MEDI-573 Alone or in Combination with Mammalian Target of Rapamycin Inhibitors, Targets the Insulin-like Growth Factor Pathway in Sarcomas

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt d'une molécule appelée MEDI-573, un anticorps anti IGF-1 et IGF-2, seul ou en combinaison avec un inhibiteur de mTOR pour le traitement des patients pédiatriques atteints d'un sarcome d'Ewing

Résumé en anglais

MEDI-573 is a human antibody that neutralizes insulin-like growth factor (IGF)-1 and IGF-2. IGFs are over-expressed in multiple types of cancer; their over-expression is a potential mechanism for resistance to IGF-1 receptor (IGF-1R)-targeting therapy. Effects of IGF on cell proliferation, differentiation, and survival are mediated through its binding to and activation of IGF-1R or insulin receptor A (IR-A). In this study, we measured the mRNA levels of IGF-1, IGF-2 and IGF-1R 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's sarcoma cell lines being the most sensitive. In addition, MEDI-573 inhibited IGF-1- and IGF-2-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 pIGF-1R, pIR-A, and pAKT and significantly blocked IGF-1- and IGF-2-induced activation of the IGF-1R and AKT pathways. MEDI-573 inhibited the growth of sarcoma xenografts in vivo and inhibition correlated with neutralization of IGF-1 and IGF-2. Combination of MEDI-573 with either rapamycin or AZD2014, another mTOR inhibitor, significantly enhanced the anti-tumor 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 IGF-1 and IGF-2, and inhibition of IGF-1 and IGF-2 by MEDI-573 results in significant slowing of tumor growth rate in sarcoma models, particularly in Ewing's sarcoma. This data provides evidence for the potential benefits of MEDI-573 and mTORi combinations in Ewing's sarcoma patients.