The potential utility of recombinant human IGF binding protein-3 (rhIGFBP-3) for the treatment of HER-2-positive breast cancer Free

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HER-2 (erbB2) is a transmembrane tyrosine kinase receptor that is overexpressed in 20-30% of highly malignant breast cancers. Herceptin (Trastuzumab) is a humanized monoclonal antibody that targets HER-2 and has demonstrated clinical activity against HER-2-overexpressing breast tumors. However, development of resistance to Herceptin is common and evidence suggests that the insulin-like growth factor receptor (IGF-IR) may be involved. Previous studies demonstrated that interference with IGF-IR signaling via treatment with recombinant human IGF binding protein-3 (rhIGFBP-3) resulted in dose-dependent growth inhibition of two Herceptin-resistant breast cancer sublines co-overexpressing the IGF-IR and HER-2 (MCF-7/HER2-18 and SKBR3/IGF-IR). Furthermore, rhIGFBP-3 elicited a strong dose-dependent increase in Herceptin sensitivity of SKBR3/IGF-IR and BT474/HerR (a HER-2-overexpressing cell culture-derived Herceptin-resistant subline, displaying moderate IGF-IR levels), but a less marked effect with MCF-7/HER2-18. Recently, rhIGFBP-3 was shown to inhibit the in vivo growth of breast, lung and colon carcinomas, alone or in combination with standard chemotherapeutic agents. The present study was undertaken to evaluate the anti-tumor activity of rhIGFBP-3 in a xenograft model of Herceptin-resistant breast cancer. Mice bearing HER-2-transfected (MCF-7/HER2-18) breast carcinomas were treated with either Herceptin (0.6 or 6mg/kg loading dose and then 0.3 or 3mg/kg, twice weekly i.p.), rhIGFBP-3 (3, 10 or 30mg/kg, twice daily s.c.) or a combination of the two agents. All three doses of rhIGFBP-3 significantly reduced tumor growth throughout the 3 week study. The greatest inhibitory effect (67%) was observed with 10mg/kg rhIGFBP-3. Treatment with low-dose Herceptin (0.3mg/kg) had negligible anti-tumor activity, however the high dose (3mg/kg) reduced tumor growth by 30%. Consistent with the cell culture studies, tumor growth inhibition (78%) by the combination of agents (3mg/kg Herceptin and rhIGFBP-3 at 10mg/kg) was superior to Herceptin alone (30%), but showed only a modest enhancement of the effect produced by rhIGFBP-3 alone (67%). Ongoing studies are aimed at characterizing the molecular signal transduction signature of naïve versus rhIGFBP-3-treated tumors. The potent single agent activity of rhIGFBP-3 against established Herceptin-resistant tumors revealed in this study indicates the value of advancing this agent into human clinical trials for HER-2-positive breast cancer patients.