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LUDWIG LINK | NOVEMBER 2019 LETTER Vice President for Communications President Vice Rachel Reinhardt Happy holidays! 21. page on said they what out Find results. reliable to more leads science decentralizing whether people Ludwig some asked we section, aScientist Ask our In treatment of and a number of other diseases. for transplantation the bone marrow that transform could a potential in blood-forming culturing breakthrough stem cells and attack; macrophage off to ward cells cancer by exploited signal” “don’t-eat-me anew of discovery the hour; the within color change— test results—via for that furnishes colon tumors urine ananotech of development preclinical the about read You’ll Branches. and Centers Ludwig’s across done being work fine the always, as illustrate, issue this in briefs research Our Institute. the from retiring soon is he if even to stopping, close even isn’t biology—and cancer in discoveries landmark afew than more made has who Institute the of member three-decade and scientist a scientist’s Web Cavenee, with is 15) (page around time this Q&A Our report). Highlights Ludwig 2019 the in Peter of profile our in (and section distinctions and Awards the in it about more alittle read You can oxygen. of availability to the respond and sense cells mammalian how of discovery their for recognized were co-recipients his and Peter University. Hopkins Johns of Semenza Gregg and Institute Cancer Dana-Farber the

in October with William Kaelin of of Kaelin William with October in Medicine or Physiology for Prize Nobel 2019 the shared who Ratcliffe, Peter Oxford’s Ludwig for more and that all been certainly has It spirit. that captures Link Ludwig of issue this find you’ll think we you, for year awhirlwind of abit been it’s If 3 LUDWIG LINK ludwigcancerresearch.org Peter Ratcliffe of Ludwig Oxford Ludwig of Ratcliffe Peter cover: the On embrane matters embrane roundup News ew Ludwig member Board move the on People research pioneering or distinctions and Awards TABLE OF CONTENTS Required reading ascientist Ask Web with Cavenee Q&A rossing guards CIRI ecessary cyst assessment acharm hree’s ncient sensor numbers in ower please? pretty me, eat on’t vulnerability n inherent eing selective maps RE-ating at target resistance orrowed For modeling possibility For modeling discovery For transformative laureate Nobel Our Small is gold is Small M N F C A n A T A P D A B C F B

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LUDWIG LINK | NOVEMBER 2019 Awards distinctions and controlled remained a mystery. Peter and his his and Peter amystery. remained controlled were they how (HIFs), though factors inducible hypoxia- as known proteins by governed to be lab Semenza’s Gregg by reported was starvation oxygen by driven expression gene The sensor. oxygen acellular to identify labs their of each in on built sequentially discoveries made winners co- two his and Peter to cancer. wound-healing to disease heart from ranging disorders and processes biological of understanding our on influence aprofound had have 2000s, early and 1990s the through independently made were which discoveries, Their University. Hopkins Johns of Semenza Gregg and Institute Cancer Dana-Farber the of Kaelin William Peter shared the prize with U.S. researchers oxygen. of availability to the respond and sense cells mammalian which by mechanisms the on discoveries landmark his for Committee Nobel the by recognized was October. He in Medicine or Physiology for Prize Nobel 2019 the received Ratcliffe Peter Sir Oxford’s Ludwig laureate Nobel Our Congratulations, Peter!Congratulations, report. Highlights 2019 Research the Ludwig in profile this see career, research his and Ratcliffe Peter on For more 12). (see page plants by shared is it that origins evolutionary its in ancient so sensor—one oxygen cellular Science in reported colleagues his and he summer, this Just metastasis. and resistance to drug significantly to contribute known is tumors solid of core the at starvation oxygen cancer: notably most processes, biological of a variety in signaling hypoxic of regulation genetic and biology molecular the out fleshed years the over has he and animals, all in found been since has Peter system discovered the oxygen-sensing of variation Some colleagues. his and Kaelin William by made simultaneously were findings Those to HIF activity. oxygen molecular of availability the link directly enzymes of a set which by mechanism elegant the described and occurs control that how discovered team 5 their discovery of an entirely novel novel entirely an of discovery their

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DISCOVERY FOR TRANSFORMATIVE Bert clearly fit that bill. that fit clearly Bert and Irv Both medicine.” regenerative for and cancer of treatment and detection for methodologies new of development to the understanding of cancer and contributed our transformed “have who to those given is Prize Albany $500,000 The co-founded. he acompany by therapy cancer new exciting an of evaluation clinical ongoing to the led also 11)—has (see page all in three discovered now has system—he immune to the cells cancer by transmitted signals “don’t-eat-me” of discovery recent more His leukemia. drive cells those in humans and described how mutations and mice in cells stem blood-forming first the isolated biology, cell stem of field the in a pioneer Irv, colleagues. Hopkins Johns Ludwig his with partnership in established Bert one including cancer, for biopsies liquid to develop racing now companies with diagnostics, in a revolution spawned genomes cancer mapping work subsequent His detection. cancer colon for kit at-home first the of development to the led and research cancer of aparadigm is , drives genes tumor and suppressor oncogenes proto- of mutation sequential the how described he which in cancer, colon on colorectal tumors. His research early on work his through research cancer transformed Bert genetics, cancer in Apioneer Prize. Albany prestigious the received Weissman Irv Director Stanford Ludwig and Vogelstein Bert Ludwig Johns Hopkins Co-director

LUDWIG LINK | NOVEMBER 2019 Awards distinctions and People on the move Ludwig Institute Ludwig Alexandra Johnson Diego San Ludwig Beata Mierzwa

Arbitration. She has served as counsel counsel as served has She Arbitration. of Court Institution Arbitration Chambers’ Swiss the of amember is and ArbitralWomen of Directors of Board the on serves Alexandra Geneva, in law. Based arbitration international in experience of years 17 has and & Karrer Bär firm law Swiss the at apartner is She Research. Cancer for Institute Ludwig the of Directors of Board to the September in appointed was Johnson Alexandra LUDWIG BOARDNEW MEMBER various media platforms, including through and person in students with connect will designer), and illustrator scientific agifted (and lab Oegema’s Karen in researcher a postdoctoral Beata, capacity, this In Ambassador. IF/THEN AAAS an as (STEM) selected mathematics and engineering technology, science, in women 125 of one is Mierzwa Beata Diego’s San Ludwig POSSIBILITY MODELING FOR 7 summit in Dallas. a in participate will Ambassadors the theirimproving visibility. In October, requires which STEM, in women about thinks world the way the to shift aspires ofinitiative Lyda Hill Philanthropies, anational IF/THEN, girls. school middle- for model arole as serve and shows, YouTube television network and which she attended as a Fulbright Scholar. aFulbright as attended she which School, Law Harvard from degree LLM an and Switzerland, Neuchâtel, of University the from degree law her earned Alexandra arbitration. to international related matters on writes and speaks regularly and arbitrator an as sits frequently also She disputes. sports-related even and toagreements acquisitions and mergers venture joint international from ranging matters on proceedings arbitration in

LUDWIG LINK | NOVEMBER 2019 News roundup News Ludwig Ludwig Ralph Weichselbaum Diego San Ludwig Paul Mischel

some characteristics of tissue resident T resident tissue of characteristics some with Tcells of proportion alarge that found colleagues his and Ralph believed. was than resilient more be might tumors Communications paper a September in reported Weichselbaum Ralph Chicago’s Ludwig by led Ateam cancer. of treatment the for immunotherapy with combination its examining trials in radiotherapy of use the in factor alimiting been long that response. This supposition has to essential are which Tcells, kill also to thought been long has it But them. activating an immune response against by part in tumors damages Radiation RESISTANCEBORROWED genetic growth-promoting and metabolic to its structure membrane cell’s cancer the in changes hallmark links LPCAT1, membranes, cell building in involved enzyme an how described Mischel Paul researchers led by Ludwig Diego’s San September a In therapy. cancer for exploited be may that dependencies them in proliferation. This induces constant their to fuel metabolites and nutrients of use and production uptake, their to reprogram forced also are cells cancer mutations, genetic by driven While MATTERS MEMBRANE paper that T cells within within Tcells that Cell Metabolism Cell in 8 Nature Nature in , TGF factor the by part in regulated to be found they acapability radiation, resist to microenvironment tumor the by cells are genetically reprogrammed T that indicated analysis Their cells. T infiltrating of infusion anew from support without tumors attack can and tumors unirradiated from Tcells than activated more are but radiotherapy, survive only not tumors irradiated in cells immunotherapy. and radio- of trials combination in results overall improve could tumors multiple of irradiation focal that suggest findings The immunosuppressive. be survival timessurvival improved. and dramatically shrank tumors cancer, lung and cancer brain aggressive the including cancer, of types depleted in mouse models of multiple genetically was LPCAT1 When enzyme. the on dependent notably are sort this of signaling. factor growth dysregulated by driven cells cancer in of proliferativetransmission signals the boosts that away in membrane cell external the of composition chemical the tweaks subtly LPCAT1 that discovered colleagues his and Paul alterations. β , which is generally thought to thought generally is , which

LUDWIG LINK | NOVEMBER 2019 CRE-ATING MAPS CRE-ATING TARGET FAT News roundup News 18,943 gene promoters in 27 human human 27 in promoters gene 18,943 inDNA its protein packaging—involving for term chromatin—the of interactions long-range the mapping by picture that to clarify sought Ren Bing Diego’s San Ludwig by led Ateam hazy. relatively remained has regulates them of each genes, or gene, which genome, human the (CREs) across elements regulatory Cis- these of thousands of hundreds identified have researchers far. While and near genes of expression the controlling by biology in role important a critically play that sequences DNA of stretches The genome is littered with small then and expression the boosting by so does It lipids. complex of construction to the molecules precursor of generation the from synthesis, lipid of stage every gene expression required for almost the controls found, they MYC, therapy. for exploited be might dependency this and lipids, other and fats making for machinery cell’s the on dependent highly paper a September theSuch cancers, researchers reported in MYC. as known gene cancer a common by driven are that tumors in vulnerability a novel uncovered University Stanford at colleagues his and Dang Van Chi Director Scientific Ludwig by led A study Cell Metabolism Cell in , are , are Nature Genetics Nature in September in published was work The diseases. and traits human of groups distinct underlying pathways molecular common many on CREs of influence the revealed maps these of analysis An 2,117 physiological traits and diseases. variant CRE sequences associated with 27,325 identified and elements regulatory candidate 70,329 of genes target the to infer information this used colleagues his and Bing begin.) should agene of sequences that where mark the reading DNA are (Promoters types. cell/tissue MYC. activate indirectly they if production acid fatty of inhibition to the susceptible are oncogenes other by driven tumors even that show University Stanford at colleagues his and Chi and cancers human in gene amplified most third the is MYC regression. to tumor led process that of step early an Inhibiting synthesis. acid fatty on dependent highly are liver and kidneys lungs, blood, the of cancers that models of MYC-induced tumors, showed mouse using and, cancers MYC-driven with associated signature lipid a identified also researchers The production. lipid controls that expression gene of regulator SREBP1—a of activity the up ramping 9 . Ludwig Institute Ludwig Dang Van Chi Ludwig San Diego San Ludwig Ren Bing

LUDWIG LINK | NOVEMBER 2019 News roundup News Ludwig Oxford Xin Lu Ludwig MIT Bhatia Sangeeta

generation sequencing, the researchers next Using genes. target of selection ’s influences p53, of inhibitor an iASPP, which by amechanism reported team her and Lu Xin Director Oxford , Ludwig ofSciences Academy National August an In understood. incompletely is it yet balance, life-or-death cellular the underpins context aspecific in p53 by controlled are genes which of Modulation cancers. human in protein mutated frequently most the also is It metabolism. to to suicide arrest growth from processes, cellular myriad in involved is that expression gene of regulator master a is p53 protein suppressor tumor The BEING SELECTIVE so MMP9, of levels high express tumors Colon MMP9. as known enzyme an by snipped specifically is that protein of strip another using protein carrier to alarge AuNCs these linked then They urine. via cleared be and systems filtration kidneys’ the through slip tumors, in accumulate to enough small are that AuNCs) (a.k.a. technology around gold nanoclusters their built colleagues her and She urine. in change acolor through hour an under in report its makes and used inexpensively and easily be can that diseases other possibly and cancer for test diagnostic colleagues have developed a prototype her and Bhatia Sangeeta MIT’s Ludwig SMALL IS GOLD paper Proceedings of the ofthe Proceedings the in 10 agents targeting p53. p53. targeting agents anticancer designing for opportunities new open could HPV—and pathogen cancer-causing the from oncoprotein an of site interaction the with overlaps intriguingly, partners—though, p53 previously characterized cellular from differs mode interaction iASPP’s selection. target p53 for explanation co-regulated genes, providing an with the signature sequences of iASPP interacts that domain ap53 disrupts iASPP that found and proteins partnered the of structure acrystal examined also They p53. and iASPP by regulated jointly are that genes of sequences DNA signature the characterized Nanotechnology paper aSeptember in appeared study the of Areport well. as diseases other to detect nanosensors the of versions modified to use hope researchers The nontoxic. and results to give quick accurate, to be detectors and without colon tumors showed the with Trials mice in test. urine asimple with tumors colon of detection the enabling blue, turn AuNCs the chemicals, right to the Subjected urine. in expunged and kidneys the through out filtered blood, the in adrift set burden, protein their of freed were they mice, in tumors such into way their made nanoparticles the when . in N in ature ature

LUDWIG LINK | NOVEMBER 2019 News roundup News cells to protect themselves. Macrophages Macrophages themselves. to protect cells cancer certain by used to be appears too it that and to macrophages signal me” eat “don’t another yet transmits CD24 Nature in reported colleagues his and Irv August, In therapy. acancer as trials clinical in today CD47, them, of one is to block developed team his and he antibody an and proteins, previously discovered a couple of such has lab Weissman’s Irv Director Stanford Ludwig so. to do not macrophages tell that proteins express often part, their for cells, Cancer response. immune cancer anti- an initiate and cells cancer up gobble can macrophages called cells Immune EAT PLEASE? ME,DON’T PRETTY Frank carcinoma. cell squamous neck and head and glioblastoma cancer brain the of models in gene EGFR the a gene—of within DNA of stretch noncoding intron—a first the within located expression gene Research Cancer paper August an in reported Furnari Frank Diego’s San Ludwig by led Ateam receptor. the to disable seek drugs cancer targeted of A number cells. cancer of types many of survival and proliferation to the contributes signals, growth-promoting transmits that protein surface acell (EGFR), receptor EGF the of Overexpression VULNERABILITY INHERENT AN their discovery that the protein protein the that discovery their two novel enhancers of of enhancers novel two Molecular Molecular in

types. cancer of spectrum abroad of treatment cover might antibodies both or either blockade—and vice versa—suggesting to CD24 susceptible are CD47 blockade resist that cancers that found also team his and Irv Notably, intervention. to such werebreast cancers especially vulnerable triple-negative and ovarian to-treat Tough- mice. the of survival the extended tumors, induced tumor regression and in mice implanted with human breast and, repast cell cancer to their back get to macrophages prompted interaction that Blocking SIGLEC-10. called receptor a through signal CD24 the sense either existing or drugs. experimental by targeted be can proteins bromodomain BET and AP1 signaling. receptor’s the on dependent highly be can which tumors, EGFR-positive to treat interactions these targeting for arationale providing EGFsuppress receptor expression, enhancers the with BET or AP1 between disruption of interactions pharmacologic or Genetic proteins. bromodomain BET and expression) gene control (which factors transcription of family AP-1 the by mediated are effects their that finding characterized these novel enhancers, Jameson Nathan student graduate and 11 Ludwig San Diego San Ludwig Frank Furnari Ludwig Stanford Irv Weissman

LUDWIG LINK | NOVEMBER 2019 News roundup News Ludwig Oxford Ratcliffe Peter Ludwig Stanford Hiro Nakauchi

dioxygenase, or ADO, which splits splits which ADO, or dioxygenase, (2-aminoethanethiol) cysteamine enzyme, an by mediated is It plants. by shared is it that ancient so one cells, animal in sensing oxygen for system asecond discovered reported colleagues his and Peter July, In hypoxia. or starvation, to oxygen adapt cells help that expression gene of programs govern HIFs, which or factors, inducible ofdependent degradation hypoxia- oxygen- the on centered system That oxygen. of availability to the respond and sense cells how ago, years 20 about discovered, first who researchers the among is Ratcliffe Peter Oxford’s Ludwig SENSOR ANCIENT of thousands even or hundreds themselves to renew cells stem the prompts that HSCs reported a method of culturing mouse paper Nature aJuly In issues. these both around away found have might Nakauchi Hiro by led Stanford Ludwig at scientists of team Now a culture. to difficult and cells rare very are they because challenging is transplantation for HSCs donor of numbers sufficient collecting that is problem Afurther (HSCs). cells stem hematopoietic or cells, stem blood-forming diseased of marrow bone their to clear radiation of chemotherapylethal—rounds and toxic—sometimes highly endure must today diseases other and cancers blood for transplants cell stem undergoing Patients NUMBERS IN POWER , they and their colleagues in Japan Japan in colleagues their and , they in Science in that they’ve they’ve that 12

many disorders, including cancer. including disorders, many for drugs of development to the lead could sensor oxygen cellular anew of discovery The timescales. different on work they ways, similar in oxygen sense HIF system the and system ADO the both While cells. plant in operates ADO, resemble which mediated known by as PCOs, enzymes system Asimilar destruction. for proteins oxidized the tagging them, modifies further that enzyme another by recognized to be cysteines the allows alteration This pathway. hypoxia discovered newly the in on its protein targets—participants cysteine, acid, amino to an pair the of atom each attaches (O2) and oxygen molecular sickle cellsickle anemia. like diseases genetic to treat therapies gene in cells stem corrected genetically own apatient’s of use the permit also could It transplantation. for HSCs blood cord umbilical of use the to expand help and transplantation marrow bone for eligible patients of number the expand dramatically could it HSCs, human on works method the If HSCs. own recipients’ the eliminating first without mice in done transplantationssuccessful could be infusion, for available HSCs of numbers large such with that, demonstrated then They culture. the of conditions physical and factors stimulating growth medium, the altering by this accomplished researchers The days. 28 just within times

LUDWIG LINK | NOVEMBER 2019 News roundup News regimen. the of trials clinical planning now is team The therapy. to anti-PD-1 well respond resembled those seen in patients who mice treated the in patterns expression gene Notably, tissues. non-malignant spared also treatment combination The alone. therapy to anti-PD-1 respond not did mice The well. as tumors untreated of cell responses that regressions induced T anti-tumor potent elicited and tumors in Tcells exhausted of to adepletion led therapy combination the that found They tumors. against responses Tcell killer exhausted reinvigorates which antibody, anti-PD-1 an of injections systemic mice the gave also They CD40. protein the against antibody astimulatory A and lipid activate APCs—monophosphoryl cooperatively that agents two with tumors multiple bearing mice in tumor asingle treated colleagues Taha their and Jedd, them. to activate to Tcells antigens present that system immune innate the of scouts (APCs), cells presenting antigen on focuses strategy The effects. without compounding autoimmune side toapproach overcome this problem novel potentially a identified Merghoub Taha and Wolchok Jedd MSK’s Ludwig Investigation paper aJuly In blockade. PD-1 like immunotherapies to poorly respond exhausted are cells T infiltrating Tumors whose CHARM A THREE’S , researchers led by by led , researchers Journal of Clinical ofClinical Journal the in Taha Merghoub MSK Ludwig Jedd Wolchok Ludwig MSK Ludwig Ludwig Johns Hopkins Johns Ludwig Bert Vogelstein 13

July in Science in TranslationalJuly Medicine findings The methods. existing using to 89% compared surgery, current methods, and 91% who needed been monitored, compared to 34% using have simply should who people of 49% detected CompCyst surgery. unnecessary avoided to have 74% might them of 60% patients, these for care to decide used been had CompCyst If criteria. preoperative standard using detected 19% to the opposed as home, sent been have predicted 60% of patients who should correctly CompCyst cysts. the of histopathologicalpost-surgical evaluation diagnostic: standard gold the against predictionscompared CompCyst’s researchers The patients. 426 another of study multicenter international, an in evaluated then was It surveillance. further be monitored and those who needed no who needed surgery, those who should people to identify patients 436 from data on trained was CompCyst answer. an produce to fluid cyst in markers biochemical and genetic and imaging, selectedassesses clinical features, coordinately that purpose this for a test to create learning machine harnessed now has Vogelstein Bert Co-director Hopkins Johns by led team research A difficult. very is cysts high-risk and low- between distinguishing But tumors. pancreatic into progress not do doctors by detected cysts pancreatic of 99% than More A CYSTA ASSESSMENT were published in in published were .

LUDWIG LINK | NOVEMBER 2019 A NECESSARY CIRI NECESSARY A News roundup News biomarkers for risk profiling. profiling. risk for biomarkers new to identify used be might CIRI how Cell in July in published paper Their methods. existing for 0.6 vs. 0.8 of score a yielded profiling risk dynamic CIRI’s score, predictive perfect a 1constitutes of value the If monitored. been had DNA tumor circulating whose patients 132 on data included also They cancer. blood acommon (DLBCL), lymphoma B-cell large diffuse for treated people 2,500 than more on data after treatment without a relapse using 24 months least at for lived patient a whether with associated patterns to detect algorithm their trained researchers The therapy. aggressive more of need in patients identify help could DNA, tumor circulating and responses treatment as things such on information incorporates which method, The treatment. during point a given at doing is patient acancer well how (CIRI) Index to assess Risk Individualized Continuous called algorithm computer a to create method the of aversion used Kurtz David and Esfahani Shahrokh Mohammad colleagues Stanford their and Alizadeh Ash and Diehn Maximillian contests. of outcomes likely the time, real near in to predict, data various of uses a continuousprobability” stream win “in-game bettors, nerdy by Favored , also showed showed , also , Ludwig Stanford Ash Alizadeh Ludwig Stanford Maximilian Diehn Ludwig Lausanne George Coukos 14

interferon- called protein asignaling release they activated, are and tumor the reach CCL5 by drawn Tcells when that report team his and George tumors. solid in present usually are that cells immune cells, dendritic and macrophages by produced is CXCL9 while cells, cancer by expressed is CCL5 tumors. solid into infiltration cell T in implicated consistently are CXCL9, and CCL5 chemokines, key two that showed colleagues his and Coukos George Cancer Cell paper aJune In immunotherapy. of outcome the and immunity tumor affect can and tumors on in home T-cells help cells, immune of traffic the mediate proteins signaling that Chemokines, CROSSING GUARDS CROSSING cancer immunotherapy. cancer for strategies new inform also will findings The to immunotherapies. responsive to be likely more patients identify help and immunotherapy for biomarkers useful be could CXCL9 and CCL5 genes. suppresses the expression of targeted that silencing epigenetic as known to DNA modification achemical with correlates expression CCL5 of loss This tumors. in Tcells killer of depletion progressive the in resulting drops, expression CXCL9 CCL5, of production suppress cells cancer when that show researchers The cells. T circulating of infiltration the boosts dramatically which CXCL9, to secrete tumor the in cells dendritic and , Ludwig Lausanne Director Director Lausanne , Ludwig γ . This causes macrophages macrophages causes . This in in

LUDWIG LINK | NOVEMBER 2019 IN CENTRAL NERVOUSIN SYSTEM CENTRAL CANCERS DIRECTO LUD CAVENEEWEB Q&A WIG INSTITUTE R OF STRATEGIC ALLIANCES

15 Anderson. Putting all of that together and and together that of all Putting Anderson. MD at Strong Louise by reported was that family aunique and UCLA at Sparkes Bob by findings cytogenetic Foxat Chase, Knudson Al by analyses epidemiological a reasonable expectation based on was thought we what had we Actually, finding? unexpected atotally this Was humans. in genes suppressor tumor of proof progression when you demonstrated its and cancer of onset the about think now scientists how You influenced Prepared for Serendipity be? title the would what biography, your wrote someone If

LUDWIG LINK | NOVEMBER 2019 progress in treating and understanding the disease. viewpoints likely more and to are accelerate approaches by investigators with varying efforts at GBM now, with the being idea that conjoint initiatives collaborative several directed are There Q&A the migratory nature of the cells that that cells the of nature migratory the chemo-resistance, inherent acquired and radio-resistance, inherent including GBM, of features intrinsic some of because is This months. 14 about of diagnosis from survival average an with lethal, most the of one unfortunately, and, tumor intracranial common most the is GBM to treat? hard so it is why (GBM), and glioblastoma is What experiment validated our expectations. the to do able be to actually took it work hard of years three the Thankfully, community. genetics cancer the in most for much so not although to us, compelling was developing Iwere and White Ray that tools new the using hypothesis the testing 16 with some of the original investigators as as investigators original the of some with #2, Defeat support will it that announced also has NBTS The trials. clinical entering now are that approaches and agents new developed has group Defeat the years, four first its In leaders. and investigators first its of one and initiative institutional multi- that of well) as was Strausberg (Bob instigators the of one being of pleasure the had I efforts. such first the of one was (NBTS), Tumor Society Brain National the of auspices the under group, Defeat The understanding and treating the disease. in progress to accelerate likely more are viewpoints and approaches varying with investigators by efforts conjoint that being idea the now, with GBM at directed initiatives collaborative several are There it. in role your and Collaborative Research GBM Defeat the Tell about us agents. therapeutic of distribution the limits which barrier, blood-brain the behind resides tumor the that is issue major Another modality. any impediment to therapeutic progress with major the been has heterogeneity GBM immunotherapy? of efficacy the limit cells glioma of heterogeneity the Does tested. being all are delivery nanoparticle or viral and radio-sensitization immunotherapies, although cells, GBM in mutations specific at targeted are treatments new Most investigated for glioblastoma? being are treatments new What tumors. the of plasticity genetic and heterogeneity the and resection, surgical complete limits

LUDWIG LINK | NOVEMBER 2019 clinical trials? other from different it makes What follow-up. scientific or clinical limited and patients; of stratification limited avery necessitated which and tested be could that drugs of numbers the limited turn in which institution, one any at enrolled be could that patients of number limited the arm; control to the assigned be patients enrolled the half that requirement the nature; serial their included That restrictions. many too way with hamstrung were They conducted. are trials clinical that way the to address need the was meetings these through identified patients. and Apersonnel issue major representatives,pharma and FDA bioinformaticians, mathematicians, neuroradiologists, researchers, neurosurgeons, neuro-oncologists, international 150 than more of views the focusing and soliciting years, of couple following the over meetings brainstorming of aseries held and answer an be might approach unified a more that We GBM. posited with patients of survival the extending in success of lack the decried we which in MD Anderson, at neuro-oncology of chair then was who advisor scientific Ludwig the Yung, Al and University State Arizona at now is who Institute, Cancer National the of Director Deputy former the Barker, Ann with ago years five nearly I had conversations from arose AGILE GBM AGILE? GBM is What progress. to accelerate continue will and has this that believe Ifully ones. new some as well Q&A

it reapproved; an international agent agent international an reapproved; it without having to revise it and have trial the exit or to enter arms allows which protocol, amaster biomarkers; of use the incorporates that assignment arm and randomization patient features: Bayesian algorithm-driven distinctive several encompasses It to design. years three took that qualities adaptability, and flexibility its in unique truly It’s mentioned. I’ve shortcomings the to address construct anew as developed was AGILE GBM 17

LUDWIG LINK | NOVEMBER 2019 patients well. as to the advantages with many comes even faster.” That “correct and fast” treatments to “fail candidate todesigned allow GBM AGILE was Q&A moved to another arm, offering them a them offering arm, to another moved quickly be can responding not is who apatient that so manner, prescribed ahighly in and carefully followed is to a drug patients of response the that means trial the of design longitudinal the and drug; experimental an receive not will who patients of numbers the minimizing arm, control acommon of use the permits trial the of arms separate in drugs several of testing the two: Just well. as patients to the advantages many with comes faster.” That even “correct and fast” to “fail treatments candidate to allow designed was AGILE GBM patient? this for adifference makes AGILE of part a Tell being how us August. past this trial AGILE GBM in a patient first its enrolled just Institute Ford Cancer Henry The combination. in and singly agents many test to rapidly patients of number asufficient provide will network extended This Israel. and Europe Australia, China, Canada, in agencies regulatory with active are discussions and evaluated being currently are US the in sites 40 Some Officer. Scientific Chief interim as and Directors of Board its on Iserve and (GCAR), Research Adaptive for Consortium Global the named organization 501(c)3 anew by sponsored is It 3trials. Phase quality 2to registration Phase randomized through drugs of combinations or drugs succeeding of transition seamless allows that design FDA-approved an and repository; tissue and analytic data acommon arm; control the for needed patients of number the to minimize as so arms, multiple group; selection

18 families. This gave us the idea in the the in idea the us gave This families. in mutations recessive of origins the tracking doing were we work from arose finding gratifying and surprising most The most surprising to you? been has yours of finding scientific What run! awonderful been has assembled in Montreal and Diego. San It I that Branches recognized widely and outstanding two the of proud and me to provided has Ludwig that support of years 33 the for grateful very Iam stage. international the on to participate and inquiry scientific for teams constructing in abilities exercise and to develop level, highest the at science to do opportunity the me afforded has Ludwig years, the over as, right exactly to be out turned it and challenge this Irelished excuses. No alone. me on depended failure or success my that understand and mirror the in to look me told he and was, catch the what Hugh asking remember Iclearly well-supported. and interactive international, was Institute the Moreover, most renowned researchers in the world. the of some included that network Ludwig developing to anewly access offered they connected, finally we when and, member, faculty grant-funded ayoung Iwas entity. unknown relatively and asmall still was it 1980s, early the in me approached first Park Donald and Butt Hugh when but research, cancer in force adominant such now is Ludwig since to believe, hard is It career? your change or advance Ludwig joining did How therapy. successful apotentially at chance second

LUDWIG LINK | NOVEMBER 2019 I had no clue what that was about and and about was that what clue no I had job.” his in interested was “I understood he that saying and world the over all to be seemed who aDr. from Butt calls phone mysterious receiving Iwas so, even but, island small the on phones of acouple only were day. There the during kids the for house atree building and evenings the in paper this writing archipelago the in house summer his at staying were families our Iand and Magnus Parenthetically, cases. many in therapies individuals and offer them curative high-risk topossible extremely identify increasingly becoming was it that time first the for showed it because bombshell a like hit this of report Angeles) Los of Hospital Children’s the at Murphree Toronto in Linn and Children Sick for Hospital the at Gallie Brenda Stockholm, in Institute Karolinska the at Department Genetics Clinical the at Nordenskjold Magnus (my friends Our surgery. or radiotherapy earlier of possibility the by justified were anesthesia of risks the that knowing earlier even examined be could they because useful also was disease the to develop likely very were who kids to identify able being even fact, tumor. In the develop not would a child that accurately very to say able were we when elated We were members. affected identifying those associated with and developed Ihad markers DNA the with genotypes following by simply disease—before it was even diagnosed— develop would family the in achild if to predict tumors their and/or siblings parents, use could we that 1980s early Q&A them. surrounding cells normal the even or cells those of growth the affect thereby and mutations oncogenic by influenced be can metabolism cell cancer that showing advances made have investigators Ludwig several where metabolism, to intracellular extended be can It general. in cancer for area promising and exciting an is This Sure. microbiome research in GBM? and nutrition for arole see you Do history! is rest The Ilanded). after morning the 6am at me called Hugh (where U.S. the to Ireturned until it ignored simply so provided. has Ludwig that of support for years grateful the 33 very Iam the international stage. on and participate to scientific inquiry teams forabilities in constructing level,highest to develop exercise and to atthe doscience opportunity the me afforded has Ludwig 19

LUDWIG LINK | NOVEMBER 2019 Q&A My greatest accomplishment is is accomplishment greatest My career? your in of proud most you are What busy. me to keep continue will them for Consulting views. my value that companies and universities institutes, and Research Adaptive for Coalition Global international organizations, including the other several are there Fortunately, right! to be continue “unfocused” me called who reviewers several the that sure be to want I both. Definitely or new pursue opportunities, or both? research GBM in remain you Will career? post-Ludwig your in see you do What

20 investigators today? investigators to young give you would advice What them! of one every of proud Iam Branches. Diego San and Montreal Ludwig the in laboratories other the in resident been have who trainees of hundreds many the as well as group, my of members been have who fellows and students 120 than more the of success ongoing and maturation scientific training, to the contributing and will be, eternally grateful to them all. to them grateful eternally be, will and Iam, dreams. those actualizing then and big dreaming when possible is anything that me taught who Old, Lloyd and facts”; “true are what about skepticism healthy that strength of conviction coupled with day every demonstrated who White, Ray friend, and mentor postdoctoral my Also, young. very Iwas when science of power the about imagination my piqued Berkeley, ofthe California, University at taught and Oil Shell for chemistry of head was who Web Sawyer, uncle, another standpoint, From ascientific life. my to lead expected Iwas how was ofbelieved—regardless consequence— I what for up standing and honest being that belief the me in instilled actively them of Both driver. truck interstate and racer car rider, dirt-track a rodeo was who Ryan, Max uncle my and officer, Force Air acareer Cavenee, father, Jim my are to mind come immediately who Those many. so been have There most? the you influenced life your in Who mind. open an with but intuition, your trust and hard work can, you everything Read

LUDWIG LINK | NOVEMBER 2019 Ask a scientist a Ask Will decentralizing science lead to more reliable results? to reliable lead science more decentralizing Will Ludwig Institute Ludwig THOMAS BALLIGAND Research. Cancer Ludwig like just teams, independent scientifically of constellation international alarge of part to is be solution optimal The partnerships. new seek to continuously labs independent for challenging be however may It top quality. of is science the that and reproducible are results that ensure help might science of Decentralization Ludwig Chicago CHAN CHRISTINA now. to accustomed is world scientific the than advancement slower but results, reliable to more lead may It world. the of understanding our deepens knowledge previous on building as inefficient, also is it but consistent the results suggest conclusions are reliable and reproducible, with teams independent multiple sword: adouble-edged is Decentralizing MSK Ludwig SCHADSARA level to ensure accurate and reliable results. each at validated data with institutions, and groups across strengthened rather but abandoned, be not should progress and discovery reagents and analysis. However, collaborative that efforts propagate protocols, varying with findings validate investigators independent Decentralizing science should enable more reproducible results as

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LUDWIG LINK | NOVEMBER 2019 Required reading Felsher DW. RN, CV, Zare Dang A, Schulze BJ, Altman ZE, Stine DK, Sullivan AL, Hsieh A, Mosley Tong L, GG, Toal A, Mancuso SJ, Raman NS, Liu K, Margulis AM, Gouw neoplastic growth. lipogenesis essential for regulate to protein binding with sterol-regulated element- cooperates oncogene MYC The print] of ahead [Epub 22 August Cell Metabolism Institute Ludwig RR. Weichselbaum Fu N, YX, Khodarev T, Sims I, Lowy H, Mauceri B, Y, Hou M, Burnette Forde JJ, Luke SJ, Chmura S, W, Pitroda Zheng C, Fernandez M, Beckett A, Arina tumors. control to radiation resist T cells Tumor-reprogrammed resident 2019 September 2 Nature Communications Chicago Ludwig

Delorenzi M, Coukos G. S, P, Rusakiewicz Foukas L, Zhang M, Irving LE, SF,Hodi Kandalaft SJ, Rodig JS, Weber DG, Jackson A, Facciabene PA, Jr, Gimotty DJ KT, Powell Montone HR, Ramay JL, Benencia F, J, Conejo-Garcia J, Tanyi Duraiswamy E, Lanitis PA, Duttagupta D, Barras C, Ronet AJ, Grimm M, Bruand D, Dangaj tumors. solid in attack immune and engraftment Tcell enables chemokines inducible and constitutive Cooperation between 10 June 2019 Cell Cancer Ludwig Lausanne AM. ,Lennon RH Hruban CL, Wolfgang B, Vogelstein KW, Kinzler N, R ,Papadopoulos Karchin C, AP, Tomasetti Klein M, Popoli N, J, Sillman Schaefer L, J, Dobbyn Ptak MG, Goggins MI, Canto M, Makary R, Burkhart MJ, He J, Weiss J, Hooft van S, Hijioka S, W, Yachida Park BH, Edil RD, J, Schulick Paulino C, Doglioni S, Crippa M, J, Falconi Geoghegan N, JY, W, Kwon Swan DW, Jang Hwang SM, Hong G, Zamboni R, Salvia R, Lawlor A, Scarpa AD, Singhi RE, W, Brand Brugge M, Mino-Kenudson C, Castillo M, Simpson RE, Fernandez-Del MA, Schmidt CM, Yip-Schneider Schattner DS, PJ, Klimstra Allen E, Thompson JD, Cohen L, Li B, Afsari CJ, Thoburn C, Douville M, Molin Dal DL, Masica S, Springer cyst. pancreatic a with patients of management the guide to test A multimodality 17 July 2019 Medicine Translational Science Ludwig Johns Hopkins

22 Wolchok JD, Merghoub T. VP, Balachandran JA, Moral JJ, Harding A, Gupta M, Schneider B, Gasmi R, Giese R, Zappasodi D, Hirschhorn S, Houghton M, Capanu K, Panageas C, Krishna RM, Samstein D, Redmond S, Budhu LF, Campesato N, Suek DN, Khalil exhaustion in distant tumors. Tcell overcomes factors defined with vaccination situ In 22 July 2019 Investigation Clinical of Journal MSK Ludwig MM. Stevens SN, Bhatia Q, Chen A, Bekdemir A, Y, Lin Najer JS, Dudani AP, Soleimany CN, Loynachan monitoring. disease vivo in for nanoclusters gold catalytic clearable Renal print] of ahead [Epub 2019 September 2 Nature Nanotechnology Ludwig MIT F, Ratcliffe PJ. F, Ratcliffe Licausi E, Flashman RJ, Hopkinson P, Perata ML, Puerta MD, White B, TP, Giuntoli Keeley N, Masson and plants. animals in hypoxia to responses dioxygenases transduce Conserved N-terminal cysteine 5 July 2019 Science X. EY, Lu Jones M, Lu Z, Chen GL, Bond C, Siebold P, J, Tan J, Ren Y, Y, Ma KF, Wang Au Y, Li S, Zhang J, Zhong Wu S, Chen recognition. DNA fine-tuning mechanism amodular through selectivity p53 mediates iASPP print] of ahead 8[Epub August Academy of Sciences USA National the of Proceedings Oxford Ludwig

Furnari FB, Cravatt BF, Mischel PS. BF, Mischel Cravatt FB, Furnari WK, TF, Cavenee Cloughesy JN, Rich HI, Kornblum WH, O, Yong Quehenberger S, Wu GR, W, Villa Zhang KM, Turner S, Ikegami A, Reed S, W, Y, Gu Chowdhry Zhang H, Yang C, TA, Zanca J, Ichu Bi remodeling. dependent on membrane lipid pathways renders cancers signaling factor growth in amplification Oncogene print] of ahead [Epub 11 July epub Cell Metabolism F. Furnari A, Parisian R, JY, Mendez Han A, Izurieta J, J, Benitez Ma NM, Jameson proteins. BET and AP-1 by mediated dependent is EGFR- In expression EGFR of Intron 1-mediated regulation print] of ahead [Epub 23 August 2019 Research Cancer Molecular B. Ren D, Kim S, Kuan B, Li CL, Barr E, Masliah C, Kim Z, Chiang S, Chee M, T, J, Tan Chan D, Liu Eom C, Yang Y, AJ, Lee Diao A, Schmitt I, Jung genome. interactions in the human centered chromatin long-range promoter- of A compendium print] of ahead 9[Epub Sep 2019 Nature Genetics Diego San Ludwig O, Barkal LJ, Weissman IL. Weissman LJ, O, Barkal J, Dorigo V, Hatakeyama Krishnan BW, Zaro SA, Barkal M, Kowarsky M, Markovic RE, Brewer AA, Barkal for cancer immunotherapy. atarget is Siglec-10 macrophage through signalling CD24 print] of ahead [Epub 31 July 2019 Nature Stanford Ludwig

LUDWIG LINK | NOVEMBER 2019 Required reading Yamazaki S. H, Nakauchi M, Y, Watanabe Nakamura KM, Loh R, Yamamoto RV, Crisostomo M, Morita K, Sudo M, Kikuchi R, Ishida AC, Wilkinson nonconditioned transplantation. allows expansion cell haematopoietic-stem- vivo ex Long-term print] of ahead [Epub 2019 May 29 Nature AA. Alizadeh M, Diehn R, Tibshirani M, J, Hallek Bahlo D, Rossi G, Gaidano AW, Roschewski M, Wilson WH, Langerak S, Böttcher M, Ritgen JR, O,Westin Casasnovas A, U, Hüttmann Dührsen AM, Newman CL, Liu F, MC, J, Jin Soo Scherer MS, Esfahani DM, Kurtz prediction. for personalized outcome biomarkers tumor serial using profiling risk Dynamic print] of ahead 4[Epub July Cell

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