Antibody Targeting GRP78 Enhances the Efficacy of Radiation Therapy in Human Glioblastoma and Non-Small Cell Lung Cancer Cell Lines and Tumor Models.
Purpose:Non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) have poor median survival. NSCLC and GBM overexpress glucose regulated protein 78 (GRP78), which has a role in radioresistance and recurrence. In this study, we determined the effect of anti-GRP78 antibody and the combined effect of the anti-GRP78 antibody with ionizing radiation (XRT) on NSCLC and GBM cell lines bothin vitroandin vivoExperimental Design:NSCLC and GBM cancer cell lines were treated with anti-GRP78 antibodies and evaluated for proliferation, colony formation, cell death, and PI3K/Akt/mTOR signaling. The efficacy of anti-GRP78 antibodies on tumor growth in combination with XRT was determinedin vivoin mouse xenograft models.Results:GBM and NSCLC cells treated with anti-GRP78 antibodies showed attenuated cell proliferation, colony formation, and enhanced apoptosis. GBM and NSCLC cells treated with anti-GRP78 antibodies also showed global suppression of PI3K/Akt/mTOR signaling. Combining antibody with XRT resulted in significant tumor growth delay in both NSCLC and GBM heterotopic tumor models.Conclusions:Antibodies targeting GRP78 exhibited antitumor activity and enhanced the efficacy of radiation in NSCLC and GBM bothin vitroandin vivoGRP78 is a promising novel target, and anti-GRP78 antibodies could be used as an effective cancer therapy alone or in combination with XRT.Clin Cancer Res; 23(10); 2556-64. ©2016 AACR.
Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri.|Medical Scientist Training Program, Washington University in St. Louis, St. Louis, Missouri.
David Y A
DYA
Dadey
Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri.
Vaishali
V
Kapoor
Medical Guidance Systems, St. Louis, Missouri.
Kelly
K
Hoye
Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri.
Arpine
A
Khudanyan
Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri.
Andrea
A
Collins
Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri. dhallahan@wustl.edu dthotala@wustl.edu.|Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Dinesh
D
Thotala
Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri. dhallahan@wustl.edu dthotala@wustl.edu.|Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri.|Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Dennis E
DE
Hallahan
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000888:Antibodies, Anti-Idiotypic; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse