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Potential therapeutic target & predictive biomarker Oncogenic IGFBP2

Potential therapeutic target & predictive biomarker Oncogenic IGFBP2. Sonya Song ( 宋韦 ) Cancer Research laboratory Beijing Shijitan Hospital Department of Oncology The Capital Medical University Beijing, China. 05/22/2010. Biomarker - Important Link . Translational Research .

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Potential therapeutic target & predictive biomarker Oncogenic IGFBP2

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  1. Potential therapeutic target & predictive biomarker Oncogenic IGFBP2 Sonya Song (宋韦)Cancer Research laboratory Beijing Shijitan Hospital Department of OncologyThe Capital Medical UniversityBeijing, China 05/22/2010

  2. Biomarker - Important Link Translational Research Basic Research Biomarker Clinical Research Clinical Practice Functions • Diagnosis • Therapeutic evaluation • Recurrence/metastasis • Prognosis • Therapeutic target Biomarker-based patient care

  3. IGFBP2 Insulin-like growth factor binding protein 2 • Secreted protein • Belong to IGFBP family

  4. First report: IGFBP2 overexpressed in ≥ 80% GBM High Low Fuller GN and Zhang W et al. Cancer Res59:4228-32,1999

  5. IGFBP2 Overexpressed in ~10 Tumors Types • Glioma • Colorectal cancer • Breast cancer • Prostate Cancer • Ovarian cancer • Melanoma • Lung cancer • Leukemia • …

  6. What’s the Role of “Reactivated” IGFBP2 in Tumor?

  7. IGF-dependent inhibitory role Under the physiological condition IGFBP2 IGF IGF - Predominant in the fetal - Low in the adult IGFBP-2 X IGF IGFI R Cell proliferation, survival etc

  8. IGFBP2 Promotes Glioma Migration & Invasion High Expresser 1 Vector Low Expressor High Expressor 2 Wang et al. Cancer Res 2003; Song et al. PNAS 2003.

  9. IGFBP2-promoting Migration & Invasion Inhibited by IIp45 Xenograft Mouse Model H&E GFP- glioma cells IGFBP2 IGFBP2 + IIp45 Song SW et al, PNAS 2003

  10. IGFBP2 Promotes Glioma Progression in RCAS-tva Transgenic Mice Cerebral cortex PDGFb O ( grade II) (Oligodendroglioma) PDGFb + IGFBP2 AO (grade III) (Anaplastic Oligodendroglioma) Brain stem Dunlap S et al., PNAS, 2007

  11. Preoperative Plasma IGFBP2 Correlates with Tumor Grade & Recurrence Grade Recurrence Recurrence p=0.010 p<0.001 P<0.001 Gliomas Jiang T and Song SW et al，Neuro-Oncology 2009

  12. Preoperative Plasma IGFBP2 Predicts Prognosis 55.7 wks 41.1 wks Glioma Jiang T and Song SW et al, Neuro-Oncology 2009

  13. IGFBP2, oncogenic gene, as therapeutic target and predictive biomarker Molecular Mechanism of IGFBP2 Action in Tumor ?

  14. IGFBP2 Interacts with IIp45 at RGD Domain IGFBP2 IIp45 Song SW et al, PNAS 2003

  15. IGFBP2-C Terminal: RGD domain (Integrin Binding Site) Does IGFBP2 Bind to Integrin ?

  16. IGFBP2 Regulates Integrin Pathway IGFBP2 Binds to Integrinα5 IGFBP2 Up-regulates Integrin Wang, G. K. et al. J. Biol. Chem. 2006

  17. Other Group Studies on IGFBP2 • β-Catenin induces IGFBP2 expressionin transformed intestinal epithelial cells. Oncogene 2005 • IGFBP2 PI3K/Akt pathway in prostate cancer, glioma and breast cancer. PNAS 2007、Growth Factors 2010

  18. Model of IGFBP2 Action in Tumor IGF-independent Stimulatory Role APC/ Wnt / β-Catenin signals IGFBP2 + RGD IIp45 Growth factors Receptors Integrin Ras FAK-Src PI3K Raf Crk Akt Motility Invasion Metastasis Survival EMT Angiogenesis Immunity etc

  19. IGFBP2 could be an “early driver” oncogene in colorectal carcinogenesis Frequent genetic alterations in colorectal cancer Smad4/TGFβRII PI3K / Akt / PTEN + 80% CRC IGFBP2 (Glioma , Prostate cancer) (Early driver) Tumor Initiator

  20. In Summary IGFBP2 as “Early Driver” Oncogene Commits Potential therapeutic target & predictive biomarker !

  21. ACKNOWLEDGMENTS MD Anderson Cancer Center Beijing Tiantan Hospital, CMU • Dr. Wei Zhang Dr. Tao Jiang • Dr. Gregory Fuller Dr. Yi Lin • Dr. Frederick F. Lang Dr. Kaijia Zhou • Dr. SaraDunlap Dr. Li Xu • Dr. George Wang Beijing Shijitan Hospital, CMU • Dr. Hua Wang Huiyuan Chen • Hong Zhen Yuchen Li • Shouming Kong

  22. Thank You！

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