title: Glycolytic inhibition alters anaplastic thyroid carcinoma tumor metabolism and improves response to conventional chemotherapy and radiation.
abstract: Anaplastic thyroid carcinoma (ATC) accounts for more than 50% of thyroid cancer mortality and is generally refractory to conventional treatment. On the basis of recent studies, we hypothesized that ATC metabolism can be targeted to improve response to chemoradiotherapy. Eight established and authenticated ATC cell lines were sequenced at 140 sites contained within 26 commonly mutated genes to identify novel potential therapeutic targets. Cellular proliferation, energy, and reducing potential stores were measured under conditions of specific nutrient deprivation. Tumor metabolism was evaluated using hyperpolarized (13)C MRI in a murine orthotopic xenograft model of ATC. Sensitivity to chemotherapeutic agents and radiation (XRT) was assayed using cytotoxicity assays. We identified mutations in BRAF, NRAS, and KIT but failed to identify generalized novel targets for therapeutic intervention. ATC cell lines exhibited a mesenchymal phenotype and generalized dependence on glucose for energy, reducing potential and survival. Glycolytic inhibition using 2-deoxyglucose (2-DG) sensitized ATC cells to conventional chemotherapy and external beam radiation. In vivo, 2-DG induced a transient, but significant reduction in ATC metabolic activity. Generalized dependence of ATC cells on glucose catabolism makes them susceptible to the sensitizing effects of 2-DG for radiation therapy and chemotherapy. Under in vivo conditions, 2-DG can inhibit ATC metabolism. However, the modest magnitude and transient nature of this effect suggest the need for antimetabolic agents with more favorable pharmacodynamics to achieve therapeutic effects.
authors.affiliation: Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Vlad C
authors.initials: VC
authors.lastname: Sandulache
authors.forename: Heath D
authors.initials: HD
authors.lastname: Skinner
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Chen
authors.forename: Cristina T
authors.initials: CT
authors.lastname: Dodge
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ow
authors.forename: James A
authors.initials: JA
authors.lastname: Bankson
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D003847:Deoxyglucose / Q000494:pharmacology / Q000627:therapeutic use*; D006019:Glycolysis; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000628:therapy*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003847:Deoxyglucose