Defining molecular mechanisms of imatinib in the treatment of GIST

LifeFest 2010:Celebrating adecade of lifeBy Marisa BologneseLRG Director Planning &DevelopmentIt has been a remarkable decade forthe GIST community as scientificdiscovery, medical treatment anddrug development have put GISTat the cutting edge of cancer treatmentand care. Between 2000 and 2010, GISThas gone from being a misdiagnosed rarecancer, with only a five percent responseto treatment, to one of the best understoodcancers, where patients can nowexpect an 85 percent initial response toThe Hyatt Regency Hotel on the HudsonRiver in New Jersey will be thelocation for Life Fest 2010.See LIFEFEST, Page 9Battling gastrointestinal stromal tumorLIFE RAFTGROUPOctober 2009 In memory of Kenneth Rowan, Nurit Mantz, Jessica Vol 10, No. 8Macneil and Linda ChuykoDefining molecular mechanisms ofimatinib in the treatment of GISTBy Dr. Anette DuensingUniversity of Pittsburgh CancerInstitute & LRG Research TeamGastrointestinal stromal tumors(GISTs) are caused bymutations in the KIT orPDGFRA (platelet-derivegrowth factor receptor alpha) receptortyrosine kinase genes and can successfullybe treated with imatinib mesylate(Gleevec®). However, despite dramaticresponse rates and more than 85 percentof the patients initially benefitting fromtherapy, imatinib treatment is not a cure.A major problem of imatinib therapy isthat a considerable proportion of patientsdevelop resistance to the drug over thecourse of treatment.A second, interrelatedproblem ofimatinib therapy isthe fact that althoughmany patientsdo achievetumor stability,complete remissionsare rare. In otherwords, oftentimesDUENSINGeven bulky tumorremains under therapyand tumors relapse once imatinibtherapy is terminated. These observationsare corroborated by scan resultsduring therapy that can show detectableSee DUENSING, Page 7Jerry Call: the man behind the sceneBy Erin KristoffLRG Newsletter EditorYou sit alone in a drearydoctor’s office; evidenceof his medical expertiseand importance adorn thewalls. Maybe you sit there with aloved one, equally as scared and unpreparedas you. The doctor hands youa verdict that says your time is up.Well now what do you do?At times like this, people feel a rangeof emotions: defeat, clarity, redemption,remorse, to name but a few. InJerry & Stephanie in Nederland, Colorado,just 3 weeks prior to Stephanie’s diagnosis.the GIST community we have alsoheard and experienced stories of triumphand miracles, rising from rockbottom and greeting the world anew. Aworld where David can and does beatGoliath.Ten years ago, Jerry Call was introducedto this world as he sat next to hiswife of 15 years, Stephanie, and learnedof her leimomyosarcoma (LMS) diagnosis.Amidst the shock and disbelief,her oncologist’s voice rang out, “This isprobably going to take you away fromus.”After two rounds of a harsh chemo-See JERRY, Page 4

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 2GIST Research: LRG Articleson the Science of GISTIt’s time to consider mutational status forresistant GIST patients: PDGFRA MutationsBy Jerry CallLRG Science CoordinatorThis is the second article in a series discussingmutational status and resistantGIST. In the last article we began with abrief overview and wild-type GIST. Inthis article we focus on PDGFRA mutationswith an emphasis on the imatinibresistantD842V mutation.Mutations in the KIT andPDGFRA gene are themost frequent geneticevent that drives the biologyof GIST tumors. Targeting thesedefects remains the primary drug therapyfor GIST. While KIT mutations aremuch more common, PDGFRA mutationsstill represent a significant percentageof GISTs. Approximately two-thirdsof PDGFRA mutations are insensitive toEditor’s Note:There are several differences betweenGISTs with PDGFRA mutations and thosewith KIT mutations. The cells of PDGFRAmutantGIST tumors are often anepithelioid type (round shape) and moreoften stain weakly or negative for KIT(Corless et al.). In addition, PDGFRAmutations occur predominantly in thestomach, but can also occur in themesentery and omentum. It has beennoted (Lasota et al) that PDGFRAmutantGISTs tend to have a lower risk ofrecurrence than KIT-mutant GIST.Gleevec. This makes the management ofpatients with PDGFRA mutations morecomplex than those with KIT mutations.In 2005, Drs. Christopher Corless, MichaelHeinrich and colleagues reportedon the PDGFRA mutational status of1,105 GIST tumors. In this group, 80tumors (7.2%) were found to have aPDGFRA mutation. The most commonPDGFRA mutation was one that occursin exon 18, a D842V mutation. D842Vmutations are insensitive to Gleevec andSutent, the two currently approved drugsfor GIST.Patients that are resistant to bothGleevec and Sutent may elect to participatein clinical trials. Many patients (atleast in the United States) will try offlabeltreatment with drugs that are approvedfor other cancers but not forGIST. The two approved KIT inhibitors(other than Gleevec and Sutent) that arethe most advanced in trials for GIST arenilotinib (Tasigna) and sorafenib(Nexavar) and patients will often try oneof these two drugs after failing Gleevecand Sutent. Both nilotinib and sorafenib,however, have shown limited effectivenessagainst the D842V mutation in thelaboratory.In 2008, Dr. Maria Debiec-Rychter ofthe Catholic University of Leuven, Belgiumand her colleagues identified twodrugs that inhibit the PDGFRA D842Vmutation and represent possible treatmentsfor patients with this mutation.Barbara Dewaele was the first author ofthe paper which was published in ClinicalCancer Research.The Leuven team found that dasatiniband IPI-504 were both effective inhibitorsof PDGFRA D842V mutations in laboratoryexperiments. These experimentsincluded tests against Ba/F3 cells (cellsThe Life Raft GroupWho are we, what do we do?The Life Raft Group (LRG) directsresearch to find a cure for a rare cancerand help those affected throughsupport and advocacy until we do.The LRG provides support, informationand assistance to patients and familieswith a rare cancer called GastrointestinalStromal Tumor (GIST). The LRGachieves this by providing an onlinecommunity for patients and caregivers,supporting local in-person meetings,patient education through monthlynewsletters and webcasts, one-on-onepatient consultations, and most importantly,managing a major research projectto find the cure for GIST.How to helpDonations to The Life Raft Group, a501(c)(3) nonprofit organization, are taxdeductible in the United States.You can donate by credit card atwww.liferaftgroup.org/donate.htm or bysending a check to:The Life Raft Group40 Galesi Dr., Suite 19Wayne, NJ 07470DisclaimerWe are patients and caregivers, notdoctors. Information shared is not asubstitute for discussion with yourdoctor.Please advise Erin Kristoff, the NewsletterEditor, at ekristoff@liferaftgroup.orgof any errors.engineered to test specific mutations)and actual tumor cells taken from a patientwith the PDGFRA D842V mutation.Dasatinib has been extremely effectivefor Gleevec-resistant chronic myelogenousleukemia (CML) and it is approvedfor that purpose in the United States andsome other countries. Dasatinib is manufacturedby Bristol-Myers Squibb andthe trade name in America is Sprycel;while in trials, it is/was called BMS-354825.After a slow start in phase I trials thatincluded 18 GIST patients, there is somerenewed interest in dasatinib for GIST,at least in some unexplored populations,such as the open phase II trial in Switzerlandfor GIST patients that haveSee PDGFRA, Page 8

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 3GIST Research: LRG Articles on the Science of GISTREGISTER Study Open in Australia,New Zealand and South KoreaBy Jim HughesClinical Trials CoordinatorAn interesting Phase 2 REGIS-TER study is ongoing andactively recruiting at 15 sitesin Australia. Two sites inNew Zealand and two sites in South Koreaare also planned.Upon entry advanced GIST patientsare classified as high or low risk basedon mutation type. Exon 9 and wildtypemutations are classified as high risk;exon 11 patients are classified as lowrisk.All patients receive imatinib at 400 mgfor up to six weeks as initial therapy.High risk patients are then escalated toimatinib 800 mg. Low risk patients canbe escalated to 800 mg imatinib undertwo scenarios:1. Incomplete response on PET scansat six weeks.2. Complete response on PET scans atsix weeks but experiencing progressivedisease (RECIST) on a regular threemonth follow-up CT scanEditor’s Note: Whilerisk is categorized inthis study by mutation,in metastatic GIST,risk is characterizednot just by mutationtype, but also tumorsize and mitotic rate.After escalationto 800 mgimatinib,patientsreceiveearly PETscans tocheck forprogression.Progressingor partially responding patients are thentreated with Nilotinib 800 mg. Sunitinibis not offered as a drug treatment in thistrial.There are multiple notable features inthis trial design:• Patients for the first time are classifiedand treated by risk (genotype)• Higher risk genotypes are automaticallyescalated to higher imatinib doses• Progression is monitored early by PETscans.• Escalation of imatinib dose is based onPET scan results for exon 11 patients.• Escalation of imatinib dose occurs insteps from 400 to 600 to 800 mg• Imatinib blood levels are tested at multiplepoints in the protocol• Sunitinib is not offered even though itis the standard of treatment for secondline.• A second line tyrosine-kinase inhibitor,nilotinib, is offered in tandem withfirst line imatinib.The trial’s primary end point is progression-freesurvival and its targetedaccrual is 100 adult patients.The AGITG website has more protocoldetail at: http://www.gicancer.org.au/trials/open/REGISTER.htmlOctober 2009 clinical trials updateBy Jim HughesClinical Trials CoordinatorTwo important new trials arehighlighted in separate articlesin this month’s newsletter:• The REGISTER trial in Australia,New Zealand and South Korea for newlydiagnosed advanced GIST.• The new five year adjuvant imatinibstudy recently opened in the UnitedStates for newly resected patients.(NCT00867113)Other GIST clinical trial news includes:• The Phase 3 imatinib with or withoutBevacizumab trial has closed to accrualin the US and Canada. No reason wasgiven. Accrual had not been as high asexpected. (NCT00324987)• A Nilotinib Pharmacokinetic (PK)study has been started in Japan. Researcherswill look at the effect of surgeryon Nilotinib PK. They are investigatinghow prior surgery might affectnilotinib absorption. (NCT00976612)• Radboud University Hospital in theNetherlands has an ongoing palliativestudy (newly listed) that is investigatingthe link between angiogenesis inhibitorssunitinib and sorafenib and fatigue anddepression in several cancers includingGIST. (NCT00979329)• Pfizer has added detailed study resultsto two major sunitinib trials includingthe phase 3 registration trial.• The Pfizer treatment-use protocol forSutent access for GIST patients remainsopen in India in Mumbai and NewDelhi. (NCT00094029)Please visit the Clinical Trials databaseat www.liferaftgroup.org/treat_trials.html for a complete listing of clinicaltrials. There you can view a table,search recruiting trials and much more.

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 4JERRYFrom Page 1therapy called MAID, her doctor announcedthat it was not working andthere were no further options for Stephanie.Having never done anything halfwayin his life, Jerry refused to acceptthis as the end. Because one doctor saidthere was nothing left to be done, shouldthey just quit? He immediately wenthome and came up with a plan to saveStephanie’s life.“I was always a very independent person.When I was diagnosed, I just lostit,” recalls Stephanie, “We knew theonly way to get control of the situationwas to get online and do research. SoJerry self taught himself. He actuallyhad to tell numerous oncologists whatwas out there for treatment and theywere not ready for that.”At home, Jerry outlined a plan of attack.First they would arrange a consultationwith Dr. George Demetri of DanaFarber Cancer Institute in Boston. Healso set up an appointment with a liversurgeon at the University of Coloradoand began investigations into an experimentaltreatment available only in Ireland.“All of a sudden we went from no options—nohope—to having three differentpaths that we were going to pursue,”recalls Jerry. A former marine, Jerrystarted issuing orders; his mother wouldarrange travel and his brother researchedpassport requirements, in case he wouldneed to travel to Ireland.In Dr. George Demetri, the Calls founda compassionate expert who was themost knowledgeable person they hadever met. He suspected Stephanie actuallyhad GIST and had been misdiagnosed(this was later confirmed by a c-kit test), but there were still no effectivetreatments for GIST. As Demetri readoff options, Jerry could tell that he hadlittle faith in them.After another strikeout with the liversurgeon, Jerry found himself on a planeto Ireland with 2,700 dollars for a threemonth supply of an experimental drug.The Call’s first year with GIST was arough one. After the MAID chemo,Stephanie began a rollercoaster of treatmentbeginning with the Irish drug; shethen had a painful biopsy test, followedby seven rounds of an additional chemocalled Taxotere, and then began takingInterferon which caused an allergic reaction.“I lost hope a few times, but Jerry keptgoing,” says Stephanie.Finally, after reading thousands ofemails he came across one very importantpiece of information: a new trial fora drug called STI-571 (Gleevec).The Gleevec trial proved to be a turningpoint forStephanieand truthfully,forJerry aswell. WhileStephanieexperiencedbenefit fromGleevec formore thanfour years,Jerry wasintroducedto more andmore GISTpatients,dozens of “Stephanies”, who neededguidance.When the LRG first formed, Jerry beganworkingfor theorganizationon apart-timebasis. Heretained hisposition asa homeJudi Lifton & Lee Emerson.inspector inhis hometownof Boulder, Colorado and was alsoable to stay home most of the time withStephanie.Using what he had learned during hiswife’s rocky first year; Jerry targeted hisefforts on the GIST patient communityas a whole, researching all he could onmolecularly targeted therapies, signalpathways and GIST biology. He hadtruly found his calling.When Executive Director, NormanScherzer introduced him at meetings, itwould be as the third smartest man in theworld.“I say that because I assume there aretwo people in the world who are smarterthan him… but I haven’t met them.”Eventually, in 2004, Jerry became thefull-time Science Coordinator of the LifeRaft Group.Says Stephanie, “We get calls frompatients 24 hours a day, seven days aweek on every phone we have. He isalways giving pep talks and positivethinking to people and different ideas.”Jerry discusses GIST care with LRG members at Life Fest 2006.One such person is Judi Lifton, whosepartner, Lee, experienced great difficultiesin his GIST journey. Over the courseof years, Jerry offered whatever help hecould: analytical and supportive.“Jerry Call is a cross between JohnnyAppleseed and Albert Einstein,” laughsJudi, “Appleseed was creative and Einsteinwas calculating. Jerry really was awonderful sounding board; he was aninnovator.”Lee passed away in January 2007, butJudi and Jerry still speak regularly, “Hebecame a friend and I can’t say enoughabout him. He is really a special guy.”This kind of story is not uncommon inthe GIST community; to many, Jerry isthe man in the machine, climbing out ofthe ether and empowering patients tomanage their own care. He works everyday to level the playing field betweenpatients and medical professionals.This has not gone unappreciated in theGIST medical community. At a 2006See JERRY, Page 6

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 5Donor appreciation never gets oldWhen compiling the list ofDaniel & Barbara CoxWarrenHillmandonors for the year 2008,the LRG inadvertently John & Ruth CraigHaraldHiolandleft out a number of donorsJosephDiasLawrence & Judith Hirschwho should have been included. Robert K. Dobbs Jeffrey & Linda HoldenAt the LRG, we are grateful for eachJudith K. EisenFrancis & Sandra Hollandand every donation and are sincerelymoved by the continued generosity of Sheryl & Gilbert R. EkArnold & Lori Horwitzour supporters.Manoucher Emani Arthur & Laraine HouseWe would like to apologize for this Harold & Louise EngleJosefinaJekermistake and have included that list ofBessEngleKevin & Mary Kadowdonors below with our deep appreciation:Burton & Diane Epstein Irving & Naomi KaminskyLarryEsterling Jeffrey M.KaplanJerome & Susan Akman WilliamEwenBruceKassonJamshidAmouzegar Mary Elizabeth Ewing Joyce B.KelleyRichardAzevedo Bruce & Sharon Feldman Kristi E.KingAmyBachelder Jospeh & Roselyn Fenton Joy & Douglas KnoppLaurenceBaden GaryFialkMatthewKrasnerJospeh & Donna Ball James & Barbara Finkelstein Lawrence J. LattoJohn P.Bankson PauletteFishman Walker Robert T.LaycockJennifer & Simon Sia Bao JoanneFleeter DevonLee MillerHarold & Gloria Baston Jay & Sue Fleming PatLemeshkaStanley & Allene Baum Christina FlepsJames & Rhoda MackenzieDavidBayles Geroge & Lucia Foster Albert B.ManolaHarvey A.Belitsky Joe & Nina Frasier Johns ElliotMcEnteeReginaldBerry Richard & Melinda FullerSusan & Robert MeehanMaryBeyda JamesGantDennisMenosThomas & Mary Billitteri JaniceGaulten Edward S.MillerFrederickBissinger Joseph D. GelbHerbert and Patricia MillerJames & Margaret Blaszak MyronGerber Harvey and Susan MininbergDeannaBoezi Sol & Nina Glasner William & Cindy MirandaJoseph & Joanne Borini JohnGlover FarnhamMosleyEmilyBowden Kenneth & Sharon Goldberg LawrenceMovshinBruce J.Bowen Robert L. Goldenberg Patricia & Brenden MullenWilliamBrackett Larry & Ellen Goldstein SeishinMurahashiS MBrown MarkGoldstein Franklin & Esther MurphyBrook & Shawn Byers Thomas C. Green Jerome C.MuysJerry & Stephanie Call AnthonyGulloJeffreyNadelSara & Guillermo Calvo Bonnie & Croc Halvorsen James & Julie NelsonHao-ChiaChen MD JohnHarman Walter & Susan OffenPhyllis & Leonard Chorazy Wallace B. HarrisPeterOgloblinStephenConger KarlHeinz Schroader BarbaraOpperJohn & Karen Cooksey Margaret E. Hennessy Dr. & Mrs. Jan OrensteinDamonCordom A.L.HenricksenSee DONORS, Page 8

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 6JERRYFrom Page 4Life Fest meeting in Dallas, Texas, Dr.Jonathan Fletcher, LRG Research Teamleader, stood before a crowd of over onehundred to accept an LRG award of“Researcher of the Year”; during hisspeech he took a few moments to thankJerry for his contribution to GIST research.A note from Jerry Call:“I speak for all of my research colleaguesin GIST in assuring you that ifthere is some angle out there which isrelevant, a new drug that is being usedfor some other tumor, that smacks of apromise in GIST, then Jerry is going toin his genteel, quiet way let us knowabout it, and he doesn’t do so in a kneejerkway. He thinksabout it, he considersthe possiblepayoff andStephanie would not be alive today without the help of manywonderful doctors and nurses. Special thanks goes to Dr. KeithSkubitz, University of Minnesota, who allowed Stephanie in to theSutent treatment-use trial. He could easily have said she was toosick to qualify. Thanks to Dr. Dwight McKee for his compassionand thinking outside the box. The ICU of Boulder CommunityHospital did a fantastic job in a crisis in 2003. Thanks to Dr.Charles Blanke who took care of Stephanie in the Gleevec phase IItrial. Thanks to Dr. George Demetri for his compassion, wisdomand support through the years. The nurses at RMCC and BCHhave done a wonderful job of taking care of Stephanie over thelast 10 years. And last, but not least, thanks to Dr. Jenny Fox,‘Stephanie’s oncologist, for taking care of Stephanie for the last 7years and for putting up with me for all that time.when we get anemail fromJerry or a callfrom Jerry, wealways knowit’s somethinggood,” announcedFletcher, “Wereally value hisoversight andjudgment whenit comes to scientificmatters.”The LRG ResearchTeam hasgrown in size andscale since that speech, but the teamcontinues to rely extensively upon Jerryfor his suggestions about important areasof research focus in GIST, insistsFletcher.Indeed, Jerry has grown to becomesomething of an icon in the GIST community.Some see him as that mysteriousbenefactor in the computer, some as thefriend they’ve been searching for, evenmore as the man who gave them thestrength to get back in the driver’s seatof their own medical care. But to onewoman—Stephanie Call—he’s still justher soul mate, the man who saved herlife.“He’s been through so much with me,”says Stephanie, “I’ve been close to deathlike three times. He is a very strong person,a very dedicated person, and loyal.”Despite numerous oncologists and specialistsproclamations to the contrary,Jerry never accepted that it was Stephanie’stime to go. In August, Jerry andStephanie celebrated their 25 th weddinganniversary; this month, they will celebrateher 10-year “cancer”versary.“He truly does love me, he doesn’twant to lose me and he doesn’t want alife without me.”Chicago-area GISTers meet!Last month’s Chicago-area meeting, was a reunion of sorts for many attendees. Dr. Margaret Shoup, surgicaloncologist at Loyola University Health System, was the group’s very first speaker in 2003 and returned for this meetingto talk about surgery in GIST. There were many questions and answers and, as always, a good time was had by all.

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 7DUENSINGFrom Page 1tumor mass in the CT scan althoughthe tumor is responding toimatinib according to a “cold”PET scan. These findings can beinterpreted in a way that not all cellshave undergone apoptosis in response toimatinib therapy, but instead have significantlyreduced their metabolism(which is measured by the PET scan).These remaining cells pose a significantrisk to the patient as it is conceivablethat they may already contain imatinibresistance mutations that can ultimatelycontribute to disease progression.It is therefore imperative to define theexact molecular mechanisms of action ofimatinib with the two major questionsbeing (a) how does imatinib lead toGIST cell death (apoptosis) and (b) howcan we explain or potentially circumventincomplete remissions? Answering thesequestions will not only identify the molecularplayers that are involved, butalso lead to the definition of novel therapeutictargets. Ultimately, our goal is toovercome resistance with an aim towardscure.Addressing the question of imatinibinducedapoptosis, we have recentlyidentified one of the molecular players:histone H2AX (1). Histones have longbeen known as mere structural scaffoldproteins that help to package the cell’s“These results indicate that imatinibtreatment provokes an either-or decisionwith respect to apoptosis or quiescence.”DNA into its nucleus. They form the socallednucleosomes, around which theDNA is wrapped. More recently, a plethoraof novel functions of histones havebeen discovered. One major finding wasthe identification of histone H2AX as akey player in the signaling cascades thatare activated after the cellular DNA isdamaged (for example, by gammairradiationsuch as X-rays). We havenow discovered yet another function ofhistone H2AX, which is separate fromits role in DNA damage response. HistoneH2AX is causatively involved inFigure 1the induction of GIST cell death afterimatinib treatment and can also lead toapoptosis in other cell types that are nottreated with imatinib (2). We found thatlevels of H2AX are massively upregulatedin GIST after imatinib, and thatmost of the H2AX molecules in thiscontext are not part of the nucleosomes,but are free in the cytoplasm or nucleusof the cell. We have shown that themechanism by which H2AX leads toGIST cell apoptosis involves the inhibitionof gene transcription. Importantly,we can now look for alternative ways totarget H2AX upregulation as a possiblemeans to circumvent imatinibresistance. (For more detailedinformation on histones, histoneH2AX and its role inimatinib-induced apoptosisplease see the December 2007issue of the LRG newsletter.)Addressing the second question, theproblem of incomplete remissions duringimatinib treatment, leads us to a fundamentaltopic in tumor biology andtherapy: tumor cell quiescence (3). Quiescentcells are not only unlikely to undergoapoptosis, but they also do notrespond to conventional anticancer treatmentsthat target dividing cells. Therefore,tumor cell quiescence is an importantproblem for cancer therapy in general.The definition of cellular quiescenceis quite simple. Quiescent cells arecells that lack growth/proliferationand that have exited the cell divisioncycle. Quiescence is a reversiblemechanism, which is in contrastto another cellular state called senescencethat is irreversible. One ofthe main molecular regulators ofquiescence is the cyclin dependentkinase (CDK) inhibitor p27 Kip1 ,whose levels are high in cells thathave entered quiescence (4). P27 Kip1levels on the other hand are regulatedby a protein called SKP2.Since the function of SKP2 is toprepare p27 Kip1 for degradation,SKP2 levels need to be kept low inquiescent cells. In contrast, dividingcells have high levels of SKP2,which results in low levels of p27Kip1 (5). The complex molecularevents of cell cycle regulation in proliferatingand quiescent cells are also depictedin Figure 1.In an attempt to explain the fact of incompleteremissions, we asked whetherimatinib is not only capable of inducingGIST cell apoptosis, but could potentiallyalso lead to tumor cell quiescencein GIST cells. To address this question,we treated a GIST cell line model(GIST882) with imatinib and looked forchanges in the levels of several knownSee DUENSING, Page 10

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 8PDGFRAFrom Page 2never had Gleevec (first-line treatmentor “Gleevec-naïve”). Gleevec-resistantGIST patients are also eligible for aphase II trial of dasatinib in advancedsarcomas in the United States.IPI-504 also effectively inhibited thePDGFRA D842V mutation in the lab by adifferent mechanism than dasatinib.While dasatinib blocks the PDGFRAsignal without damaging the PDGFRAprotein, IPI-504 treatment results in thedestruction of the PDGFRA protein. IPI-504 is an HSP90 inhibitor that was inphase III trials for GIST. This trial wasterminated in April of 2009 because of ahigher than anticipated mortality rate forpatients receiving IPI-504. It remains tobe seen whether other HSP90 inhibitorsin trials will be effective in GIST in generalor the D842V mutation in particular.Several other drugs have also shownsome activity in the lab against theD842V mutation or the closely relatedD816V mutation in KIT. Given the similaritybetween these two mutations onecould speculate that a drug that inhibitsone mutation would have a good chanceof inhibiting the other. In fact, this hasbeen demonstrated with dasatinib whichwas shown to inhibit the KIT D816VDONORSFrom Page 5Richard & LindaStuartMaryTheresa & RichardRobertRichard & EthelSolJohnCatherine & DavidJames H.JohannDonald R.MartinMargaret & RobertOttoPalmerPatzPaylorPedemontePedrickPeelzPelavinPerryPickarPopePraderQuartelRaffnerRafnerRaggambimutation in 2006(Shah et al) andPDGFRA D842Vin 2008 (Dewaeleet al).Some other drugsthat have shown in-vitro activityagainst the D842Vor the KIT D816Vmutation and arestill in clinical trialsare:• MP470 (in phaseI trials) – activeagainst D842V• PKC412 (inphase II trials) –active against D842V• MLN518 (in phase II trials) – hasshown activity against D816V mutation.Drugs that have shown in-vitro activityagainst the D816V or D842V mutationbut appear to have been withdrawn fromdevelopment include:• AP23464• AP23848• XL820 (Trials terminated in GIST)The last few paragraphs illustrate boththe promise and the perils of in-vitroJohn & Elizabeth ReedEgbertRichardsonFrankRidgeMariettaRobinsonMarvin & June RogulChristopher & Carol RooneyJoshuaRozenDavid & Arpi SahrJoel M.SavitsSusanSchechterMarvin J.SchneiderRexfordSchroyerIrwinSchumanM. Patricia ShapiroAnnShowell MarinerStanleySilvermanThomas & Deborah SimpkinsGlenn E.SkaggsThe D842V mutation that occurs in 63% of PDGFRAmutations is resistant to Gleevec and Sutent.testing. It is important to note that onlytwenty percent of drugs that enter intoclinical trials will be approved. Theymay have unacceptable toxicity, limitedeffectiveness, or they may be directedagainst a target that turns out to be lessimportant than it was thought to be.However, for patients with a D842Vmutation entering a clinical trial, in-vitrotesting may prove to be the best availabledetermining factor in choosing adrug treatment.RobertSneedShalerStidham Jr.Mary & William StilesSueStinson MathiosHarveyStorkRonna & Arthur StraussAliceSulkowskiLeo T.Surla Jr.SherylSwansonThelmaSwindellGeorge & Karren TerenNicholas ThornerRichardTompkinsNeofytos TsangarisJohnVanwert Jr.Clarence W.R. WadeWilliam E. Wainrwright Jr.See DONORS, Page 9

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 9DONORSFrom Page 5Heathcote W.CarolJames D.EugeneRay & BeltzSam & DinaAileenKimLIFEFESTFrom Page 1WalesWebbWeillWesleyWhiteheadWileyWishnowWoodwardtreatment. The year 2010 marks thetenth anniversary of a breakthrough inGIST treatment as the first group of patientsto receive a drug to treat metastaticGIST will reach their ten-year survivalbenchmark.The Life Raft Group will be celebratingthis amazing decade of achievementover the course of the next year througha number of events and initiatives, allculminating with Life Fest 2010 on June25-27, 2010 at the Hyatt Regency inJersey City, NJ.On Friday night, June 25, Life Fest2010 will open with a gala event: GIST2010—A Decade of Difference. Theevening will feature a look back at thekey scientific and medical milestonesover the last ten years and a look forwardto the most promising treatmentsPatriciaWoobertElizabeth & Raymond YonkeJudith & Leo ZicklerPeter & Judi ZimmermanSeth D.ZinmanSidney Berger & Co Inc.Executive Health of Coral Gables LCAlbert & Lillian Small FoundationAlliant Energy FoundationBryan & Bryan General PartnersFanman of Rockville. Inc.GE FoundationLloyd DyerM. Cohen CorporationMatrixgroupMBITM Holdings IncNational Steel Rule DiePfizer Foundation Matching GiftsPorter ConsultantsZeitler J. & Engelmann P.If you have any questions or comments aboutthis list, please email us at liferaft@liferaftgroup.org or call us (973) 837-9092.and discoveries on the horizon. Specialrecognition will be given to the 10 WhoMade A Difference, honorees from theGIST patient, medical and scientificcommunities who have not only madesignificant contributions to the understandingand treatment of GIST, butwhose accomplishments have made adifference to the survival of GIST patients.The celebration will continuethroughout the course of the weekendwith other key awards including Humanitarianof the Year, Clinician of theYear and Volunteer of the Year. WithLife Fest 2010’s emphasis on achievementand survival, a new annuallyawardedhonor will be unveiled; TheBeacon of Hope Award for the mostpromising scientific or pharmaceuticalbreakthrough.A retrospective of GIST scientific discoveriesand medical advances as wellas profiles of the Life Fest 2010 honoreeswill be featured in the LRG Newslettersand communications in the monthsleading up to Life Fest 2010. The completeGIST historical retrospective andhonoree profiles will then be compiledfor a special commemorative programthat every Life Fest 2010 attendee willreceive.Finally, in the next ten months, theLife Raft Group will be gathering storiesfrom all those who’ve been involved onthe front lines of GIST—patients, familymembers as well as the scientists, doctorsand nurses who fight alongsidethem. These stories of courage, perseveranceand determination will be featuredthroughout Life Fest 2010, and in amulti-media production to be premieredat Friday night’s gala.Most important of all, Life Fest 2010is a celebration of survival and hope anda time to recognize the enormous courageof every patient and family memberwho has battled and continues to battleGIST. Life Fest 2010 will offer the entireGIST community—GISTpatients, their friends and familymembers, GIST medical professionals,researchers and scientists—anopportunity to cometogether to honor and celebratethe past and to forge a path forwardto find a cure.The view from the Hyatt Regency Hotel of New York City, just a short trip across the river.For more information or to volunteerto help plan Life Fest2010, please contact the LifeRaft Group office at 973-837-9092. If you’d like to share yourstory or that of a loved one,please send us an email atliferaft@liferaftgroup.org.

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 10DUENSINGFrom Page 7regulators of quiescence, includingSKP2 and p27 Kip1 . We indeed found thatlevels of SKP2 decreased in a timedependentmanner after imatinib treatmentas would be expected for cells exitingthe cell division cycle. Consequently,because low levels of SKP2 arenot sufficient to earmark p27 Kip1 for destruction,levels of p27 Kip1 increasedover this period of time indicating thatthe cells were entering quiescence as adirect result of imatinib treatment (6).We next asked which pathways downstreamof KIT are important for enteringquiescence after imatinib treatment. Ithas been shown previously that the socalledPI3K/AKT/mTOR pathway iscrucial for GIST cell survival and that aparallel pathway, the MAPK pathway, isless important in this context. Interestingly,we now found that the same istrue for the induction of quiescence afterimatinib treatment (7).The next question that we addressedwas whether undergoing apoptosis orexiting the cell cycle after imatinib therapyare events that are mutually exclusive.In fact, our experiments showedthat nearly all cells that did not die inresponse to imatinib treatment indeedentered quiescence as indicated by positivityfor p27 Kip1 . These results indicatethat imatinib treatment provokes an either-ordecision with respect to apoptosisor quiescence. However, it is notclear at this point how this decision istriggered within a cell. We then wentone step further and engineered GISTcells to express high amounts of theSKP2 protein. When these cells weretreated with imatinib, they were protectedfrom cell cycle exit and kept proliferating.This indicates that the SKP2/p27 Kip1 axis is actively involved in regulatingthe entry into quiescence duringimatinib.Finally, we wondered whether it wouldbe possible to make use of our findingsand translate them into a clinical application.We decided to look at levels ofthe SKP2 protein in a number of GISTresection specimens and to correlate theresults with clinical parameters. We designeda small tissue microarray containingsamples from about thirty primaryGISTs. When we stained the array forexpression of the SKP2 protein, wefound that the level of SKP2 positivelycorrelated with the mitotic index, indicatingthatthese two parametersare Figure 2related to eachother. Moreimportantly,we found thatthe level ofSKP2 expressionalso correlatedwith anincreased riskfor recurrencemaking highSKP2 expressiona potentialprognosticparameter.In closing, Iwould like tointroduce you to our current model ofthe molecular mechanism of imatinib inGIST (Figure 2). Our findings provideevidence that imatinib has several modesof action in GIST. It is not only able toinduce apoptosis, but also to directlyinduce tumor cell quiescence. Therefore,imatinib itself seems to set the stage forfuture resistance by leading to a pool ofcells that are not actively dividing, butthat are not dead and may already containresistance mutations. These cellscould ultimately give rise to an imatinibresistantclone. Our findings could alsobe the explanation for the fact that evenpatients that do respond to therapy stillhave bulky disease, which bears the riskof relapse when taken off imatinib. Wedo not know which of these two pathwaysprevails in an individual setting.This could be different from patient topatient and from tumor to tumor andcould possibly depend on many factors,such as the mutation type as well as othersthat still need to be defined. Nevertheless,our results indicate that in pursuingour goal to find a cure for GIST wemay need to look for pathways that canmanipulate quiescent tumor cells to undergoapoptosis.References(1) Liu Y, Tseng M, Perdreau SA, Rossi F,Antonescu C, Besmer P, Fletcher JA, DuensingS, Duensing A. Histone H2AX is a mediator ofgastrointestinal stromal tumor (GIST) cellapoptosis following treatment with imatinibmesylate. Cancer Research 2007; 67:2685-2692.(2) Liu Y, Parry JA, Chin A, Duensing S, DuensingA. Soluble histone H2AX is induced byDNA replication stress and sensitizes cells toundergo apoptosis. Molecular Cancer 2008;7:61.(3) Jackson RC. The problem of the quiescentcancer cell. Advances in Enzyme Regulation1989; 29:27–46.(4) Sutterluty H, Chatelain E, Marti A, WirbelauerC, Senften M, Müller U, Krek W.p45SKP2 promotes p27Kip1 degradation andinduces S phase in quiescent cells. Nature CellBiology 1999; 1:207–14.(5) Bashir T, Pagano M. Don't skip the G1phase: how APC/CCdh1 keeps SCFSKP2 incheck. Cell Cycle. 2004; 3:850-852.(6) Liu Y, Perdreau SA, Chatterjee P, Wan L,Kuan, SF, Duensing A. Imatinib mesylate inducesquiescence in gastrointestinal stromaltumor (GIST) cells through the CDH1-SKP2-p27 Kip1 signaling axis. Cancer Research 2008,68:9015-23.(7) Bauer S, Duensing A, Demetri GD, FletcherJA. KIT oncogenic signaling mechanisms inimatinib-resistant gastrointestinal stromal tumor:PI3-Kinase/AKT is a crucial survivalpathway. Oncogene 2007; 26:7552-7559.

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 11Rowan passes with family by his sideMr. Kenneth Ray Rowan, ofMuse, Oklahoma. passedaway peacefully at hisresidence September 30,2009 while in the presence of family andclose friends. He is now in his newhome, serving the Lord as he did here onearth, with love and joy.Kenneth was born in Muse, Oklahomaon September 23, 1941, the son of thelate Earl and Katheryn (Carmack)Rowan.He was a member of Muse Assemblyof God Church and Walnut Ridge MasonicLodge #390 of Hot Springs, Arkansas. He was also Past Master ofSumpter Masonic Lodge in Hot Springs,Arkansas.He was the husband of Jane(Bellinghausen) Rowan. They were marriedDecember 12, 1996 in Reno, Nevada.Kenneth is survived by his wife,Jane of the home, two daughters,Billie Ray Combs and DannyRobichaux of Midwest City,Oklahoma, Tammie MaeNurit Mantz, 46, of ReaganStreet, passed away onWednesday, Sept. 2, 2009, atGeisinger Medical Center,Danville.She was born Oct. 28, 1962, in Israel, adaughter of Uri and Jemina Finkelstein,of Israel. On July 9, 1988, she marriedRichard Mantz, who survives.She was a 1981 graduate of North HollywoodHigh School in Florida and attendedBroward Area Community College,Florida.Nurit was employed byCounty Hearthside Inn,Selinsgrove, and formerlywas employed at Weis FoodService, Northumberland.She enjoyed gardening, beachvacations and trips to NewBisineeru-McDaniel and husband Randyof Moore, Oklahoma, a son, ThomasEdward Rowan and wife Cheryl ofMcCloud, Oklahoma, a step son, SeanTravis Hillyer of Redding, CA.He is also survived by 19 Grandchildren& seven Great Grandchildren, numerousnieces & nephews as well asmany wonderful heartfelt friendsKenneth is preceded in death by hisparents, a son, Gary Rowan, a brother,York City. She was dedicated to herfamily, especially to her two sons andtheir basketball and baseball interests.She attended all their games and keptlarge scrapbooks of their achievements.In addition to her husband, she is survivedby her sons, Andrew, 19, and Taylor,15; two sisters, Vered Reese andDaganit Finkelstein; her father andmother-in-law, Richard and DrenaMantz, of Sunbury; sister-in-law,Melissa Whitmer; and one niece,Jennifer Whitmer.In lieu of flowers, donationsmay be made inNurit's memory tothe Shikellamybasketball team'sfund for its trip to Ireland,in care of TimRichard Earl Rowan, and a sister, BarbaraJean Barrett-Hart.Mark your calendars!GIST Support International is sponsoringan event for GISTers at MD AndersonCancer Center in Houston on October10. Go to www.gistsupport.org/gsi-community/gists.php for more.• GISTers in the New England area willbe meeting on October 17 for a luncheonat the home of Susan Farmer. ContactSusan at sfarmer10@cox.net fordetails.• GCRF still has 2 more walks to go thisyear: October 17 in Washington andOctober 25 in San Jose. Please visitwww.gistinfo.org for information on howto participate.• St Louis GISTers will be meeting onOctober 24. Please emailgiststlouis@hotmail.com for moreinformation.• The LRG will be holding its 4thAnnual NYC Poker Tournament on November19, so email us atliferaft@liferaftgroup.org if you want thedetails.Nurit Mantz, wonderful wife and mother, passes away at 46Foor, 12 Calvin Drive, Selinsgrove, PA17870.

Ensuring That No One Has To Face GIST Alone — Newsletter of the Life Raft Group — October 2009 — PAGE 16T HE LIFE RAFT GROUPStaffExecutive DirectorProgram DirectorScience CoordinatorDirector of Planning & DevelopmentProgram CoordinatorCommunications CoordinatorPatient Registry SupervisorAccounts ManagerDatabase AdministratorFinance ManagerAdministrative AssistantAdministrative AssistantNorman ScherzerTricia McAleerJerry CallMarisa BologneseSara RothschildErin KristoffMagda SarnasGale KennyRoberto PazminoMike VaccariNicole BurkeMatthew MattioliContact the Life Raft GroupVolunteersGeneral Counsel Thomas OverleyDatabase Consultant Steven RiggOfficial Greeter Gail MansfieldFundraising Chairs Marietta RobinsonJohn Poss& Gerald KnappScience Team Jim HughesDavid JosephyMichael JosephyOmer MercierRick WareGlenn WishonRafael VegaPaula VettelBoard of DirectorsExecutive CommitteeJerry Cudzil, PresidentStan BunnRay Montague, Secretary-TreasurerDirectorsRobert BookMia ByrneChris CarleyJim HughesJerry KnappJohn PossMarietta RobinsonRodrigo SalasLarry SelkovitsSilvia Steinhilber40 Galesi DriveWayne, NJ 07470Phone: 973-837-9092Fax: 973-837-9095Internet: www.liferaftgroup.orgE-mail: liferaft@liferaftgroup.orgAlabama Pat George patgeorge@bham.rr.comAlaska Frank Domurat patient@oncologyalaska.comArizona Janeen Ryan tabascocook@yahoo.comColorado Jerry Call jcall@liferaftgroup.orgCalifornia Floyd Pothoven floyd@fastsemi.comMartha Zielinski john.martha@sbcglobal.netConnecticut Helen Steinnagel ahjs@sbcglobal.netFlorida Skip Ryan skipryan@tampabay.rr.comGeorgia Pat Lemeshka riyank@bellsouth.netHawaii Richard Palmer richardpalmer@hawaii.rr.comIdaho Janet Conley jkconley73@cableone.netIllinois Paula Vettel paulav2@sbcglobal.netIndiana Robert Book RMBook2@aol.comIowa Barbara Kepple kepbjk@aol.comLouisiana Jackie Welsh jackie.welsh@mms.govMaine Jodi Merry merryhillacres@hotmail.comMaryland Bonnie Emerson bteensey2@hotmail.comMassachusetts Maura Cesarini mauracesarini@hotmail.comMichigan Ellen Rosenthal ebrosenthal@comcast.netAustralia Katharine Kimball katharine_kimball@hotmail.comBelgium Kris Heyman kh@contactgroepgist.beBolivia Virginia Ossio vossiop@gmail.comBrazil Alexandre Sakano alexandre@sakano.com.brCanada David Josephy djosephy@uoguelph.caChile Piga Fernández piga.fernandez@gmail.comChina Ruijia Mu mu_ruijia@yahoo.comColombia Rafael Vega ravega63@yahoo.esCosta Rica Michael Josephy mjosephy@gmail.comCyprusGeorge Constantinou george@gnora.comDominican Republic Alejandro Miranda ma.689.1215@gmail.comFrance Estelle LeCointe info@ensemblecontrelegist.orgGermanyMarkus Wartenberg wartenberg@lebenshauspost.orgGreeceGeorge Constantinou george@gnora.comHungary Tünde Kazda cmlgist@cmlgist.huIran Negar Amirfarhad negaraf@sympatico.caIreland Carol Jones roycal-re-gist@hotmail.comIsrael Avi Zigdon zigdona@gmail.comItaly Anna Costato anna.costato@virgilio.itJapan Sumito Nishidate eujc@mbj.nifty.comJordan Mohammed Milhem mohammed-milhem@uiowa.eduKenya Francis Kariuki bridgestone@coopkenya.comLithuaniaVirginija Zukauskiene virginija.starkute@gmail.comLife Raft regional chaptersMinnesota Sharon Boudreau redsmb@comcast.netMissouri Katie Campbell campbellksoup@hotmail.comMontana Donna Capps BBR950@aol.comNebraska Sally Norton nordeane@cox.netNevada Erik Krauch erik.krauch@cox.netNew Jersey Anita Getler acgetler@gmail.comNew YorkPat Bonda Swenson pbondaswenson@yahoo.comNorth Carolina Chuck Korte pckorte@att.netOhio Kaye Thompson tnt.1@sbcglobal.netOklahoma Jane Rowan jrowan30@aol.comOregon Gail Mansfield timothy.mansfield1@verizon.netPennsylvania Kimberly Trout musikwithkim@yahoo.comRhode Island Susan Farmer sfarmer10@cox.netSouth Carolina Al Boyle captboo@windstream.netTennessee Alice Sulkowski sulkowskiab@msha.comTexas Kerry Hammett hammett@uthscsa.eduVirginia Sally Jackson spjackson@cox.netWashington Deanne Snodgrass g-d-snodgrass@comcast.netWisconsin Rick Ware rkwelmwood@yahoo.comLife Raft country liaisons: Learn more about the Global GIST Network: www.globalgist.orgMalaysia Yong Choo Sian ycspj2005@yahoo.comMexico Rodrigo Salas rsalas@maprex.com.mxNetherlands Contactgroep GIST bestuur@contactgroepgist.nlNorwayOdd Andreas Tofteng oddandreas@yahoo.comPakistanMuhammad Shahid Rafique rsr_srs@yahoo.comPoland Stan Kulisz listy@gist.plRomania Simona Ene si_mi_ene@yahoo.comRussia Tanya Soldak soldak@rpxi.orgSamoa John Galuvao leasii@gmail.comSaudi Arabia Mohamed-Elbagir Ahmed mohamedelbagir@live.comScotlandHelena Koumbouzis hkoumbouzis@yahoo.comSingapore Robert Richardson jambo@pacific.net.sgSouth Korea Changhoon Lee chlee@mobismiami.comSpainMaria Teresa Jimenez Saladomariateresa.jimenezsalado@telefonica.esSudanMohamed-Elbagir Ahmed mohamedelbagir@live.comSwitzerland Helga Schnorf ulrich.schnorf@bluewin.chThailandKittikhun Pornpakakul kittikun_p@yahoo.comTurkey Haver Tanbay tanbay@tanbay.netU.K. Judith Robinson Judith@ndrobinson.plus.comUruguay Fabrizio Martilotta fabrizio.martilotta@gmail.comVenezuelaMaría Isabel Gómez asaphe_venezuela@yahoo.com