Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer
ABSTRACT Background The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. Methods In an open-label, single-group, phase 2 study, we treated 93 patients who had pro- gressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radio- graphic review. Additional end points included the duration of the response, pro- gression-free survival, safety, and changes in serum thyroglobulin concentration. Results Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective re- sponse rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval (CI) was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). Conclusions Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)
Full-textDOI: · Available from: Salvador J Diaz-Cano, Sep 03, 2015
- SourceAvailable from: Wee J Chng
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- "In recent years, phase II clinical trials of various small molecule tyrosine kinase inhibitors (including sorafenib, motesanib and pazopanib) (Gupta-Abramson et al. 2008; Sherman et al. 2008; Bible et al. 2010) have shown modest activity against thyroid cancers (mainly stabilization disease by RECIST criteria) (Cabanillas et al. 2010). The exact mechanism of action of these agents is still uncertain given the poor correlation between the predicted in vitro targets (e.g., RET and BRAF inhibitors) of these agents, mutational status of the tumors (RET and BRAF mutations ) and clinical response. "
ABSTRACT: Advanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo activity of two relatively new histone deacetylase inhibitors (HDACIs), belinostat and panobinostat, and a variety of tyrosine kinase inhibitors (TKIs) against a panel of nine human thyroid cancer cell lines. The anti-proliferative activity and the effects of HDACIs, TKIs and their combinations on thyroid cancer cells were determined by cytotoxicity assays, microarray and immunoblot analyses. Synergism between HDACIs and TKIs was assessed by the median effects model of Chou-Talalay (Calcusyn(®)). Belinostat and panobinostat were active against the thyroid cancer cell lines irrespective of their mutational composition, and belinostat was effective in preventing growth of human thyroid cancer xenografts in immunodeficient mice. Further studies showed that both HDACIs induced apoptosis. HDACI also elevated acetylated histone 3, p21(Waf), and PARP, and decreased levels of phosphorylated ERK and AKT (Ser473). RNA assay analysis suggested both HDACIs modulated genes associated with the cell cycle, DNA damage and apoptosis. Most of the TKI (pazopanib, motesanib, sorafenib and dasatinib) were either inactive in vitro or were active only at high doses. However, the novel combinations of either pazopanib or dasatinib TKIs with either belinostat or panobinostat synergistically inhibited cell growth of thyroid cancer cells in vitro. In summary, these HDACIs either alone or combined with selected TKIs may have a role in treatment of aggressive thyroid cancer.Journal of Cancer Research and Clinical Oncology 07/2013; 139(9). DOI:10.1007/s00432-013-1465-6 · 3.01 Impact Factor
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ABSTRACT: The arrival of a great number of new antineoplastic agents has made it necessary to reclassify all of them. Virtually any mechanism that can provide tumour cells with proliferative advantages over normal cells is being investigated in the search for active drugs. Growth factors and their receptors, intracellular metabolic pathways, pro-angiogenic molecules and many more have become potential targets. We herein propose a classification of anticancer drugs based on the target. Drug may act at different levels: cancer cells, endothelium, extracellular matrix, the immune system and host cells. The tumour cell can be targeted at the DNA, RNA or protein level. Most classical chemotherapeutic agents interact with tumour DNA, whereas monoclonal antibodies and small targeted molecules are directed against proteins. The endothelium and extracellular matrix may also be affected by specific antibodies and small molecules.