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 – Phase III trial is getting underway Synta – HSP90 inhibitor (intravenous) – Phase II trial ongoing

Genotyping for Clinical Trials PERSIST trial – Ron DeMatteo’s trial of 5 years of adjuvant imatinib – More than 50% enrolled ImClone – Antibody against PDGFRA – Phase II trial for KIT-mutant or PDGFRA-mutant tumors resistant to imatinib & sunitinib Phase I/II trial for a new drug that Mike will talk about

‘Next Generation’ DNA Sequencing Traditional DNA sequencing is limited to just one part of one gene at a time Second-generation DNA sequencers are now available and have begun to revolutionize cancer research by generating information on thousands of genes simultaneously Starting last summer, we have been using this new technology to study GISTs

Sequencing Data Human 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 sequenced Cost: $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 SourceStatusGenotypesSource OHSUCompleted3 tumors; 1 KIT & 2 PDGFRA D842VPrimary Debiec- Rychter Completed 6 tumors; KIT exon 9 or 11; some with resistance mutations Primary & Metastatic Fletcher Data analysis in progress 5 tumors; KIT exon 9 with varying resistance mutations Metastatic BauerPending9 tumors; KIT exon 9 or 11; some with resistance mutations Primary & Metastatic

Confirmed Mutations

Knight Diagnostic Laboratories The Corless laboratory has recently been integrated into the new Knight Diagnostic Laboratories These Labs are now operating independent from OHSU Hospital Mandate from Dr. Druker: – Offer the most advanced genotyping in the country – Expand outreach to serve as many cancer patients as possible