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Abstract

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 both in vitro and in vivo

Experimental 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 determined in vivo in 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 both in vitro and in vivo GRP78 is a promising novel target, and anti-GRP78 antibodies could be used as an effective cancer therapy alone or in combination with XRT. 

Author information​

Dadey DYA1,2, Kapoor V1, Hoye K3, Khudanyan A1, Collins A1, Thotala D4,5, Hallahan DE4,6,5.

1 Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri.

2 Medical Scientist Training Program, Washington University in St. Louis, St. Louis, Missouri.

3 Medical Guidance Systems, St. Louis, Missouri.

4 Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri. dhallahan@wustl.edu dthotala@wustl.edu.

5 Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.

6 Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri.