Projects per year
Abstract
Hepatocellular carcinoma (HCC) is highly refractory to current therapeutics used in the clinic. DX-2647, a recombinant human antibody, potently neutralizes the action of insulin-like growth factor-II (IGF-II), a ligand for three cell-surface receptors (IGF-IR, insulin receptor A and B isoforms, and the cation-independent mannose-6-phosphate receptor) which is overexpressed in primary human HCC. DX-2647 impaired the growth of tumor xenografts of the HCC cell line, Hep3B; however, xenografts of the HCC cell line, HepG2, were largely unresponsive to DX-2647 treatment. Analysis of a number of aspects of the IGF signaling axis in both cell lines did not reveal any significant differences between the two. However, while DX-2647 abolished phospho (p)-IGF-IR, p-IR and p-AKT signaling in both cell lines, HepG2 showed high levels of p-STAT3, which was unaffected by DX-2647 treatment and was absent from the Hep3B cell line. The driver of p-STAT3 was found to be a secreted cytokine, and treatment of HepG2 cells with a pan- JAK kinase inhibitor resulted in a loss of p-STAT3. These findings implicate the activation of STAT3 as one pathway that may mediate resistance to IGF-II–targeted therapy in HCC.
Original language | English |
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Pages (from-to) | 971-978 |
Number of pages | 8 |
Journal | Translational Oncology |
Volume | 11 |
Issue number | 4 |
DOIs | |
Publication status | Published - 1 Aug 2018 |
Keywords
- IGF-II
- antibody therapy
- resistance
- STAT3
- signalling
- hepatocellular carcinoma
- Bioavailability
Projects
- 1 Curtailed
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Developing new therapeutic strategies for brain cancer
Johns, T.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/17 → 27/11/17
Project: Research