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

Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Head & Neck (Impact Factor: 2.64). 02/2011; 33(2):189-98. DOI: 10.1002/hed.21419
Source: PubMed


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.
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.
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).
These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC.

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Available from: Dale Ludwig, May 06, 2014
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    • "Recent success involving the therapeutic use of antibodies and small molecule inhibitors against tyrosine kinases have generated considerable interest in research aimed at targeting these receptors in a wide variety of malignancies. In an attempt to improve the treatment of cSCC, Galer [81] explored the effect of inhibition of two of these receptors on cutaneous tumor growth in vitro and in vivo. The insulin-like growth factor-I receptor(IGF-IR) is a ubiquitous transmembrane tyrosine kinase composed of two extracellular alpha subunits and two intracellular beta subunits [82-83]. "
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    ABSTRACT: Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC.
    Cancers 12/2011; 3(2):2255-73. DOI:10.3390/cancers3022255
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    • "The increased expression or dysregulation of EGFR in NMSC makes use of cetuximab an attractive avenue of research for treatment of cSCC [96, 97]. Anti-insulin-like growth factor antibody with anti-EGFR antibody has shown induced apoptosis in vitro and improved survival in mice with cSCC [98]. Future avenues of therapy with monoclonal antibodies are becoming increasingly more studied for use in cSCC. "
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    ABSTRACT: Cutaneous squamous cell carcinoma of the head and neck is an epidemic that reaches all parts of the world. Making the diagnosis relies on the acumen of the clinician and pathologist. Various pathologic subtypes exist and differ in histology and prognosis. High-risk tumors need aggressive treatment and vigilant surveillance to monitor for recurrence. Large tumors, deep tissue invasion, perineural involvement, recurrence, location in high-risk areas, and immunosuppression are implicated in worsening prognosis. Surgery is the mainstay of treatment with adjuvant radiation therapy as needed for aggressive tumors; however, other modalities are potentially useful for low-risk lesions. The use of Mohs surgery has become increasingly useful and has shown high success rates. Involvement of parotid and neck lymph nodes significantly affects outcomes and the physician should be comfortable with management of this complex disease. This paper examines the diagnosis, pathology, clinical course, and treatment options for cutaneous squamous cell carcinoma of the head and neck.
    02/2011; 2011(61, supplement):502723. DOI:10.1155/2011/502723
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    ABSTRACT: The use of monoclonal antibodies (mAbs) has become a general approach for specifically targeting and treating human disease. In oncology, the therapeutic utility of mAbs is usually evaluated in the context of treatment with standard of care, as well as other small molecule targeted therapies. Many anti-cancer antibody modalities have achieved validation, including the targeting of growth factor and angiogenesis pathways, the induction of tumor cell killing or apoptosis, and the blocking of immune inhibitory mechanisms to stimulate anti-tumor responses. But, as with other targeted therapies, few antibodies are curative because of biological complexities that underlie tumor formation and redundancies in molecular pathways that enable tumors to adapt and show resistance to treatment. This review discusses the combinations of antibody therapeutics that are emerging to improve efficacy and durability within a specific biological mechanism (e.g., immunomodulation or the inhibition of angiogenesis) and across multiple biological pathways (e.g., inhibition of tumor growth and induction of tumor cell apoptosis).
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