Potential therapeutic target & predictive biomarker Oncogenic IGFBP2 Sonya Song ( 宋韦 ) Beijing Shijitan Hospital Department of Oncology The Capital Medical University Beijing, China 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 Basic Research Translational Research Clinical Research Clinical Practice Biomarker Biomarker-based patient care DiagnosisDiagnosis Therapeutic evaluationTherapeutic evaluation Recurrence/metastasisRecurrence/metastasis PrognosisPrognosis Therapeutic targetTherapeutic target Functions

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

Fuller GN and Zhang W et al. Cancer Res 59: ,1999 First report: IGFBP2 overexpressed in ≥ 80% GBM High Low

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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. Sara Dunlap Dr. Li Xu – Dr. George Wang Beijing Shijitan Hospital, CMU – Dr. Hua Wang Huiyuan Chen – Hong Zhen Yuchen Li – Shouming Kong

Thank You ！