Head and neck cancer as a clinical model for molecular targeting of therapy: Combining EGFR blockade with radiation

Purpose/Objective: The primary purpose of this presentation is to develop t he concept that molecular blockade of specific growth factor receptors and signal transduction pathways in combination with radiation will prove a val uable cancer therapeutic strategy. More specifically, the rationale for mol ecular blockade of the epidermal growth factor receptor (EGPR) system in co mbination with ionizing radiation For epithelial tumors, such as squamous c ell carcinomas (SCCs) of the head and neck (H&N), is described. Methods and Materials: Preclinical experimentation with in vitro and in viv o model systems regarding the capacity of EGFR blockade, using the monoclon al antibody C225, to modulate SCC tumor growth behavior and response to rad iation is presented. The rationale for new clinical trials that are current ly exploring this concept are presented, Results: Blockade of the EGFR system in SCC cell lines with C225 induces G( 1) cell cycle arrest with an associated decrease In the S-phase fraction. I nhibition of tumor cell proliferation is readily measured following C225 ex posure and the corresponding alterations in expression of key regulators of the G(1)-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 tu mor xenografts in athymic mice is similarly demonstrated following systemic administration of C225, Preliminary studies are presented regarding potent ial underlying mechanisms of action for this enhanced tumor response to the combination of C225 and radiation including: (a) proliferative growth inhi bition, (b) enhancement of radiation-induced apoptosis, (c) inhibition of d amage repair, and (d) downregulation of tumor angiogenic response. Prelimin ary observations from the Phase III multicenter clinical trial examining C2 25 plus radiation therapy for advanced H&N cancer patients are provided, Conclusion: Molecular inhibition of the EGFR signal transduction system in combination with radiation represents a promising investigational area in c ancer therapeutics. Epithelial tumors that are rich in their expression of EGFR (e.g., SCC of the H&N) hold special promise for receptor blockade appr oaches. 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, (C) 2001 Els evier Science Inc.