OR05-02 The IGFBP-3/IGFBP-3 Receptor Axis Is a New Therapeutic Target for Triple Negative Breast Cancer

Insulin-like growth factor binding proteins (IGFBPs) are components of the IGF signaling system, which is comprised of ligands IGF-I and IGF-II as well as a family of transmembrane receptors including the IGF-IR and IGF-IIR. IGFBPs bind to both IGF-I and IGF-II with high affinity and are essential for transporting IGFs. This prolongs their half-lives and regulates the availability of free IGFs for interaction with IGF receptors, thereby modulating the effects of IGFs on growth and differentiation. Amongst the six IGFBPs, IGFBP-3, the only IGFBP species regulated by the p53 tumor suppressor, is a well-documented potent tumor suppressor in a variety of human cancer. IGFBP-3 has been further suggested as a potent anti-metastatic factor. Recently, more direct evidence for antitumor effect of IGFBP-3 has been reported in various cancer cells including triple negative breast cancer (TNBC) cells in vitro and in vivo, but the underlying mechanisms of antitumor action of IGFBP-3 are largely unknown. We have identified a new class of cell death receptor called IGFBP-3R, which constitutes a novel cell-death receptor that mediates the anticancer effects of IGFBP-3 in human cancer. IGFBP-3 is significantly reduced whereas IGFBP-3R is broadly expressed in many human cancer types such as breast, prostate, lung and colon cancer. In order to discover novel IGFBP-3/IGFBP-3R antitumor signaling as a therapeutic target, a panel of IGFBP-3R specific monoclonal antibodies (mAbs) have been generated and further identified IGFBP-3R agonistic mAbs acting like IGFBP-3 showing anticancer effects in human cancer cells. Further in vivo studies using a bioluminescent orthotopic TNBC mouse model and Patient Derived Xenograft (PDX) TNBC mouse models demonstrated that administration of IGFBP-3R agonistic mAbs results in significant shrinkage of primary and metastatic tumors up to 75%, accompanying induction of caspase-dependent apoptosis and suppression of tumor-activated NF-κB signaling. More importantly, IGFBP-3R agonistic mAbs have synergistic anticancer effects with therapeutic agents such as carboplatin and Bcl-2 family inhibitors in a variety of human cancer including TNBC, and it was further identified molecular mechanisms involved in its synergy in vitro. These findings clearly demonstrate the IGFBP-3/IGFBP-3R system as a new target and the IGFBP-3R agonists such as IGFBP-3R agonistic mAbs as a new monotherapy and a combination therapy with therapeutic agents for TNBC.