Potential therapeutic target & predictive biomarker

Oncogenic IGFBP2

Sonya Song (Sonya Song ( 宋韦宋韦 )) Cancer Research laboratory

Beijing Shijitan Hospital Beijing Shijitan Hospital Department of OncologyDepartment of Oncology

The Capital Medical UniversityThe Capital Medical UniversityBeijing, ChinaBeijing, China

05/22/2010

Biomarker - Important Link

Basic Research

Translational Research

Clinical ResearchClinical

Practice

Biomarker

Biomarker-based patient care

• Diagnosis Diagnosis

• Therapeutic evaluationTherapeutic evaluation

• Recurrence/metastasisRecurrence/metastasis

• PrognosisPrognosis

• Therapeutic targetTherapeutic target

Functions

IGFBP2IGFBP2

• Secreted protein

• Belong to IGFBP family

Insulin-like growth factor binding protein 2

Fuller GN and Zhang W et al. Cancer Res 59:4228-32,1999

First report: IGFBP2 overexpressed in ≥ 80% GBM

High

Low

IGFBP2 Overexpressed in ~10 Tumors TypesIGFBP2 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

IGFIGF

X

IGF

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 2003Song SW et al, PNAS 2003

IGFBP2-promoting Migration & InvasionIGFBP2-promoting Migration & Invasion Inhibited by IIp45

Xenograft Mouse Model

IGFBP2 Promotes Glioma Progression in RCAS-tva Transgenic Mice

Dunlap S et al., PNAS, 2007

PDGFbPDGFb

PDGFbPDGFb

++

IGFBP2IGFBP2

O ( grade II)O ( grade II)

(Oligodendroglioma) (Oligodendroglioma)

AO (grade III)AO (grade III)

(Anaplastic Oligodendroglioma)(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<0.001p=0.010 p<0.001

Grade Recurrence 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 2003Song 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. 2006

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

IIp45RGD

Growth factors

Receptors

Ras

RafPI3K

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” oncogenein 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！