Anti-tumor Activity of IGF-1R Kinase Inhibitor PQIP in Colon Cancer

Abstract

Insulin-Like Growth Factors (IGFs) and their receptor, IGF-1R, are frequently expressed in human colon cancers and play important roles in promoting malignancy. We demonstrate that colon cancer cells show dependence upon an IGF2/IGF-1R autocrine loop and have characterized the effects of an IGF1R kinase inhibitor (designated PQIP in vitro and in vivo). PQIP abrogated IGF-1R mediated activation of IRS-1/Akt to inhibit survival signaling and induce apoptosis. Furthermore, PQIP inhibited mitogenesis and anchorage-independent growth in soft agarose at concentrations consistent with inhibition of IGF-1R phosphorylation. Thus, PQIP showed potent in vitro antitumor activity in colon cancer cells. The effects of PQIP on the growth of orthotopically implanted GEO colon cancer xenografts were determined following daily treatment with 75 mg/Kg of drug by oral gavage. Decreased tumor burden in BALB/c nude mice without significant weight loss and toxicity was observed. Fluorescence intensity of the GFP labeled tumors was 3-fold higher in control mice than in treated mice. MRI analysis showed a 5-fold decrease tumor volume in treated mice. TUNEL analysis of treated and sham treated tumors indicated an 8-fold higher rate of apoptosis in PQIP treated tumors. Western blot analysis of the treated tissue samples showed inhibition of IGF1R activation and Akt signaling relative to sham treated animals. Therefore, PQIP represents an attractive therapeutic candidate for targeting IGF1R-dependent colon cancer.