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Literature Report

Literature Report. Article source : Gut 2013;62:1415--1424. 李丽婷 2014.3.19. Content. Introduction. Methods. Results . Conclusion. Prospect. Part1: Introduction. Introduction. The basic background. 1.Over 1390 000 diagnoses per annum

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Literature Report

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  1. Literature Report Article source : Gut 2013;62:1415--1424 李丽婷 2014.3.19

  2. Content Introduction Methods Results Conclusion Prospect

  3. Part1: Introduction

  4. Introduction The basic background 1.Over 1390 000 diagnoses per annum 2.By 2030,the 10th leading cause of global mortality. 3.In the western world, over fivefold in 30 years 4.5-year survival: 15% New therapy!!!

  5. Introduction Molecularly targeted therapy (Abnormality : key driver) Inter-patient heterogeneity Therapy resistance Not been broadly adopted ???(target at initial presentation) The aim:1.Determine the most frequently active cell signaling pathways 2.RTK array measuring phosphorylation status could be used to select the most effective and broadly applicable therapy strategies. 3.Apply this approach to human tissue samples as a proof of principle.

  6. Part2: Methods

  7. Methods 1.samples:(1)cancer cohort for gene expression profiling n=75 (2)cases for P-Erkimmunostaining n=434 (3)patient samples for RTK array n= 46 2.Cell line:14 sorts 3.Inhibitor :EGFR/ErbB2 inhibitor,Mekinhibitor,other TIKs(EGFR TKI,Met TKI,FGFR TKI,Ret TKI) Materials 1.GSEA and HOPACH clustering 2.Immunohistochemistry for P-ERK 3.RTK phosphorylation profiling 4.Proliferation assays 5.Apoptosis arrays 6.Protein phosphorylation status MAPK? Experiments RTK? In patients?

  8. Methods

  9. Part3: Results

  10. Results 1.MPAK :enrichment pathway (1)Enrichment scores( figure A)by HOPACH GSEA KEGG (2)50.7%(38/75)of samples enriched for overexpression of signaling pathway (3)MPKA pathway is enriched in 42.7%(32/75)of samples. NE: Normal oesophagus BE:Barrett’soesophagus DYS;Dysplastic Barrett’s AC:Adenocarcinoma GSEA :Gene set enrichment analysis REGG : molecular signatures database HOPACH :cluster simples using pathway enrichment scores

  11. Results 2.Phospho-Erk status confirms MAPK as a key pathway 148/434(34.3%) of cases expressed high levels of phosphorylated (2+,3+)

  12. Results 3.Selective inhibition of activated RTKs inhibits MAPK signalling RTK array : Drug selection to ensure the maximal therapeutic effect. MKNI RTK activation profile Full RTK array In MKNI,with no active RTKs,TKIs or Mek inhibition did not inhibit proliferation until the uM range Proliferation dose-response of MKN1 to TKIs

  13. Results • 3.Selective inhibition of activated RTKs inhibits MAPK signalling One:An obvious dominant RTK Therapy with a singer TKIs RTK activation profile Proliferation dose response to TKIs MEK Cell cycle profile in response to TKIs Western blotting for downstream MAPK components Atk and ERK NOTE:EGFR/ErbB2for OE19,Met ,MKN45,FGFR for KatoIII

  14. Results • 3.Selective inhibition of activated RTKs inhibits MAPK signalling Two :ComplexRTKs activation RIK activation profile Proliferation dose-response to TKIs (Mek inhibition) Cell cycle profile in response to TKIs • Western blotting for downstream MAPK components Atk and ERK • NOTE:FGFR2for HSC39,EGFR,ErbB2,ErbB3,FGFR3,Met and RET for OE33

  15. Results SUMMARY Cell line: OE19,MKN45, KatoIII An obvious RTK activation Therapy with a single TKI HSC39:a combination of three TKIs OE33:dual agent treatment(TKI combination and Mek inhibitor Cell line: HSC39,OE33 Complex PTK activation Patient cohort

  16. Results RTK activation in a patient cohort If RTK array could help in drug selection in patients? RTK activation ? Patient Samples:n=46 RTK array Results :

  17. Part4:Conclusion

  18. Conclusion 1.The MAPK pathway is commonly activated in oesophago –gastric cancer secondary to activation of number of RTK. 2.The RTK activity profile ,using RTK arrays, is useful to guide which TKI would offer therapeutic efficacy.(cell lines) 3.If multiple RTKs are active , inhibition of downstream signaling might offer an alternative clinical approach. (Mek inhibitor) 4. Using an RTK array in patients could help in drug selection to ensue the maximal therapeutic effect.

  19. Part5:Prospect

  20. Prospect 1.Which are the most clinically relevant therapeutic targets? 2.Which is more effective , using a single inhibitor or a combination? 3.How do we translate this information into a therapeutic strategy with maximise outcomes and minimize toxicity?

  21. 李丽婷 邮箱：lilypretty12@163.com

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