gdc-0449 and Squamous-Cell-Carcinoma-of-Head-and-Neck

Surgical treatment remains the standard of care for nonmelanoma skin cancer and is successful for the vast majority of patients with these tumors. The treatment of patients with metastatic or unresectable nonmelanoma skin cancer, however, has until recently been based solely on traditional methods of chemotherapy and radiation. However, these methods have high rates of treatment failure, morbidity, and mortality, and alternative treatment modalities for patients with aggressive or advanced disease are needed. As in other areas of cancer therapeutics, recent research elucidating the molecular basis of cancer development, and the subsequent arrival of targeted molecular inhibitors for cancer therapy, have been met with much excitement. In this review, we seek to illuminate recent developments and future possibilities in the use of targeted molecular inhibitors for treatment of advanced squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans.

Topics: Anilides; Antineoplastic Agents; Benzamides; Carcinoma; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dermatofibrosarcoma; ErbB Receptors; Head and Neck Neoplasms; Humans; Imatinib Mesylate; Molecular Targeted Therapy; Neoplasms, Squamous Cell; Piperazines; Pyridines; Pyrimidines; Skin Neoplasms; Squamous Cell Carcinoma of Head and Neck

The Wnt/β-catenin, EGFR, and PI3K pathways frequently undergo upregulation in head and neck squamous carcinoma (HNSCC) cells. Moreover, the Wnt/β-catenin pathway together with Hedgehog (Hh) signaling regulate the activity of cancer stem cells (CSCs). The aim of this study was to investigate the effects of the combinatorial use of the Wnt/β-catenin and Hh pathway inhibitors on viability, cell cycle progression, apoptosis induction, cell migration, and expression of CSC markers in tongue (CAL 27) and hypopharynx (FaDu) cancer cells. Co-inhibition of Wnt signaling with EGFR or PI3K pathways was additionally tested. The cells were treated with selective inhibitors of signaling pathways: Wnt/β-catenin (PRI-724), Hh (vismodegib), EGFR (erlotinib), and PI3K (HS-173). Cell viability was evaluated by the resazurin assay. Cell cycle progression and apoptosis induction were tested by flow cytometric analysis after staining with propidium iodide and Annexin V, respectively. Cell migration was detected by the scratch assay and CSC marker expression by the R-T PCR method. Mixtures of PRI-724 and vismodegib affected cell cycle distribution, greatly reduced cell migration, and downregulated the transcript level of CSC markers, especially

Topics: Apoptosis; beta Catenin; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Erlotinib Hydrochloride; Head and Neck Neoplasms; Hedgehog Proteins; Humans; Phosphatidylinositol 3-Kinases; Squamous Cell Carcinoma of Head and Neck; Wnt Signaling Pathway

The hedgehog signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened, and based on molecular data, may prevent resistance to EGFR targeting.. To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation. Colony formation (CF) of primary HNSCC cells was studied utilizing the FLAVINO-protocol. Combinatory effects were analysed regarding antagonism, additivity or synergism. Associations between the ex vivo detected mode of action of vismodegib with other treatments related to patient characteristics were assessed and progression-free survival (PFS) in patient groups compared using Kaplan-Meier curves.. Vismodegib suppressed BrdU incorporation significantly stronger than MTT turnover; CF was significantly inhibited at ≥20 µM vismodegib while concentrations <20 µM acted hormetic. Combining 20 µM vismodegib plus docetaxel (T), cisplatin (P), and cetuximab (E), additively enhanced anti-tumoral activity in HNSCC samples from patients with superior PFS highlighting a potential role for ex-vivo testing of this combination for use as a prognostic classifier.. We provide ex-vivo evidence for vismodegib's potential in HNSCC therapies, especially if combined with cetuximab, cisplatin and docetaxel.

Topics: Anilides; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cetuximab; Dose-Response Relationship, Drug; Drug Interactions; ErbB Receptors; Female; Head and Neck Neoplasms; Hedgehog Proteins; Humans; Male; Pyridines; Signal Transduction; Squamous Cell Carcinoma of Head and Neck