title: Targeted therapeutic approach for an anaplastic thyroid cancer in vitro and in vivo.
abstract: Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies, being responsible for the majority of thyroid cancer-related deaths. Despite multimodal therapy including surgery, chemotherapy, and radiotherapy, the outcome of ATC is poor. The human ATC cell line MB1, derived from tumor tissue of a 57-year-old man with thyroid cancer and pronounced neutrophilia, was established from surgically excised tumor tissue. The karyotype of the cell line shows many chromosomal abnormalities. Preclinical investigations have shown antitumor activity and effectiveness of the BRAF kinase inhibitor Sorafenib and the proteasome inhibitor Bortezomib. After establishment of the MB1 cell line these agents were applied in vitro and, showing activity in a cell culture model, were also used for in vivo treatment. Sorafenib had some clinical effect, namely normalization of leucocytosis, but had no sustained impact on subsequent tumor growth and development of distant metastasis. Molecular diagnostics of the tumor demonstrated no BRAF mutations in exons 11 and 15 concordant with a rather modest effect of Sorafenib on MB1 cell growth. Clinical benefit was seen with subsequent bortezomib therapy inducing a temporary halt to lymph node growth and a progression-free interval of 7 weeks. Our observations together with previous data from preclinical models could serve as a rationale for selecting those patients suffering from ATC most likely to benefit from targeted therapy. A prospective controlled randomized trial integrating kinase and proteasome inhibitors into a therapeutic regime for ATC is warranted.
authors.affiliation: Medical Oncology, Department of Internal Medicine, University Hospital, Zurich, Switzerland. frank.stenner@usz.ch
authors.forename: Frank
authors.initials: F
authors.lastname: Stenner
authors.forename: Heike
authors.initials: H
authors.lastname: Liewen
authors.forename: Martin
authors.initials: M
authors.lastname: Zweifel
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Joelle
authors.initials: J
authors.lastname: Tchinda
authors.forename: Beata
authors.initials: B
authors.lastname: Bode
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Samaras
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Alexander
authors.initials: A
authors.lastname: Knuth
authors.forename: Christoph
authors.initials: C
authors.lastname: Renner
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011719:Pyrazines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D001897:Boronic Acids; D010671:Phenylurea Compounds; D011719:Pyrazines; D011725:Pyridines; D009536:Niacinamide; D000069286:Bortezomib; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf