The Efficacy of IGF-I Receptor Monoclonal Antibody against Human Gastrointestinal Carcinomas is Independent of k-ras Mutation Status

Abstract

Purpose: Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation.Experimental Design: We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice.Results Conclusions: IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations. Clin Cancer Res; 17(15); 5048-59. Ó2011 AACR.

A Phase I Study of Continuous Oral Dosing of OSI-906, a Dual Inhibitor of Insulin-Like Growth Factor-1 and Insulin Receptors, in Patients with Advanced Solid Tumors

“…Several retrospective assessments of KRAS status in phase III, randomized trials of therapies targeting EGF receptor have confirmed that the activity of these agents is restricted to patients with KRAS wild-type tumors (29,30). In contrast, the efficacy of figitumumab, a monoclonal antibody against IGF1R, has been shown to be independent of KRAS mutational status in cancer cell lines and xenograft models (31). It is noteworthy that the results of the mutation analysis performed in a subset of patients with colorectal cancer in the present study suggest that KRAS-activating mutations do not correlate with a poor response to OSI-906 treatment.…”

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

“…Additionally, the blockage of IGF-1R signaling has been shown to enhance chemotherapy response in preclinical studies of several cancer types including pancreatic and non small-cell lung cancers as well as Ewing's sarcoma [43, 47, 48]. Since IGF-1R and IR are highly homologous, antagonist development was initially focused towards monoclonal antibodies that selectively target IGF-1R and not affect IR signaling, which could lead to dysregulation of glucose homeostasis [21]. Initial clinical studies with IGF-1R antibodies showed some responses in monotherapy and in combination with cytotoxic chemotherapy [49].…”

“…IGF-1R shares significant structural homology with IR, and targeting IGF pathway with IGF-1R inhibitor antibodies is sensible as it only blocks IGF-1R induced mitogenic signaling but is not affecting IR signaling, which could lead to dysregulation of glucose homeostasis [20, 21]. IGF-1R antibodies demonstrated clinical activity in phase 2 studies in small number of patients with select tumor types including Ewing sarcoma, thymoma and thymic carcinoma [22–24].…”

Current and Future Approaches to Target the Epidermal Growth Factor Receptor and Its Downstream Signaling in Metastatic Colorectal Cancer

“…130,131 Signaling of IGFR1 occurs most prominently through the PI3K/AKT pathway and the MAPK pathway, 132 and blockade of IGFR1 suppressed tumorigenicity of several gastrointestinal cancer cell lines in vitro or in murine xenografts in vivo. 133 Although signaling through the insulin receptor might also contribute to cell growth and antiapoptotic 134 Because of these negative results, further development of figitumumab is not being pursued. Ganitumumab is a human IgG1 mAb that targets the IGFR1.…”