efatutazone and Thyroid-Neoplasms

Anaplastic thyroid carcinoma (ATC) is a rare malignancy, accounting for 1-2% of all thyroid cancers. Although rare, ATC accounts for the majority of deaths from thyroid carcinoma. ATC often originates in a pre-existing thyroid cancer lesion, as suggested by the simultaneous presence of areas of differentiated or poorly differentiated thyroid carcinoma. ATC is characterized by the accumulation of several oncogenic alterations, and studies have shown that an increased number of oncogenic alterations equates to an increased level of dedifferentiation and aggressiveness. The clinical management of ATC requires a multidisciplinary approach; according to recent American Thyroid Association guidelines, surgery, radiotherapy and/or chemotherapy should be considered. In addition to conventional therapies, novel molecular targeted therapies are the most promising emerging treatment modalities. These drugs are often multiple receptor tyrosine kinase inhibitors, several of which have been tested in clinical trials with encouraging results so far. Accordingly, clinical trials are ongoing to evaluate the safety, efficacy and effectiveness of these new agents. This Review describes the updated clinical and pathological features of ATC and provides insight into the molecular biology of this disease. The most recent literature regarding conventional, newly available and future therapies for ATC is also discussed.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Deglutition Disorders; Dyspnea; GTP Phosphohydrolases; Hoarseness; Humans; Membrane Proteins; Neck Pain; Neoplasm Staging; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Radiation Exposure; Radiotherapy; Respiratory Sounds; Risk Factors; Stilbenes; Telomerase; Thiazolidinediones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy

A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid cancer.. Patients received efatutazone (0.15, 0.3, or 0.5 mg) orally twice daily and then paclitaxel every 3 weeks. Patient tolerance and outcomes were assessed, as were serum efatutazone pharmacokinetics.. Ten of 15 patients were women. Median age was 59 years. Seven patients received 0.15 mg of efatutazone, 6 patients received 0.3 mg, and 2 patients received 0.5 mg. One patient receiving 0.3 mg of efatutazone had a partial response from day 69 to day 175; 7 patients attained stable disease. Median times to progression were 48 and 68 days in patients receiving 0.15 mg of efatutazone and 0.3 mg of efatutazone, respectively; corresponding median survival was 98 vs 138 days. The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing. Ten patients had grade 3 or greater adverse events (Common Terminology Criteria for Adverse Events), with 2 of these (anemia and edema) related to efatutazone. Thirteen events of edema were reported in 8 patients, with 2 of grade 3 or greater. Eight patients had ≥1 serious adverse event, with 1 of these (anemia) attributed to efatutazone and 1 (anaphylactic reaction) related to paclitaxel. The maximal tolerated dose was not achieved. Angiopoietin-like 4 was induced by efatutazone in tissue biopsy samples of 2 patients.. Efatutazone and paclitaxel in combination were safe and tolerated and had biologic activity.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Immunohistochemistry; Male; Middle Aged; Paclitaxel; PPAR gamma; Thiazolidinediones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of the disease for which new therapeutic options are desperately needed. Previously, we showed that the high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, RS5444, inhibits cell proliferation of ATC cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21). We show here that up-regulation of RhoB is a critical step in PPARgamma-mediated activation of p21-induced cell stasis. Using multiple independently derived ATC cell lines, we found that treatment with RS5444 leads to the up-regulation of RhoB and subsequent activation of p21, and that silencing of RhoB by RNAi blocks the ability of RS5444 to induce p21 and to inhibit cell proliferation. Our results show that transcriptional regulation of RhoB by the nuclear transcription factor PPARgamma is responsible for the induction of p21 mRNA and protein. We further implicate RhoB as a key signaling effector for the growth inhibition of ATC, as treatment with a histone deacetylase inhibitor shown to increase RhoB expression in lung cancer cells caused the up-regulation of RhoB in ATC cells accompanied by increased expression of p21 and inhibition of cell proliferation; this effect occurred even in ATC cells that were unresponsive to RS5444 due to a lack of expression of PPARgamma. Our results implicate RhoB as a novel intermediate in critical signaling pathways and as an additional target for therapeutic intervention in ATC.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Division; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Lentivirus; Mice; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; rhoB GTP-Binding Protein; Suppression, Genetic; Thiazolidinediones; Thyroid Neoplasms; Transplantation, Heterologous

The anti-tumour activity of the novel thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARgamma) agonist CS-7017 was investigated. CS-7017 activated PPARgamma-mediated luciferase expression with an EC(50) of 0.20 nM. In addition, CS-7017 was shown to be highly selective for PPARgamma amongst other PPAR subfamilies. CS-7017 inhibited the proliferation of the human anaplastic thyroid tumour cell line DRO and the pancreatic tumour cell line AsPC-1 in vitro at concentrations as low as 10 nM. In xenograft studies, CS-7017 inhibited the growth of the human colorectal tumour cell line HT-29 in nude mice as well as DRO in nude rats in a dose-dependent manner. At the same dose, an increase in the levels of adiponectin, a surrogate marker for PPARgamma activation, was also observed. CS-7017 prolonged the survival of mice inoculated with murine colorectal tumour Colon 38 with marginal tumour growth inhibition. These preclinical results support the potential utility of CS-7017 in a clinical setting.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Luciferases; Mice; Mice, Nude; PPAR gamma; Thiazolidinediones; Thyroid Neoplasms; Xenograft Model Antitumor Assays

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARgamma fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARgamma, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARgamma agonist (RS5444) that is dependent upon PPARgamma for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC50 for growth inhibition is approximately 0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited three- to fourfold in nude mice. siRNA against PPARgamma and a pharmacological antagonist demonstrated that functional PPARgamma was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARgamma is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Chromans; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor Proteins; Female; Humans; Mice; Paclitaxel; PPAR gamma; Thiazolidinediones; Thyroid Neoplasms; Troglitazone