that showed also They exit. disassembly prior to appropriate mitotic of MCC its and assembly the for both required cancers—is many in overexpressed also paradoxically, is, that suppressor reported that the TRIP13—a enzyme tumor Cleveland Diego’s Don San by Ludwig led QUALITY CONTROL QUALITY in Nature in Communications , a team , ateam Ludwig San Diego Don Cleveland Ludwig Harvard Ludwig Harvard 12

Sida Liao

September in cancer.in results The resistance of drug causes the expose to method apowerful vets also It responsive cancers to inhibitors. BET midline carcinoma but perhaps other NUT only not to treating approach new animal models. The study suggests a inhibitors—halted tumor growth in inhibitors CDK4/6 and two drugs—BET versionsCombining pre-clinical of the inhibitors—are involved in resistance. of drugs—CDK4/6 class by another targeted pathways that out turned it Notably, inhibitors. to BET resistance in arole play pathways signaling and genes of classes six some that determined They carcinoma. midline NUT in identified had lab the that genes driver several to study tools editing gene used colleagues their and Liao Sida Elledge, Stephen investigators Harvard Ludwig of resistance, mechanisms these in Interested of ways. avariety in therapy the evolve to resist usually cells cancer but trials, clinical in currently are which inhibitors, (BET) domain extraterminal treatedbe with and bromodomain can Patients diagnosis. from months 7 than of less time survival a median year, with every aggressive, is it but US the in carcinoma midline NUT with diagnosed are people 100 Fewer than BETS OFF AGAIN BETS Genes & Development. &Development. Genes were published in in were published

LUDWIG LINK | MARCH 2019 News roundup also the signaling identified circuit through researchers The metastasis. its and tumor 3medulloblastoma Group primary of the growth the both regulates protein, surface NOTCH1, that found Cheshier acell and Mitra Samuel Suzana Siddhartha Kahn, researchers Stanford October,in Ludwig study cognitive In a physical and disabilities. lasting in result can that regimen grueling of a chemotherapy, doses high and by followed of radiation surgery, consists treatment current The tumors. such all 20% of forapproximately accounting of childhood, tumor brain malignant common most the is Medulloblastoma ONE SWITCH OPERATION Ludwig Stanford Suzana Kahn reported in Nature Communications

Ludwig Stanford Siddhartha Mitra

side effects and better outcomes. outcomes. better and effects side fewer in result will hope they treatment a NOTCH1 formedulloblastoma, therapy anti- to test trial aclinical developing currently are researchers The signaling. its NOTCH1 binds that blocks and antibody an using animals of lives the the extend and tumor of the metastasis the slow could team the tumors, medulloblastoma In mouse models implanted with human spine. to the to migrate inclined more and spot to their likely to stick cells—less stem the cells—particularly cancer malignant makes activation cancer, its that showing the in effects NOTCH1which its exerts 13 Ludwig Stanford Samuel Cheshier

LUDWIG LINK | MARCH 2019 News roundup Oxford’s Benjamin Schuster-Böckler Biology Genome signatures”. In a September “mutational so-called in resulting genome, the in of bases combinations distinct favor Manycarcinogens. of these processes chemical and light like UV of mutagens result the are mutations Other of DNA. errors made during normal replication through occur mutations Some disorders. other and cancer cause turn, in can, that sequences regulatory and to gene or A to G—introducing potential errors to A, mutate Ccan ways—for example, different several in mutate can bases These genes. T, encode G) that Cand (A, of bases four asequence contains DNA Ludwig Oxford Benjamin Schuster-Böckler SIGNATURE ANALYSIS , a team led by Ludwig by Ludwig led , ateam

paper Ludwig Oxford Kriaucionis Skirmantas in in in the development of esophageal cancer. of esophageal development the in akey plays role strand DNA replicating the into incorporated are that of bases pool to the damage oxidative that example, for evidence, discovered They types. cancer certain underlying mechanisms of the reveals novel aspects also analysis The not. or of carcinogens product the genome, regardless of whether they’re the across signatures mutational all nearly of distribution the influences replication DNA that found They replication. DNA of asymmetry and timing to the regard of cancer—with 19 types in 3,056 patients analysis of mutational signatures—from and Skirmantas Kriaucionis reported its

14

LUDWIG LINK | MARCH 2019 Clinical trials Ludwig Stanford Ravi Majeti Ludwig Stanford Weissman Irv

STIMULUS PACKAGE STIMULUS New England Journal of Medicine. Journal England New results The remission. into complete went third one- about therapy, to the and response apositive had trial the in enrolled people 22 of study. the into the Half to entry prior to rituximab 21/22 were refractory and relapse were in cancer. patients All aslow-growing lymphoma, follicular of NHL—and type common most the lymphoma— B-cell large diffuse of NHL: types of two one had trial the in enrolled Patients rituximab. called antibody a commercially available anti-cancer and Ravi and by Irv developed was that antibody, Hu5F9-G4, experimental an therapy evaluated in the trial combined The US. the in deaths cancer-related seventh the is originates in the lymphoid system and NHL of Directors. Board its on serve and Inc. Seven Forty co-founded who Stanford’s Weissman Irv and Ravi Majeti, by Ludwig led originally program the licensed that startup abiotech Inc., Seven by Forty sponsored trial clinical multicenter of aphase-1b results to the Hodgkin’s lymphoma (NHL), according non- cancer blood the with patients in foruse safe appears macrophages, ingestion by the immune system’s to escape exploit cells cancer that CD47 receptor, me” signal a“don’t eat A novel immunotherapy targeting the were published in November in most common cause of cause common most 15 The The

LUDWIG LINK | MARCH 2019 Special event Special exactly these wholesome habits habits wholesome these exactly how But of illness. odds the reduce can alcohol on back cutting and that exercising, pounds shedding know generally people and world, onimpact cancer in the western smoking have had considerable Policies diet. poor to discourage use, and physical inactivity, obesity alcohol and like tobacco factors preventable from to stem thought are US the in deaths cancer-related of half roughly and diagnoses cancer 40% of Some reason. good With to cancer. comes it when certainly recommended prevention over cure, business, but doctors have long for thing best the be not may It REIMAGINING DIETARY PREVENTION CANCER in early December. The meeting Nutrition Conference in London convened a Cancer Prevention and 2015— in prevention cancer launched a program in dietary Foundation—with which Ludwig Hilton N. Conrad the and Research Cancer (CRUK), Ludwig Cancer Researchquestions, UK aWith shared interest in these case. each in for whom and doesn’t, cancer prevention—what works, what and diet on to dispense advice validated scientifically consistent, to offer by way specific, of little have very rate, any at Doctors, deter remains cancer largely unclear. 16 collaborative research environment to enable a further vigorous is goal Our cancers. of deadly development and progression to prevent the utilized better be of how nutritional choices can limitations in our understanding biology, public and health to discuss in epidemiology,scientists cancer brought together distinguished interactive meeting very “This and policymakers. information to medical professionals to providing precise and actionable eye an with prevention, cancer and diet between links causal identifying to approaches best the on focused

LUDWIG LINK | MARCH 2019 Special event Special presented studies or overviews of overviews or studies presented sessions of these each in Speakers associated policies would play out. and prevention cancer dietary which in world real of the environment food the and recurrence; cancer preventing cancer; and diet development; the genome, the interplay of diet and human links;mechanisms and causal clinicaland to studies pin down of laboratory, epidemiological studies; the linking epidemiological we’ve learned from ongoing conference covered what sessionsSequential of the CRUK. and behavioral research at funding head of population, prevention this,”enable Reddington, Fiona said to Foundation Hilton N. Conrad the and Research Cancer Ludwig with our colleagues at partnering to be We delighted are space. this in proposals to keen encourage are we and CRUK, at Strategy Research of our pillars four of the one forms inthinking this area. Prevention catalyze we hope, and, networks conversations, broaden collaborative new to spark opportunity exciting an provides that and space shared interests in the nutrition diverse grouping of with scientists a such together to bring rare is “It scientific director. Strausberg, Bob Ludwigsaid deputy healthy,” to people keep advances scientificto achieve impactful on exercise and cancer prevention. cancer and exercise on year— fornext planning are Ludwig and CRUK meeting up: Ajoint Next research community. with the and policymakers broader proceedings and recommendations its to share best how on options considering are CRUK and Ludwig and about alot to think with theAttendees left conference way forward. best the about concerns and insights suggestions, their to got share audience the discussionopen-floor in which an and sessions ofof the each by day asummary second the on were followed discussions panel and their research. The presentations 17 Ludwig Institute Bob Strausberg healthy.” advances to keep people scientific impactful environment to achieve collaborative research vigorous a enable goal“Our is to further

LUDWIG LINK | MARCH 2019 Q&A A pioneerofcancergeneticsandchampiontranslationalresearch LUDWIG HOPKINS JOHNS CO-DIRECTOR BERT VOGELSTEINBERT

18 Science is about reality and understanding understanding and reality about is Science by this? you mean did What writer.” fiction like ascience think should “YouYou’ve saying, as quoted been bombs. time ticking asense, in all, cancer. one we’re So have least at would of us most of years, 300 we age live to an older. we get as If dramatically increases low, it but very fortunately is of cancer incidence the wehow children, For live. to, or we exposed are what matter no mutations, more making always are they so life our throughout dividing are cells our that sense the in cancer. inexorable It’s of development to the contribute can that gene gene—a adriver in occur will one mutations are occasionally, harmless but, occur. those mutations of Most new five approximately divides, acell time Every random errors during normal cell division. is cancers, many in mutations of the most causes factor, actually A third that one unknown. are mechanisms the but cancer correlation with the development of strong avery has Obesity disease. the drive that mutations the in result factors These radiation. or smoke cigarette as such exposures environmental and heredity are were recognized twothat first diseases with many The possible origins. of group acomplex cancer—it’s causes factor single No of stochasticity. question a just It’s will. we all enough, If we live long Why don’t haveWhy we all cancer?

LUDWIG LINK | MARCH 2019 Q&A the genetic basis of cancer, basis I’m optimistic genetic the about much so we understand that Now curable. still are they possible—while is them early enough so that intervention treating and them rather detecting but not entail preventing their occurrence occurring. prevention Secondary does ever from cancers preventing case our in ever occurring—and from disease preventionPrimary is preventing the of prevention. atype is detection Early change the tide of cancer research? Why do you think early detection will that are working worth towards. scientists—those are the of kinds things other of most radar the even on not and unanticipated were totally that discoveries make scientists Occasionally from. come advances real the where that’s but viable, are that like this projects to choose wisdom and of judgment amount good a now. from requires It decades several possible be might what about to think But two. or year next even the or month next the or now done be can what about to not think them counsel Iwould writers. fiction like science think should and can careers science of their years formative the like. in are Young who be might people future the what on focus but now do can we to what limited not are and reality on the other hand, are not tethered to Scienceand understand. fiction writers, we know that technology the on based future near the in feasible seems what at now. We done be look can reality—what to tethered very are me, including Scientists, right. it get not will usually they future, the to predict scientist a If you ask we live in. universe the

to early detection and prevention. Think Think prevention. and detection to early directed 40%to to see 50% efforts of our I’d like cancers—but prevent all never will we critically important—because certainly are efforts Such disease. metastatic fight to drugs developing efforts of our amount Yes. inordinate an now, Right we spend industry? underappreciated by the pharmaceutical early detection and prevention are of concepts these you think Do early detection. and prevention on energy intellectual and resources of our more spend and efforts our cancer, toin readjust need interested of those we, acommunity as that think Ialso But to come. years the in detection early in we’ll make progress might possible be several from decades now. even year the next or two. But to think about what about what done be can now or month the next or fiction writers. I would counsel them not to think science careers and can should think like science Young people who are in the formative years of their

19

LUDWIG LINK | MARCH 2019 Q&A or new ways of prevention. The sooner we sooner The of ways prevention. new or detection for earlier tests new developing new therapeutics than there are for economic incentives for developing from ever occurring. there And are more to is prevent acancer it than remission into cancer advanced an with apatient put to why. dramatic reasons more much It’s alot are of There cancers. curing on been has focus our and proactive than rather reactive more generally are societies longer. be will All of treatment duration later. much the And detected those on than earlier detected cancers those on better work will produces industry then whatever drugs the pharmaceutical earlier, detected are it—if cancers about 20 a late Friday afternoon. We did the usual usual We the did Friday afternoon. a late on clinic into the came she when clearly very Iinternship remember in pediatrics. my doing I was when to me assigned patients first of the one was girl little That cancer? on career research particular girl drive you to focus your diagnosed with leukemia. Why did that with a four-year-old daughter who you internship you encountered a family There’s a famous story that during your occur. will area this in advances more sooner the mortality, and therapy for reducing cancer morbidity than important more, not if least, at is come to the realization that prevention

LUDWIG LINK | MARCH 2019 Q&A our research building and it’s still filled filled still it’s and building research our from street the across right hospital the at look I because satisfied not still I’m But less. have accomplished would Iprobably accomplished, I’ve what with If Iwere satisfied more. to accomplish me drives Which much. so accomplished I’ve thinking not is of my secret Part much? so to accomplishing secret your is What things. many,and other many digital PCR that enabledliquid biopsies invented of transciptomes, concept the created cancers, colorectal most underlie APC in mutations that found suppressor. YourP53 atumor was group thatdiscover Your to first the was group Your scientific discoveries are legendary. disease. the to understand we needed then it, get die from the disease or perhaps not even wouldn’t like his girls little that so future, the in like this cases treat to prevent or of able If were. we were to it ever be idea what the molecular underpinnings We no had people. attacked and space outer from came that beast strange some cancer. like about was It nothing we knew 1974 in was This my on. life to spend and wouldthis question a be valuable thing moment, it seemed to me that answering Atthat all. at question his answer not girl to have disease? this horrible I could wife his little that caused do anything his or he did was, to know wanted really he answer. what no I had that, only Not tothis happen girl?” my little beautiful did “Why me, asked He my age. about and amathematician was father Her smear. blood her from leukemia had she that obvious was it and studies diagnostic

with less risk, that is more certain. As a As certain. more is that risk, less with else,do something easier, something go then fire, on world the towant set don’t If fire. on you world the to set you want because school graduate in you’re that is them Itell things of the to incoming graduate students, one Ispeak When publish. and grants to get pressures of the all because and easier is evolutionary and that’s it’s because today of research majority vast The step. obvious next very the simply is Evolutionaryup new research vistas. for revolutionary research that opens Don’t do evolutionary research; try lab? your want to join who scientists you give to young advice some is What goal. to that closer us get that things new to do We’re trying street. continually the across hospital that out emptying discoveries.making important It’s about and papers publishing just not is goal to do Our something end important. trying than important less it’s but bad, is credit that Not credit. the about Ken care (Kinzler) Ireally nor partner CREDIT. my THE research GETS Neither WHO CARE DOESN’T SHE OR HE IF ACCOMPLISH CAN APERSON MUCH HOW AMAZING IT’S reads that wall my on up asign had always I’ve that is work hard. The third extremely thing who scientists creative ofup careful, made been always has trainees, the thing is that my group, and particularly second The disease. adifferent with wouldbuilding devoted be to patients have done that much. If I had, then that Icouldn’t so patients, cancer with up 21

area will occur. will area this in advances sooner more mortality, the morbidity and reducing cancer therapy for than important least, if not more, prevention is at that realization come to the The sooner we

LUDWIG LINK | MARCH 2019 Q&A and how to treat it better. think about how to prevent it better know enough so that we begin can to is astill huge amount to learn but we progress in the years to come. There I’m optimistic we’ll make continued about the genetic basis of cancer, ... now that we understand so much even in the next decade but now that we that now but decade next the even in not maybe or year next won’t come Nowit effective. likely to be more is that means treatmentan earlier stage at acancer earlier. spotting them And to to ways detect lead can tumors fueling about the genetic faults understanding Adeeper it. about something to do you’ll able be disease, the understand you once that shows Yes. Medicine cancers? life-threatening prevent to able be we will biology—that of cancer future the about optimistic you generally Are where no one has ever gone before”. scientist, you have go “to the opportunity 22

devoted to those goals. todevoted those are my all efforts older, virtually getting Iam that Now cancers. in alterations novel basedon the therapeutics genetic developing and prevention in basically are fromme reaching my which main goals, publication but they probably distracted of by metrics were productive that of research areas some in engaged I’ve know I one. adifferent to try tempted day, today. next one you’re The that try me let good, looks one that to say easier it’s that from choose to flavors wonderful by many so surrounded shop you’re candy the in kid often, like that So two. or decade next over the accomplish you can thing one the on to focus hard very be can It my time. way to spend best the necessarily weren’t they but Nature in were published they that extent to the were successful we’ve done were and they important could of accomplish. Some the things things I consider the most important I what on more have focused would differently—I have done of Iwould what terms In Your limited. is goals. your time to reach left time of amount infinite have an you don’t and you’re mortal you realize that 60s, your you reach As your career, what would that be? If you were to change anything about optimistic. extremely I am run, long better. it tohow the treat in So, and to better how prevent it about think to begin we can that so enough we know but to learn amount huge astill is There to come. years the in progress continued of we’ll cancer,basis make I’m optimistic so much about the geneticunderstand or Science or

,

LUDWIG LINK | MARCH 2019 Ask ascientistAsk cancer researchcancer care? and intelligence How willrevolutionize artificial Ludwig Harvard institutions. multiple to incentivize aggregation of data from barriers—we will creative need approaches institutional will be now bottleneck The models. the to “train” of data a great deal is there is that around time this powerful have recently. improved makes it what But algorithms machine-learning that It is true Hopkins Johns Ludwig follies. the avoiding and faced with defining the true opportunities we will be tool, any new with equipped questions addressed with scientists As it. and data supplied asthe asgood be only will successes its and intelligence true not However, fields. is AI scientific and medical for the potential similar has and activities everyday many revolutionized already has AI PETER J.PETER PARK KINZLER KEN

23

LUDWIG LINK | MARCH 2019 Ask ascientistAsk Ludwig Harvard available. becomes data reproducible and quality high asmore disciplines research across patterns accuracy, and discovering complicated options by increasing automation, prognosis treatment and prognosis in assist greatly will This patterns. discovering at proficient is extremely that tool is apowerful AI Ludwig Lausanne personalized therapies. to guide data clinical and molecular designing AI strategies bringing together we are actively Lausanne, In started. already has transition this convinced am I when. but care, and research cancer of akey will be AI component whether breakthroughs, the question is no longer AI concurrent the and tumors interrogate multidimensional techniques to in advances recent the With NATHAN T. JOHNSON OLIVIER MICHIELIN

24

LUDWIG LINK | MARCH 2019 Required reading Elledge SJ. Elledge K, O, Cichowski Maertens S, Liao CDK4/6is. and BETis between uncovers a synergism of NUT midline carcinoma dependency BRD4-NUT the of modifiers Genetic September 1 2018 &Development Genes K. Polyak F, Michor AA, Gimelbrant R, P,Jeselsohn JD, Jaffe Sicinski A, Meissner M, Brown N, Wagle A, Simeonov A, Jadhav DJ, Maloney G, Rai M, Lal-Nag SC, Kales O, Cohen G, Peluffo L, Ding M, Papanastasiou SB, Egri A, T, Fassl Madsen KN, Yamamoto KJ, TO, Igarashi McDonald S, Vigneau HJ, Wu K, Hinohara to therapeutic resistance. transcriptomic heterogeneity linksactivity cellular KDM5 histone demethylase December 10 Cancer Cell 2018 Ludwig Harvard Weichselbaum RR. NN, Khodarev GL, Moldovan SJ, Kron R, Parry A, Arina MJ, Bolt X, Huang CM, Nicolae AD, Parekh S, Mallon RC, Widau DRE, Ranoa chromosomal stability. of cell proliferation and viahomeostasis regulation promotes STING [Epub ahead of print] 27 2018 November Cancer Research Ludwig Chicago

NL, Luther SA, Petrova TV. Petrova SA, Luther NL, C, Jeon F, C, Kiefer Betsholtz Halin C, Olsson AH, Willrodt K, Son S, Kim B, Prat-Luri A, Sabine E, Bovay node development. vessels in peripheral lymph Multiple roles of lymphatic Medicine 2018 November 5 Experimental of Journal M. Sternberg Bassani- M, Müller I, Xenarios G, D, Coukos Gfeller HS, C, Pak C, Chong Iseli I, Beer R, Mylonas ligandome. the HLA-I proteasomal spliced peptides to Estimating the contribution of 1 2018 December Molecular & Cellular Proteomics Lausanne Ludwig Vogelstein B, Zhou S. PB, Papadopoulos N, Kinzler KW, Rothman GJ, Riggins ML, Davila M, Darvas K, RY, V, Kim Bai Staedtke cytokine release syndrome. catecholamine loop reduces Disruption of a self-amplifying Nature 2018 December Ludwig Johns Hopkins A. Regev B, Izar Yoon CH, LA, O, Garraway Rozenblatt-Rosen A, Rotem BE, D, Johnson Schadendorf Wucherpfennig Van K, EM, Allen PK, Sorger I, Tirosh AK, Shalek DA, Barbie MA, C, Forget Bernatchez P, Hwu S, Malu AM, Luoma ANR, Cartwright B, Schilling I, Cañadas Thummalapalli R, Kowalczyk MS, RW, Jenkins M, Herlyn KT, Flaherty T, Moll B, DT, Miao Frederick RJ, Sullivan GM, Boland FS, Hodi R, Haq EI, Buchbinder PA, O, Ott Zhang G, Margolais C, Ashenberg D, Liu B, Rabasha S, Wang JR, Lin S, Mei A, Kanodia R, Leeson JC, Melms MJ, C, Su Rodman MS, P, Shah Cuoco L, Jerby-Arnon to checkpoint blockade. T cell exclusion and resistance A cancer cell program promotes 1 2018Cell November 25 LA, Yoon CH, Izar B, Regev A. Regev B, Izar Yoon CH, LA, O, Garraway Rozenblatt-Rosen A, Rotem BE, D, Johnson Schadendorf Wucherpfennig Van K, EM, Allen PK, Sorger I, Tirosh AK, Shalek DA, Barbie MA, C, Forget Bernatchez P, Hwu S, Malu AM, Luoma ANR, Cartwright B, Schilling I, Cañadas Thummalapalli R, Kowalczyk MS, RW, Jenkins M, Herlyn KT, Flaherty T, Moll B, DT, Miao Frederick RJ, Sullivan GM, Boland FS, Hodi R, Haq EI, Buchbinder PA, O, Ott Zhang G, Margolais C, Ashenberg D, Liu B, Rabasha S, Wang JR, Lin S, Mei A, Kanodia R, Leeson JC, Melms MJ, C, Su Rodman MS, P, Shah Cuoco L, Jerby-Arnon to checkpoint blockade. T cell exclusion and resistance A cancer cell program promotes 1 2018Cell November MIT Ludwig Schuster-Böckler B, X. Lu Schuster-Böckler CP, Ponting MR, D, Middleton P, Buck Piazza A, Green ND, C, Maynard Ruiz-Puig LM, Wang R, Goldin A, Bailey B, DT, Braden Severson MJ, RP,Owen White submucosal glands. oesophagus and oesophageal similarity between Barrett’s profound transcriptional revealsSingle cell RNA-seq October 15 Nature Communications 2018 Oxford Ludwig AY. Rudensky CS, JP, Leslie Y, GB, Hsin Lu Loeb cell types. regulation in four major immune on miR-155-mediated gene The effect of cellular context October Nature Immunology 2018 MSK Ludwig Schuster-Böckler B. Schuster-Böckler S, Tomek J,Kriaucionis M, Tomkova timing and strand asymmetry. varies with DNA replication Mutational signature distribution September 10 2018 Biology Genome CR. Goding EE, Patton KLB, Borden E, Steingrímsson Filippakopoulos P, H, Knowles S, Knapp R, Lisle R, Fischer S, Picaud G, Berridge H, Brunsdon L, Volpon S, Andrews Z, Zeng L, Li HJ, KC, Friedrichsen Ngeow nuclear export. converges to control MITF signaling GSK3 and BRAF/MAPK September 11 2018 USA Sciences of Academy Proceedings of the National Liddelow S, Vogel H, Monje M. Monje H, Vogel S, Liddelow BA, PJ, Woo Barres L, Ni AK, Goldstein AC, Geraghty JJ, Greene PN, Tam LT, Pallegar A, LS, Wood Gibson EM, Nagaraja S, Ocampo impairment. chemotherapy-related cognitive dysregulation that underlies induces persistent tri-glial Methotrexate chemotherapy 10 2019Cell January Stanford Ludwig KD, Cleveland DW. Corbett K, Myung MA, McMahon Ly P, JS, Han Ye DH, Q, Kim produced MCC. and unattached kinetochore- interphase- of turnover by exit mitotic APC15 drive and TRIP13 October 19 Nature Communications 2018 SanLudwig Diego

LUDWIG LINK | MARCH 2019 Required reading Greenleaf WJ, Chang HY. Genome Atlas Network, Analysis C; Cancer Curtis PW, Laird JC, BP,Berman LM,Zenklusen Staudt MAA, Castro I, Felau NC, Sheffield AG, Robertson KA, Hoadley MR, AT, Mumbach SW, Satpathy Cho CK, C, Wong TC, Groeneveld Silva W, Zhou JA, Seoane BH, Louie S, Corces MR, Granja JM, Shams cancers. landscape of primary human The chromatin accessibility Science 2018 October 26 SM. MP,Chao Smith CH, Takimoto IL, Weissman R, Majeti J, Huang B, JP,JY, Agoram Volkmer GP, T, Tran J,Chen Collins Lynn A, LaCasce M, J,Roschewski Kline N, Ghosh NL, Bartlett A, Forero L, Popplewell I, Flinn R, Advani lymphoma. and Rituximab in non-Hodgkin’s Hu5F9-G4 by CD47 blockade Medicine 2018 November 1 of Journal England New Mitra SS,Mitra Cheshier SH. IL, Weissman YJ, MD, J, Cho Taylor Reimand RJ, Wechsler-Reya G, Li D, FJ, Sahoo Swartling M, Edwards Ramaswamy V, R, Esparza Liu KW, S, Bolin L, Wadi TD, Azad G, J,Hutter Theruvath S, Gholamin RT, Nitta X, Wang SA, Kahn of Group 3 medulloblastoma. self-renewal and metastasis of Notch1 regulates the initiation October 8 Nature Communications 2018 26

LUDWIG LINK | MARCH 2019 Page 11: Aviv Regev by Casey Atkins Casey by Regev Aviv 11: Page Institute Koch courtesy Vise, Samara by Amon Angelika 4: Page Photo credits 27

LUDWIG LINK | MARCH 2019 LUDWIGCANCERRESEARCH.ORG