gdc-0449 and Head-and-Neck-Neoplasms

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

To demonstrate the efficacy of the hedgehog pathway inhibitor GDC-0449 in the treatment of advanced basal cell carcinoma.. Case series.. Three patients treated in a referral center for locally advanced basal cell carcinoma, one with metastases, were referred for treatment in a GDC-0449 phase I clinical trial. The treatment was once per day continuous therapy with oral GDC-0449.. Two patients showed complete clinical and radiologic resolution of disease, whereas one patient had significant reduction in tumor burden with radiologic evidence of slowly progressive local disease. Side effects were taste changes, mild to moderate hair loss, and muscle cramps in one patient.. GDC-0449 showed significant inhibitory activity in the treatment of advanced basal cell carcinoma.

Topics: Adult; Anilides; Biopsy; Carcinoma, Basal Cell; Diagnosis, Differential; Female; Follow-Up Studies; Head and Neck Neoplasms; Hedgehog Proteins; Humans; Male; Middle Aged; Positron-Emission Tomography; Pyridines; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome

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

Vismodegib, an inhibitor of the Hedgehog signaling pathway, is an approved drug for monotherapy in locally advanced or metastatic basal cell carcinoma (BCC). Data on combined modality treatment by vismodegib and radiation therapy, however, are rare. In the present study, we examined the radiation sensitizing effects of vismodegib by analyzing viability, cell cycle distribution, cell death, DNA damage repair and clonogenic survival in three-dimensional cultures of a BCC and a head and neck squamous cell carcinoma (HNSCC) cell line. We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells. Furthermore, vismodegib significantly reduced proliferation in both cell lines, while additional irradiation only slightly further impacted on viability. Analyses of cell cycle distribution and cell death induction indicated a G1 arrest in BCC and a G2 arrest in HNSCC cells and an increased fraction of cells in SubG1 phase following combined treatment. Moreover, a significant rise in the number of phosphorylated histone-2AX/p53-binding protein 1 (γH2AX/53BP1) foci in vismodegib- and radiation-treated cells was associated with a significant radiosensitization of both cell lines. In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Line, Tumor; Combined Modality Therapy; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Hedgehog Proteins; Histones; Humans; Organ Specificity; Pyridines; Radiation-Sensitizing Agents; Signal Transduction; Skin Neoplasms; Survivin; Tumor Suppressor Protein p53; Zinc Finger Protein GLI1

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

Definitive radiotherapy and vismodegib, an oral inhibitor of the hedgehog pathway, are both established treatment options for locally advanced basal cell carcinomas (BCC). Both have shown good results in local tumor control; however, the effects concerning advanced tumors are often not of a lasting nature and to date no systematic data about the combination of the two modalities are available.. We retrospectively analyzed four patients who received vismodegib and radiotherapy in combination. Radiation doses varied between 50.4 Gy and 66.0 Gy. Three patients had recurrent BCC. One patient had locoregional lymph node involvement. Vismodegib was taken once a day (150 mg) during the entire time of irradiation and beyond upon instructions of the attending dermatologist.. In three cases a persistent complete response was observed, in one case the tumor remained stable for approximately 6 months until further tumor progression was documented. The combined therapy was well tolerated in all cases. No exceptional side effects pointing at a drug-radiation interaction were observed.. The combination of vismodegib and radiation seems feasible and the initial results are promising. In our cohort, there was no increase in unexpected side effects. Further research is needed to evaluate the significance of this combined therapy.

Topics: Aged; Aged, 80 and over; Anilides; Carcinoma, Basal Cell; Chemoradiotherapy; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Pyridines; Radiotherapy Dosage; Retrospective Studies; Skin Neoplasms

Vismodegib has been approved for treatment of locally advanced or metastatic basal cell carcinoma (BCC). Its use for postirradiation multiple BCCs has not yet been reported.. We sought to investigate the effectiveness and safety of vismodegib for the treatment of recurrent radiation-induced multiple BCCs.. Patients with recurrent multiple BCCs treated with vismodegib and a history of exposure to radiation treatment were followed up prospectively at a tertiary dermato-oncology clinic during a 19-month period.. Eight patients met the study criteria. Mean duration of vismodegib treatment was 29 weeks (range 2-52), and of follow-up, 34 weeks (range 8-64). Drug tolerability was acceptable in 7 patients, of whom 4 showed a partial response and 3 had stable disease. In 1 patient, vismodegib was discontinued soon after its initiation because of a severe drug-induced eruption.. Small sample size and short follow-up time are limitations.. Vismodegib holds promise for the treatment of the subpopulation of patients with radiation-induced multiple BCCs in whom therapeutic options have so far been limited.

Topics: Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Neoplasms, Radiation-Induced; Pyridines; Scalp; Skin Neoplasms

Topics: Anilides; Antineoplastic Agents; Basal Cell Nevus Syndrome; Drug Resistance, Neoplasm; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoadjuvant Therapy; Pyridines; Scalp; Skin Neoplasms; Skin Transplantation