Objective To determine if microbubble-mediated ultrasound therapy (MB-UST) can improve cisplatin or cetuximab cytotoxicity of head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo by increasing tumor-specific drug delivery by disruption of tumor cell membranes and enhancing vascular permeability. Study Design In vitro and in vivo study. Setting University medical center. Subjects Immunodeficient mice (6 weeks old) and 4 HNSCC cell lines. Methods Changes to cell permeability were assessed in vitro after MB-UST. Cellular apoptosis resulting from adjuvant MB-UST with subtherapeutic doses of cisplatin or cetuximab was assessed by cell survival assays in vitro. The in vivo effect of adjuvant MB-UST in flank tumors was assessed in vivo with histological analysis and diffusion-weighted magnetic resonance imaging (DW-MRI). Results In vitro results revealed that MB-UST can increase cell permeability and enhance drug uptake and apoptosis in 4 HNSCC cell lines. In vivo adjuvant MB-UST with cetuximab or cisplatin showed a statistically significant reduction in tumor size when compared with untreated controls. TUNEL analysis yielded a larger number of cells undergoing apoptosis in tumors treated with cetuximab and adjuvant MB-UST than did cetuximab alone but was not significantly greater in tumors treated with cisplatin and adjuvant MBUST compared with cisplatin alone. DW-MRI analysis showed more free water, which corresponds to increased cell membrane disruption, in tumors treated with MB-UST. Conclusion MB-UST promotes disruption of cell membranes in tumor cells in vitro, which may be leveraged to selectively improve the uptake of conventional and targeted therapeutics in vivo.
Introduction Merck's MK-2206 is an orally active, allosteric inhibitor of AKT; a component of the phosphatidylinositol-3 kinase (PI3K) pathway. The PI3K-AKT pathway is a downstream signaling pathway that has recently been found to play an important role in head and neck squamous cell carcinoma (HNSCC). Here we examine the role AKT inhibitors may play in preventing metastasis in HNSCC. Methods Cell migration after 24 hour treatment with sub-therapeutic doses of MK-2206 was assessed using an ELISA assay in 4 HNSCC cell lines: CAL27, FaDu, SCC-1 and SCC-5). In vitro effect of MK-2206 on cell migration was assessed by making linear scratches in culture plates after cell lines were grown to confluency. Images were taken at 8, 16 and 24 hours. In vivo analysis was performed on Nude mice with human SCC1-orthotopic tongue tumors. After tumors were allowed to grow for 7 days, mice were treated with oral dosing of 120 mg/kg of MK-2206 every other day for 2 weeks. Tumor size was assessed after each treatment using a pair of digital calipers. At the end of the treatment period, mice were sacrificed and cervical lymph nodes were assessed for metastasis using flourescent imaging of tumor cell markers. Results Sub-therapeutic doses of MK-2206 was sufficient to significantly reduce cell migration a in FaDu, SCC-1 and SCC-5 cell lines (p<0.001) but not in Cal27 (p=0.09). In vitro scratch test results in SCC-1 cells yielded significant reduction in cell movement at 8, 16 and 14 hours (p<0.001). In vivo orthotopic model yielded significant reduction in primary tumor size (p=0.04) and reduction in positive cervical lymph nodes (p=0.01) between treatment and control mice. In addition we found 100% survival of MK-2206 treated mice after two weeks of treatment compared with 70 % survival in our control group (p=0.03). Conclusions Treatment with MK-2206 is sufficient to inhibit HNSCC chemotaxis and migration in vitro. In an orthotopic model, treatment with MK-2206 reduces primary tumor size and cervical metastasis while improving survival. MK-2206 currently being used in phase II clinical trials for combination treatment of metastatic solid tumors and may be useful for treating HNSCC as well.
Purpose To evaluate by sequential 18F-FDG PET/CT imaging the therapeutic response to a novel monoclonal antibody targeting human EMMPRIN (extracellular matrix metalloproteinase inducer) in combination with gemcitabine in a pancreatic-tumor xenograft murine model. Procedures Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with PBS, gemcitabine (120mg/kg BW), anti-EMMPRIN antibody (0.2mg), or combination, respectively twice weekly for 2 weeks, while 18F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUVmean) of 18F-FDG and volume of tumors were determined. Results The tumor SUVmean change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group. Conclusions These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment.
Targeting the molecular pathways associated with carcinogenesis remains the greatest opportunity to reduce treatment-related morbidity and mortality. Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a cell surface molecule known to promote tumor growth and angiogenesis in preclinical studies of head and neck carcinoma making it an excellent therapeutic target. To evaluate the feasibility of anti-EMMPRIN therapy, an ex-vivo human head and neck cancer model was established using specimens obtained at the time of surgery (n=22). Tumor slices were exposed to varying concentrations of anti-EMMPRIN monoclonal antibody and cetuximab for comparison purposes. Cetuximab is the only monoclonal antibody currently approved for the treatment of head and neck carcinoma. After treatment, tumor slices were assessed by immunohistochemistry and western blot analysis for apoptosis (TUNEL) and EMMPRIN expression. Of the tumor specimens 33% showed a significant reduction in mean ATP levels after treatment with cetuximab compared with untreated controls, whereas 58% of the patients responded to anti-EMMPRIN therapy (P<0.05). Samples, which showed reactivity to anti-EMMPRIN, also had greater EMMPRIN expression based on immunohistochemistry staining (49%) when compared with nonresponders (25%, P=0.06). In addition, TUNEL analysis showed a larger number of cells undergoing apoptosis in antibody-treated tumor slices (77%) compared with controls (30%, P<0.001) with activation of apoptotic proteins, caspase 3 and caspase 8. This study shows the potential of anti-EMMPRIN to inhibit proliferation and promote apoptosis and suggests its future role in the targeted treatment of head and neck carcinoma.
Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were co-cultured with fibroblasts or inoculated with fibroblasts into SCID mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Co-culture experiments demonstrated fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN silenced cells compared to control vector transfected cells, while inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast co-culture, suggesting the importance of FGFR2 signaling in fibroblast mediated tumor growth. Analysis of xenografted tumors revealed EMMPRIN silenced tumors had a larger stromal compartment compared to control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast independent tumor growth.
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