Head and neck cancer as a clinical model for molecular targeting of therapy: combining EGFR blockade with radiation.
OBJECTIVE
The primary purpose of this presentation is to develop the concept that molecular blockade of specific growth factor receptors and signal transduction pathways in combination with radiation will prove a valuable cancer therapeutic strategy. More specifically, the rationale for molecular blockade of the epidermal growth factor receptor (EGFR) system in combination with ionizing radiation for epithelial tumors, such as squamous cell carcinomas (SCCs) of the head and neck (H&N), is described.


METHODS
Preclinical experimentation with in vitro and in vivo model systems regarding the capacity of EGFR blockade, using the monoclonal antibody C225, to modulate SCC tumor growth behavior and response to radiation is presented. The rationale for new clinical trials that are currently exploring this concept are presented.


RESULTS
Blockade of the EGFR system in SCC cell lines with C225 induces G1 cell cycle arrest with an associated decrease in the S-phase fraction. Inhibition of tumor cell proliferation is readily measured following C225 exposure and the corresponding alterations in expression of key regulators of the G1-S cell cycle phase transition are identified. Exposure of SCCs to C225 in culture enhances radiosensitivity following single-dose radiation exposure. Profound augmentation of the in vivo radiation response of SCC tumor xenografts in athymic mice is similarly demonstrated following systemic administration of C225. Preliminary studies are presented regarding potential underlying mechanisms of action for this enhanced tumor response to the combination of C225 and radiation including: (a) proliferative growth inhibition, (b) enhancement of radiation-induced apoptosis, (c) inhibition of damage repair, and (d) downregulation of tumor angiogenic response. Preliminary observations from the Phase III multicenter clinical trial examining C225 plus radiation therapy for advanced H&N cancer patients are provided.


CONCLUSIONS
Molecular inhibition of the EGFR signal transduction system in combination with radiation represents a promising investigational area in cancer therapeutics. Epithelial tumors that are rich in their expression of EGFR (e.g., SCC of the H&N) hold special promise for receptor blockade approaches. More broadly, the ultimate therapeutic effect of selected molecular agents which block specific growth factor receptors and signaling pathways may be enhanced when delivered in combination with radiation.
Harari
P M
PM
Department of Human Oncology, University of Wisconsin School of Medicine and Comprehensive Cancer Center, Madison, WI 53792-0600, USA. harari@mail.humonc.wisc.edu
Huang
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance; D011853:Radiobiology; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors; D000068818:Cetuximab