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|Ref Type||Journal Article|
|Authors||Zhong H, Fazenbaker C, Breen S, Chen C, Huang J, Morehouse C, Yao Y, Hollingsworth RE|
|Title||MEDI-573, alone or in combination with mammalian target of rapamycin inhibitors, targets the insulin-like growth factor pathway in sarcomas.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|MEDI-573||IGF1/2 Antibody 2||MEDI-573 is an antibody that targets IGF-1 and IGF-2, resulting in decreased IGF-mediated signaling and potentially leading to decreased tumor growth (PMID: 25193511).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Ewing sarcoma||not applicable||MEDI-573 + Sirolimus||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of MEDI-573 and Rapamune (sirolimus) resulted in decreased Rapamune (sirolimus)-induced AKT activation and inhibited growth of a Ewing sarcoma cell line in culture and inhibited tumor growth Ewing sarcoma cell line xenograft models, with increased efficacy compared to either as a single agent (PMID: 25193511).||25193511|
|Unknown unknown||Ewing sarcoma||not applicable||MEDI-573 + Vistusertib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of MEDI-573 and Vistusertib (AZD2014) inhibited proliferation of a Ewing sarcoma cell line in culture, and inhibited tumor growth in a Ewing sarcoma cell line xenograft model, with increased efficacy compared to either as a single agent (PMID: 25193511).||25193511|