Dual inhibition of epidermal growth factor receptor and insulin-like growth factor receptor I: reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma.
BACKGROUND
Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancer. Most of the approximately 250,000 cases occurring annually in the United States are small, nonaggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures, and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and can have an increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve the outcomes for patients with aggressive CSCC.


METHODS
We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-insulin-like growth factor-I receptor (IGF-IR) antibody, A12, alone or in combination with an anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC.


RESULTS
Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of squamous cell carcinoma (SCC) cell lines in vitro. Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA), microvessel density, and increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92%, respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = .044 and p < .001, respectively).


CONCLUSIONS
These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC.
Galer
Chad E
CE
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Corey
Christina L
CL
Wang
Zhuoying
Z
Younes
Maher N
MN
Gomez-Rivera
Fernando
F
Jasser
Samar A
SA
Ludwig
Dale L
DL
El-Naggar
Adel K
AK
Weber
Randal S
RS
Myers
Jeffrey N
JN
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000873:Anthracenes; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C040207:compound A 12; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000068818:Cetuximab