heinrich & corless laboratories gist research updates: may 2011

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Heinrich & Corless Laboratories GIST Research Updates: May 2011. Genotyping for Clinical Trials. Regorafenib (Bayer) phase II trial Tyrosine kinase inhibitor 3rd/4th line therapy for resistant GISTs Initial results will be reported at ASCO FDA has put the drug on fast-track for review - PowerPoint PPT Presentation

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  • Heinrich & Corless Laboratories

    GIST Research Updates: May 2011

  • Genotyping for Clinical TrialsRegorafenib (Bayer) phase II trialTyrosine kinase inhibitor3rd/4th line therapy for resistant GISTsInitial results will be reported at ASCOFDA has put the drug on fast-track for reviewPhase III trial is getting underwaySyntaHSP90 inhibitor (intravenous)Phase II trial ongoing

  • Genotyping for Clinical TrialsPERSIST trialRon DeMatteos trial of 5 years of adjuvant imatinibMore than 50% enrolledImCloneAntibody against PDGFRAPhase II trial for KIT-mutant or PDGFRA-mutant tumors resistant to imatinib & sunitinibPhase I/II trial for a new drug that Mike will talk about

  • Next Generation DNA SequencingTraditional DNA sequencing is limited to just one part of one gene at a timeSecond-generation DNA sequencers are now available and have begun to revolutionize cancer research by generating information on thousands of genes simultaneouslyStarting last summer, we have been using this new technology to study GISTs

  • Sequencing DataHuman genome consists of 3.2 billion letters (A, C, T, G)Genes comprise only ~2% of our DNA (about 64 million letters)We pre-select the genes, so that only the 64 million letters of interest get sequencedCost: $3,000 per sample

  • Sequencing Data First experiment: 8/2010 Illumina GAIIX~1,000,000,000 letters per experiment Most recent experiment: 4/2011 Illumina HiSeq ~10,000,000,000 letters per experiment

  • Sequencing GIST Tumors

    SourceStatusGenotypesSourceOHSUCompleted3 tumors; 1 KIT & 2 PDGFRA D842VPrimaryDebiec-RychterCompleted6 tumors; KIT exon 9 or 11; some with resistance mutationsPrimary & MetastaticFletcherData analysis in progress5 tumors; KIT exon 9 with varying resistance mutationsMetastaticBauerPending9 tumors; KIT exon 9 or 11; some with resistance mutationsPrimary & Metastatic

  • Confirmed Mutations

    PatientGeneAA Change# exonsExon affectedChrSequence confirmed?1PDGFRAD842V23184q11-q13yesHNRNPA2B1S36G1237p15yes2PDGFRAD842V23184q11-q13yesTP53C135G11517p13.1yesMDN1E661K102146q15yesKELT421M19117q33yesTACR3S435N554q25yesCTNND2N1211S21215p15.2yesINSRS995A221619p13.3-p13.2yes3KITV559D21114q11-q12yesLAS1LQ634L1412Xq12-q13yesODZ1R1519C3124Xq25yesTP53L348S111017p13.1yesCOL1A2G430E52237q22.1yesTP53G245C11717p13.1yesDDEF1/ASAP1W18C2918q24.1-q24.2yesSAT1H53Q33Xp22.1yes

  • 10(A)10(B)PatientGeneAA Change# exonsExon affectedChrSequence confirmed?Gene function4BAZ2BS554F3792q23-q24pendingbromodomain adjacent to zinc finger domainFAM134AV296M982q35pendingPossible relationship with lung ca metastasis?TNFRSF11BI312T558q24pendingosteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligandSERINC2T245N1061p35.1pendingNothing knownSHBGA210V8517p13-p12pendingSteroid binding globulinC10orf82L149M4510q25.3pendingNothing knownIFNGR1N433Y776q23-q24pendinginterferon gamma receptor 1PCDHB16P390H115q31pendingCa++ Cell adhesion7(A)KITD816G21174q11-q12yesLASS2L45M1121q21.2pendingGrowth regulation; sphingolipid synthesisFAM176AV12M432p12pendingApoptosis/autophagyAAASA167T16612q13pendingCOL1A2A683D52347q22.1pending7(B)KITY823D21174q11-q12yesLASS2L45M11212q13pendingGrowth regulation; sphingolipid synthesisFAM176AV12M432p12pendingApoptosis/autophagy8GIPC2L206P641p31.1pendingPDZ-containing proteinPRAMEF2E83K421p36.21pendingNothing knownKITINS_AY502-5032194q11-q12yesKITD816H21174q11-q12yesTP53G245S11717p13.1pendingKITINS_AY502-5032194q11-q12yesKITD820E21174q11-q12pendingTP53G245S11717p13.1pending

  • Knight Diagnostic LaboratoriesThe Corless laboratory has recently been integrated into the new Knight Diagnostic LaboratoriesThese Labs are now operating independent from OHSU HospitalMandate from Dr. Druker:Offer the most advanced genotyping in the countryExpand outreach to serve as many cancer patients as possible