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Sarcoma Research Laboratory Houston, TX

The desmoid tumor proteome: identifying molecular markers using a clinically annotated tissue microarray. Shohrae Hajibashi, Wei-Lien Wang, Alexander J.F. Lazar, Daniel Tuvin, Carla L. Warneke, Dolores Lopez-Terrada, Raphael E. Pollock, Dina Lev. Sarcoma Research Laboratory Houston, TX.

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Sarcoma Research Laboratory Houston, TX

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  1. The desmoid tumor proteome: identifying molecular markers using a clinically annotated tissue microarray Shohrae Hajibashi, Wei-Lien Wang, Alexander J.F. Lazar, Daniel Tuvin, Carla L. Warneke, Dolores Lopez-Terrada, Raphael E. Pollock, Dina Lev Sarcoma Research Laboratory Houston, TX

  2. Unresolved clinical issues • Lack of prognostic markers • Need for better therapeutics

  3. Bridging the biological gap • Impediments to progress: • Relative rarity • Limited collected human specimens • No cell lines • No animal models • Molecular determinants not well understood

  4. UTMDACC desmoid tissue microarray (TMA) • Formalin-fixed, paraffin-embedded desmoid tumors (195 specimens from 160 patients; 1985-2005) • Clinical information including: • Demographic • Therapeutic • Clinical outcome

  5. UTMDACC desmoid TMA • Automated TMA apparatus: 0.6-mm punch samples (2/case) formatted into three recipient blocks • 195 specimens: 110 primary/ 85 recurrent; 27 autologous pairs; 18 scars • H&E-staining of 4-µm TMA sections used to verify all samples

  6. Clinical annotation • Gender: F 62%; M 38% • Median age: 32 yr old • Site • Superficial trunk 39% • Extremity 38% • Deep trunk/mesentery 13% • Head and neck 10% • Median size: 6 cm • FAP associated: 8%

  7. Desmoid TMA: useful for identifying over-expressed proteins

  8. Example: high -catenin TMA nuclear expression correlates with outcome High, n=49 Low-moderate, n=40 p=0.0406 TMA: ~98% of the desmoids showed nuclear reactivity

  9. Specific mutations in the -catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors Am J Path. 173(5):1518-27; Nov 2008 47 (53%) 20 (22%) 15 (17%) p=0.0002

  10. Next steps…an algorithm for desmoid investigation 1. “Up front” identification of potential desmoid-related/specific over-expressed genes 2. Confirm that gene over-expression leads to protein over production (TMA; different samples) 3. Validate these proteins as prognostic markers 4. Examine as possible targets for therapy

  11. 1. “Up front” identification of potential desmoid-related/specific over-expressed genes Human exonic evidence based oligonucleotide (HEEBOChip) microarray 10 desmoid tumor samples (20 additional specimens; van de Rijn/West; Stanford)

  12. 1. “Up front” identification of potential desmoid-related/specific over-expressed genes

  13. 2. Confirm that gene over-expression leads to protein over production (TMA) ADAM12 MDK Scar Desmoid Scar Desmoid 100% (+) 43% (+)

  14. 3 & 4. Examine ADAM12 as a prognostic marker; possible target for (future) desmoid therapy? ADAM12 protein: disintegrin and metalloprotease; up-regulated in many human cancers Role in tumor progression ECM remodeling resistance to apoptosis prognostic marker: breast/prostate cancers

  15. ADAM12 Actin 3 & 4. Examine ADAM12 as a prognostic marker; possible target for (future) desmoid therapy? ADAM12 over-expressed in desmoid cell cultures NHF Des 12 Des 2 Des 15 Anti-ADAM12 agents in pipe line…

  16. Conclusions and implications: • Needed: comprehensive strategies to identify desmoid-related prognostic markers and therapeutic targets • High throughput gene/protein expression arrays for target identification: a potential approach • TMA studies: intense nuclear -catenin expression associates with less aggressive desmoid behavior • ADAM12: highly expressed in desmoids; currently being studied as a prognostic factor and therapeutic target

  17. Acknowledgements • The Sarcoma Research Laboratory • D. Lev, MD • R. Pollock, MD/PhD • A. Lazar, MD/PhD • Colleagues and staff • Stanford University Medical Center • M. van de Rijn, MD/PhD • R. West, MD/PhD • Desmoid Tumor Research Foundation

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