Down-Regulation of Insulin-Like Growth Factor I Receptor Activity by NVP-AEW541 Has an Antitumor Effect on Neuroblastoma CellsIn vitroandIn vivo

Abstract

Purpose: Signaling through insulin-like growth factor I receptor (IGF-IR) is important for growth and survival of many tumor types. Neuroblastoma is sensitive to IGF. Experimental Design: We assessed the ability of NVP-AEW541, a recently developed small molecule that selectively inhibits IGF-IR activity, for neuroblastoma growth effects in vitro and in vivo. Our data showed that, in a panel of 10 neuroblastoma cell lines positive for IGF-IR expression, NVP-AEW541 inhibited in vitro proliferation in a submicromolar/micromolar (0.4-6.8) range of concentrations. Results: As expected, NVP-AEW541 inhibited IGF-II^mediated stimulation of IGF-IR and Akt. In addition to growth inhibition, the drug also induced apoptosis in vitro. Oral administration of NVP-AEW541 (50 mg/kg twice daily) inhibited tumor growth of neuroblastoma xenografts in nude mice. Analysis of tumors from the drug-treated animals revealed a marked apoptotic pattern and a decrease in microvascularization compared with controls. Interestingly, quantitative real-time PCR detected both in vitro and in vivo a significant down-regulation of mRNA for vascular endothelial growth factor (VEGF) caused by NVP-AEW541. In addition, in Matrigel-coated chambers and in severe combined immunodeficient mice tail vein injected with neuroblastoma cells, tumor invasiveness was significantly reduced by this agent. Analysis of IGF-IR expression in a series of 43 neuroblastoma primary tumors revealed IGF-IR positivity in 86% of cases. Conclusions: Taken together, these data indicate that NVP-AEW541 can be considered as a novel promising candidate for treatment of neuroblastoma patients.

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

“…These findings are consistent with reports showing that IGF-IR activation regulates vascular endothelial growth factor production by tumor cells (42,43) and that inhibition of IGF-IR action by antisense, antibody, or tyrosine kinase inhibitor reduces both neovascularization and vascular endothelial growth factor expression in neuroblastoma and Ewing's sarcoma tumors (28,44). Importantly, vascular endothelial growth factor levels are elevated in sera from children with neuroblastoma, osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma (45).…”

“…Epidemiologic data have linked elevated plasma levels of IGF-I and IGF-II with increased risk for major cancers such as breast, colon, lung, and prostate cancers, although no such data are currently available for pediatric cancers (6,(23)(24)(25). Importantly, selective impairment of IGF-IR using different approaches, including antisense technologies, dominant-negative mutants of IGF-IR, tyrosine kinase inhibitors, and neutralizing anti-IGF-IR antibodies, inhibited tumor cell growth, induced tumor cell apoptosis, increased tumor sensitivity to cytotoxic drugs, and decreased metastasis of cancer cells of both adult and pediatric origins (16,(26)(27)(28)(29)(30)(31). These observations provide a strong rationale for targeting IGF-IR against pediatric cancers.…”

Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model

“…26 The ability of Dasatinib to inhibit in vitro invasion of NB cells was tested by using Matrigel-coated invasion chambers. Cells were seeded in the upper chamber in medium supplemented with 5% FCS.…”

Repression of Malignant Tumor Progression upon Pharmacologic IGF1R Blockade in a Mouse Model of Insulinoma

“…It exhibits antitumoral activity upon transplantation of human neuroblastoma, human Ewing sarcoma, human multiple myeloma, and murine fibrosarcoma cells in immunodeficient mice (29)(30)(31)(32). In vitro, IGF1R inhibition has been shown to induce apoptosis in cells relying heavily on IGF1R signaling.…”