Purpose: No effective treatment options currently are available to patients with anaplastic thyroid cancer (ATC), resulting in high mortality rates. Epidermal growth factor (EGF) has been shown to play a role in the pathogenesis of many types of cancer, and its receptor (EGFR) provides an attractive target for molecular therapy.Experimental Design: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. We assessed the potential of the EGFR inhibitor gefitinib ("Iressa," ZD1839) to inhibit EGFR activation in vitro and in vivo, inhibit ATC cellular proliferation, induce apoptosis, and reduce the growth of ATC cells in vivo when administered alone and in combination with paclitaxel.Results: EGFR was overexpressed in ATC cell lines in vitro and in vivo and in human ATC specimens. Activation of EGFR by EGF was blocked by the addition of gefitinib. In vitro studies showed that gefitinib greatly inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of thyroid carcinoma cells injected subcutaneously.Conclusions: ATC cells consistently overexpress EGFR, rendering this receptor a potential target for molecular therapy. Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation, and induces apoptosis in vitro. Our in vivo results show that gefitinib has significant antitumor activity against ATC in a subcutaneous nude mouse tumor model and therefore is a potential candidate for human clinical trials.

Expression of the epidermal growth factor (EGF) and activation of its receptor (EGFR), a tyrosine kinase, are associated with progressive growth of head and neck cancer. Expression of the vascular endothelial growth factor (VEGF) is associated with angiogenesis and progressive growth of tumor. The tyrosine kinase inhibitor NVP-AEE788 (AEE788) blocks the EGF and VEGF signaling pathways. We examined the effects of AEE788 administered alone, or with paclitaxel (Taxol), on the progression of human head and neck cancer implanted orthotopically into nude mice. Cells of two different human oral cancer lines, JMAR and MDA1986, were injected into the tongues of nude mice. Mice with established tumors were randomized to receive three times per week oral AEE788, once weekly injected paclitaxel, AEE788 plus paclitaxel, or placebo. Oral tumors were resected at necropsy. Kinase activity, cell proliferation, apoptosis, and mean vessel density were determined by immunohistochemical immunofluorescent staining. AEE788 inhibited cell growth, induced apoptosis, and reduced the phosphorylation of EGFR, VEGFR-2, AKT, and mitogen-activated protein kinase in both cell lines. Mice treated with AEE788 and AEE788 plus paclitaxel had decreased microvessel density, decreased proliferative index, and increased apoptosis. Hence, AEE788 inhibited tumor vascularization and growth and prolonged survival. Inhibition of EGFR and VEGFR phosphorylation by AEE788 effectively inhibits cellular proliferation of squamous cell carcinoma of the head and neck, induces apoptosis of tumor endothelial cells and tumor cells, and is well tolerated in mice. These data recommend the consideration of patients with head and neck cancer for inclusion in clinical trials of AEE788.

Purpose: To develop an orthotopic model of anaplastic thyroid carcinoma (ATC) in athymic nude mice.Experimental Design: Various thyroid carcinoma cell lines were injected into the thyroid gland of athymic nude mice to determine whether such injection was technically feasible. ATC cells were then injected into the thyroid gland or the subcutis of nude mice at various concentrations, and the mice were then followed for tumor development. The tumors were examined histopathologically for local invasion or regional or distant metastasis.Results: Injection of tumor cells into the thyroid glands of nude mice was technically feasible and resulted in the formation of thyroid tumors. The ATC cell line DRO showed significantly higher tumorigenicity in the thyroid gland than in the subcutis. In contrast, oral squamous cell carcinoma cell line TU167 shows no significantly higher tumorigenicity in the thyroid gland than in the subcutis. ATC tumors established in the thyroid gland also produced symptomatic compression of the esophagus and the trachea. Local invasion of the larynx and trachea was as well as high rates of pulmonary metastasis were also observed. Immunohistochemical staining showed higher microvessel density as well as higher expression of vascular endothelial growth factor and interleukin-8 in the orthotopic thyroid tumors than in ectopic tumors.Conclusion: An orthotopic model of ATC in athymic nude mice was developed that closely recapitulates the clinical findings of human ATC. This model should facilitate the understanding of the pathogenesis of ATC and aid in the development of novel therapies against ATC.

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SummaryTherapies that target signaling pathways critical to the pathogenesis and progression of squamous cell carcinoma of the head and neck (HNSCC) are needed. One such target, phosphatidylinositol 3-kinase, and its downstream target serine/threonine kinase, Akt, are up-regulated in HNSCC. Targeted therapy could consist of inhibitors of these kinases or, alternatively, of inhibitors of the pathways that they regulate. To explore the effect of Akt inhibition on the growth and survival of HNSCC tumors, we evaluated the effect of a novel Akt inhibitor, KP372-1, on the growth, survival, and sensitivity to anoikis of HNSCC cell lines in culture. Using Western blotting of head and neck cancer cell lines and squamous mucosa and carcinoma specimens, we found that Akt was highly phosphorylated in head and neck cancer cell lines and human head and neck squamous carcinoma specimens. Treatment of HNSCC cell lines with KP372-1 blocked the activation of Akt, inhibited head and neck cancer cell proliferation, and induced apoptosis and anoikis in several HNSCC cell lines. Furthermore, KP372-1 decreased the phosphorylation of the S6 ribosomal (Ser240/244) protein, which is a downstream target of Akt. Taken together, these findings indicate that KP372-1 may be a useful therapeutic agent for HNSCC and should be further evaluated in preclinical models of HNSCC.