ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumors
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Transcript of ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumors
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ETV1 IS A LINEAGE SURVIVAL FACTOR THAT COOPERATES WITH KIT IN GASTROINTESTINAL STROMAL TUMORSIntroductionTim ButlerMarch 8th, 2012
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Topics for Today
•GI Stromal Tumors (GIST)•KIT Signaling•KIT targeted therapy•ETV1
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Interstitial Cells of Cajal• Discovered by Ramon Cajal • Identified by IHC using KIT• Pacemaker for smooth muscle contraction in gut
Courtesy of Dr. Heinrich
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GI Stromal Tumors (GIST)• Median age of presentation: 65• 75% contain mutations in KIT• 1 case in 100K• Surgery curative in ~50% of patients• Tumors arise from ICCs
Courtesy of Dr. M. Heinrich
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GI Stromal Tumors (GIST)• Median age of presentation: 65• 75% contain mutations in KIT• 1 case in 100K• Surgery curative in ~50% of patients
TumorGastric mucosa
Courtesy of Dr. C. Corless
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KIT
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KIT Signalling
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Targeted KIT Therapy: Imatinib
• With longer term follow up median survival is 5-6 years• 39% of patients alive at 7 years
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Imatinib mesylate
Chemotherapy
Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.
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Imatinib Resistance• Most patients initially
respond to Imatinib therapy
• Over time resistance occurs via secondary mutations
• 2nd and 3rd line therapies used that are unaffected by mutations
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Beyond Imatinib
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Targeted Therapy
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ETS Variant 1 (ETV1)• Member of ETS family of transcription factors• KO mice show defects in motor/sensory neuron
development
Arber et al. 2000 Cell 101:5
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ETV1 and Cancer• ETV1 previously identified as oncogenic
• Recurrent gene fusion in prostate cancer • Amplification in Melanoma
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ETV1 Signaling