Abstract
MEDI-573 is a human antibody that neutralizes insulin-like growth factor (IGF) I and IGFII. IGFs are overexpressed in multiple types of cancer; their overexpression is a potential mechanism for resistance to IGFI receptor (IGFIR)-targeting therapy. Effects of IGF on cell proliferation, differentiation, and survival are mediated through its binding to and activation of IGFIR or insulin receptor A (IR-A). In this study, we measured the mRNA levels of IGFI, IGFII, and IGFIR in human pediatric sarcoma xenografts, and protein levels in sarcoma cell lines. MEDI-573 potently inhibited in vitro proliferation of sarcoma cell lines, with Ewing sarcoma cell lines being the most sensitive. In addition, MEDI-573 inhibited IGFI- and IGFII-induced sarcoma cell proliferation in vitro. The effect of MEDI-573 on IGF signaling was also examined. Treatment with MEDI-573 markedly reduced levels of pIGFIR, pIR-A, and pAKT and significantly blocked IGFI- and IGFII-induced activation of the IGFIR and AKT pathways. MEDI-573 inhibited the growth of sarcoma xenografts in vivo and inhibition correlated with neutralization of IGFI and IGFII. Combination of MEDI-573 with either rapamycin or AZD2014, another mTOR inhibitor (mTORi), significantly enhanced the antitumor activity of MEDI-573, and this response correlated with modulation of AKT and mTOR signaling. In summary, sarcoma cells respond to autocrine or paracrine growth stimulation by IGFI and IGFII, and inhibition of IGFI and IGFII by MEDI-573 results in significant slowing of tumor growth rate in sarcoma models, particularly in Ewing sarcoma. These data provide evidence for the potential benefits of MEDI-573 and mTORi combinations in patients with Ewing sarcoma.
Highlights
Insulin-like growth factors (IGFI and IGFII) are involved in regulating cell proliferation, survival, differentiation, and transformation
It has been shown that downregulation of IGFI receptor (IGFIR) expression or blocking its signaling leads to inhibition of tumor growth, both in vitro and in vivo [8, 9], and overexpression of insulin receptor A (IR-A) and IGFII may lead to resistance to IGFIR-directed therapies [10, 11]
IGFI, IGFII, and IGFIR levels and IR-A:IR-B ratio in primary sarcoma xenografts and sarcoma cell lines mRNA levels of IGFI, IGFII, IGFIR, and the IR-A:IR-B ratio in 20 primary sarcoma (Ewing’ sarcoma, osteosarcoma, and rhabdomyosarcoma) xenografts were determined by qRT-PCR (Fig. 1A)
Summary
Insulin-like growth factors (IGFI and IGFII) are involved in regulating cell proliferation, survival, differentiation, and transformation Both IGFI and IGFII are expressed ubiquitously and act as endocrine, paracrine, and autocrine growth factors [1,2,3]. They activate multiple intracellular signaling cascades including the insulin receptor substrate (IRS) protein family, AKT, and MAPK pathways by binding to the insulin-like growth factor 1 receptor (IGFIR) and insulin receptor A isoform Inhibition of IGF signaling increases the susceptibility of tumor cells to chemotherapeutic agents in vivo [2, 4, 8, 12] Inhibition of both IR-A and IGFIR signaling may enhance therapeutic efficacy against IGF-driven cancers [9]
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