Type 1 insulin-like growth factor signalling in malignant melanoma

• Main Author: Goodfellow, Mark
• Published: University of Oxford 2013
• Subjects: 619.99477
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599998

Novel therapeutic strategies are sorely required for malignant melanoma, which has been shown to overexpress the type 1 insulin-like growth factor receptor (IGFIR) compared benign naevi. The 10Ft R mediates many features of the malignant phenotype and is an attractive anti-cancer therapeutic target. Inoculation with lGFlR depleted tumour cells has been shown to upregulate MHC Class 1 expression and confer protection from tumour rechallenge in vivo. The initial aim of this project was to investigate effects of IGFlR depletion on MHC Class I expression and its functional significance in melanoma cells IGF 1 R gene silencing, but not IGFIR inhibition, caused a significant increase in surface MHC Class 1 expression in one murine cell line, B16.FIO, but 0/8 human melanoma cell lines. In B16.FI0 cells, increased MHC Class 1 did not affect cell lysis or cytokine production by, or proliferation of, activated T lymphocytes in vitro. These results indicate that the increase in MHC Class I in melanoma cells is not of functional significance. The main focus of this project then addressed a key issue relevant to clinical trials of IGF I R inhibition. Identifying features which render melanoma cells sensitive to IGF1R inhibitors is important to select patients suitable to receive this therapy. The approach was to define changes in gene expression after IGFl or IGflR inhibitor treatment of melanoma cells. Initial experiments were performed to select concentrations of IGF1 and IGFlR inhibitor AZ1225380 I, the latter based on GI50 concentrations. An IGF gene signature was created which was significantly correlated to Ki67 expression, a proliferation marker, in clinical datasets. This suggests a rationale for IGFlR targeting in clinical melanoma. Gene expression profiling identified that IGF and IGflR inhibition had reciprocal effects on expression of HBP1, a transcriptional repressor of prognostic significance in breast cancer. HBPl was validated as an IGFI regulated gene, and experiments using signalling inhibitors indicated that IGFlR regulates HBP I via the P13K pathway. HBPI depletion did not influence effects of IGF IR inhibition on proliferation. However HBP1 induction appeared to mediate effects of AZ12253801 on inhibiting the WNT pathway, measure1 by TOPIFOP reporters, and HBP l depletion enhanced basal and WNT-induced NMYC expression. NMYC has not previously been reported to be a Wnt/β catenin target gene in neoplastic cells. These results encourage further investigation into the effects of IOF 1.K! In regulating HBPl, particularly with respect to dual lGFlR Wnt/β catenin targeting