MAb 806 enhances the efficacy of ionizing radiation in glioma xenografts expressing the de2-7 epidermal growth factor receptor.
OBJECTIVE
Mutations of the epidermal growth factor receptor (EGFR) are common in glioma. The most frequent mutation, de2-7 EGFR/EGFRvIII, occurs in approximately 40% of high-grade gliomas and confers resistance to ionizing radiation (IR). We have previously shown that mAb 806, a novel EGFR-specific antibody, is able to inhibit the growth of U87MG.Δ2-7 glioma xenografts expressing the de2-7 EGFR and may have potential as a therapeutic.


METHODS
Nude mice bearing U87MG.Δ2-7 xenografts were treated with mAb 806 and/or IR. Comparison of tumor volumes, the effect of treatment on angiogenesis as determined by mean vessel density, and expression changes in prosurvival protein pAkt between treatment groups were undertaken.


RESULTS
Treatment of mice bearing U87MG.Δ2-7 xenografts with mAb 806 and IR resulted in schedule-dependent radiosensitization. Maximal benefit was obtained when antibody treatment was given before irradiation, with the greatest inhibition of both tumor angiogenesis and tumor growth. Combination treatment mediated radiosensitization by selectively blocking the phosphorylation of the prosurvival protein Akt at serine 473, a process that is independent of DNA-dependent protein kinase catalytic subunit.


CONCLUSIONS
Our results provide a rationale for the use of mAb 806 in combination with IR for the treatment of glioma and potentially other solid tumors bearing the de2-7 EGFR.
Johns
Terrance G
TG
Ludwig Institute for Cancer Research, Heidelberg, Victoria, Australia.
McKay
Michael J
MJ
Cvrljevic
Anna N
AN
Gan
Hui K
HK
Taylor
Caitlin
C
Xu
Huiling
H
Smyth
Fiona E
FE
Scott
Andrew M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000379:methods; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005910:Glioma / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D011838:Radiation-Sensitizing Agents; C410723:epidermal growth factor receptor VIII; C518939:monoclonal antibody 806; D066246:ErbB Receptors; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt