Cotargeting Ephrin Receptor Tyrosine Kinases A2 and A3 in Cancer Stem Cells Reduces Growth of Recurrent Glioblastoma.

Autor:	Qazi MA; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., Vora P; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., Venugopal C; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., Adams J; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Singh M; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., Hu A; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Gorelik M; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Subapanditha MK; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., Savage N; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., Yang J; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Chokshi C; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., London M; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Gont A; The Hospital for Sick Children, Toronto, Ontario, Canada., Bobrowski D; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada., Grinshtein N; The Hospital for Sick Children, Toronto, Ontario, Canada., Brown KR; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Murty NK; Department of Surgery, McMaster University, Hamilton, Ontario, Canada., Nilvebrant J; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Kaplan D; The Hospital for Sick Children, Toronto, Ontario, Canada., Moffat J; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Sidhu S; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Singh SK; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario Canada. ssingh@mcmaster.ca.; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 Sep 01; Vol. 78 (17), pp. 5023-5037. Date of Electronic Publication: 2018 Jun 26.
DOI:	10.1158/0008-5472.CAN-18-0267
Abstrakt:	Glioblastoma (GBM) carries a dismal prognosis and inevitably relapses despite aggressive therapy. Many members of the Eph receptor tyrosine kinase (EphR) family are expressed by GBM stem cells (GSC), which have been implicated in resistance to GBM therapy. In this study, we identify several EphRs that mark a therapeutically targetable GSC population in treatment-refractory, recurrent GBM (rGBM). Using a highly specific EphR antibody panel and CyTOF (cytometry by time-of-flight), we characterized the expression of all 14 EphR in primary and recurrent patient-derived GSCs to identify putative rGBM-specific EphR. EPHA2 and EPHA3 coexpression marked a highly tumorigenic cell population in rGBM that was enriched in GSC marker expression. Knockdown of EPHA2 and EPHA3 together led to increased expression of differentiation marker GFAP and blocked clonogenic and tumorigenic potential, promoting significantly higher survival in vivo Treatment of rGBM with a bispecific antibody against EPHA2/A3 reduced clonogenicity in vitro and tumorigenic potential of xenografted recurrent GBM in vivo via downregulation of AKT and ERK and increased cellular differentiation. In conclusion, we show that EPHA2 and EPHA3 together mark a GSC population in rGBM and that strategic cotargeting of EPHA2 and EPHA3 presents a novel and rational therapeutic approach for rGBM. Significance: Treatment of rGBM with a novel bispecific antibody against EPHA2 and EPHA3 reduces tumor burden, paving the way for the development of therapeutic approaches against biologically relevant targets in rGBM. Cancer Res; 78(17); 5023-37. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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