HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: ERC-08-0335v1 16/3/715    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Woyach, J. A Articles by Shah, M. H PubMed PubMed Citation Articles by Woyach, J. A Articles by Shah, M. H

¹ Department of Internal Medicine
² The Ohio State University Comprehensive Cancer Center, The Ohio State University, A438 Starling-Loving Hall, 320 West 10th Avenue, Columbus, Ohio 43210, USA

(Correspondence should be addressed to M H Shah at The Ohio State University Comprehensive Cancer Center, The Ohio State University; Email: manisha.shah{at}osumc.edu)

	Abstract

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
The spectrum of thyroid cancers ranges from one of the most indolent to one of the most aggressive solid tumors identified. Conventional therapies for thyroid cancers are based on the histologic type of thyroid cancers such as papillary or follicular thyroid cancer (differentiated thyroid cancer (DTC)), medullary thyroid cancer (MTC), or anaplastic thyroid cancer (ATC). While surgery is one of the key treatments for all such types of thyroid cancers, additional therapies vary. Effective targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid stimulating hormone suppression and radioactive iodine therapy. However, for the iodine-refractory DTC, MTC, and ATC there is no effective systemic standard of care treatment. Recent advances in understanding pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed the field of clinical research in thyroid cancer. Over the last five years, incredible progress has been made and phases I–III clinical trials have been conducted in various types of thyroid cancers with some remarkable results that has made an impact on lives of patients with thyroid cancer. Such history-making events have boosted enthusiasm and interest among researchers, clinicians, patients, and sponsors and we anticipate ongoing efforts to develop more effective and safe therapies for thyroid cancer.

	Background

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
Thyroid cancer is the most common malignancy of the endocrine system, and a disease whose incidence has been increasing over the past 20 years (Davies & Welch 2006). This heterogeneous disease is classified into differentiated thyroid carcinoma (DTC), undifferentiated (anaplastic) thyroid carcinoma (ATC), poorly DTC, and medullary thyroid carcinoma (MTC). DTCs are by far the most common, and include the major subtypes of papillary and follicular as well as rare tumors derived from these subtypes. Most DTCs are indolent tumors, and, when identified at an early stage, are almost always cured through surgery and/or radioactive iodine therapy (¹³¹I). However, 5-year disease-specific survival of patients with DTC with distant metastases is <50% (Shaha et al. 1997, Hundahl et al. 1998). Current guidelines for treatment of progressive DTC include optimization of thyroid stimulating hormone (TSH) suppression, ¹³¹I, resection of selected metastases, and bisphosphonates for bony metastases. While doxorubicin is the only cytotoxic chemotherapy currently approved through the Food and Drug Administration (FDA) of the USA, due to low short-lasting response rates and high toxicity profile, it is not routinely used in the management of thyroid cancers (Gottlieb & Hill 1974, Shimaoka et al. 1985, Williams et al. 1986, De Besi et al. 1991, Argiris et al. 2008).

Unlike DTC, MTC is derived from parafollicular C cells of the thyroid and can occur as part of the inherited syndromes such as multiple endocrine neoplasia (MEN)-2. Surgery is the only effective therapy, however, at the time of diagnosis 50–80% of patients have metastatic disease. Like DTC, patients with metastatic disease do poorly, with a 5 year survival of <50% (Hundahl et al. 1998). ATC are almost always aggressive and often not diagnosed until advanced stages (Kebebew et al. 2005). For ATC, multimodality treatment including surgery, radiation, and chemotherapy is the standard of care. However, median survival of this group of patients is <1 year.

	Novel insights in the pathogenesis of thyroid cancer

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
Cancer therapy has been revolutionized by the advent of therapies that selectively target cancer cells while sparing normal cells. Initial interest in this field grew with the successful development of the tyrosine kinase inhibitor imatinib for chronic myelogenous leukemia (Druker et al. 2001). Since this time, numerous small molecule tyrosine kinase inhibitors have been developed and tested in a variety of tumor types. The success of these inhibitors hinges on the discovery of appropriate targets so integral in tumorigenesis that their disruption is catastrophic for the tumor. The phenomenon called ‘oncogene addiction’, where the growth and survival of tumor can often be impaired by the inactivation of a single oncogene, has been described in a variety of tumors (Weinstein 2002, Weinstein & Joe 2008). In thyroid cancer, the targets that have been best described include the RET/papillary thyroid carcinoma (PTC), RAS, and BRAF. Non-overlapping rearrangement of RET/PTC, and mutations of RAS, BRAF, and neurotrophic tyrosine kinase receptor 1 (NTRK1) have been found in 70% of PTC (Xing 2005).

With the juxtaposition of various genes to the RET gene, a chimeric protein, RET/PTC, is produced, whose constitutive expression has been implicated in the development of PTC (Viglietto et al. 1995, Jhiang et al. 1996). Similarly, germline mutations of RET are hallmark of the MEN-2 (Santoro et al. 1990), and these mutations are seen in 26–48% of sporadic MTC (Shan et al. 1998, Uchino et al. 1999, Dvorakova et al. 2008, Elisei et al. 2008). Activating mutations of RAS occur in 30% of follicular thyroid carcinoma (FTC). In 2002, Davies et al. (2002) reported a breakthrough discovery of activating mutations in BRAF gene in human cancer. Soon after discovery of BRAF as an oncogene for variety of human cancers, BRAF was found to be mutated (BRAF^V600E) in 28–69% of PTC (Cohen et al. 2003, Fukushima et al. 2003, Kimura et al. 2003, Namba et al. 2003, Nikiforova et al. 2003, Soares et al. 2003, Xu et al. 2003, Trovisco et al. 2004, Xing et al. 2004). BRAF is a non-receptor serine threonine kinase involved in the RAS/RAF/MAPK/ERK signaling cascade (Fig. 1). Targeted expression of BRAF^V600E in thyroid cells of transgenic mice induces goiter and invasive PTC, which transforms into poorly differentiated carcinomas (Knauf et al. 2005). Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type BRAF and BRAF^V600E induced a comparable reduction of cancer cell viability. In addition to PTC, BRAF mutations also have been observed in 10–25% of ATC (Nikiforova et al. 2003, Santarpia et al. 2008). Like the RET/PTC, mutations in BRAF are thought to occur early in tumorigenesis (Nikiforova et al. 2003) and have been seen in aggressive thyroid cancers making this an attractive target for molecular therapies as well. Metalloproteinases (MMP) were shown to be induced by BRAF, particularly MMP3, MMP9, and MMP13 in an experimental model using rat thyroid PCCL3 cells (Mesa et al. 2006).

View larger version (60K): [in this window] [in a new window]   Figure 1 The RAS–RAF–MAP kinase signaling pathway. Reprinted by permission from Macmillan Publishers Ltd: Pollock PM & Meltzer PS 2002 Nature 417(6892) 906–907, copyright (2002).

Another receptor tyrosine kinase that has gained interest in thyroid cancer in addition to other malignancies is c-Met, a proto-oncogene that is the high-affinity receptor for hepatocyte growth factor and is important for regulation of cell migration, proliferation, differentiation, and angiogenesis (Jiang et al. 1999). In PTC, overexpression of c-Met has been found in 70% of patients (Di Renzo et al. 1992), and ATC is associated with constitutively active c-Met as well (Bergstrom et al. 1999). In PTC, high levels of c-Met expression correlate inversely with the presence of distant metastasis (Belfiore et al. 1997). It has also been shown that the epidermal growth factor receptor (EGFR) is important in the regulation of c-Met (Bergstrom et al. 2000), and that RAS and RET upregulate c-Met (Ivan et al. 1997), identifying all as potential therapeutic targets.

The EGF and its receptor are attractive molecular targets for cancer therapy. EGF has shown to stimulate thyroid follicular cell proliferation (van der Laan et al. 1995) and increase the proliferation and invasion of DTC cells in culture and in nude mice (Hoelting et al. 1994).

Although it has been known for decades that angiogenesis is central to tumor development, we consider it relevant to mention its role in thyroid cancer pathogenesis (Lennard et al. 2001, Lewy-Trenda & Wierzchniewska-Lawska 2002, Tanaka et al. 2002, Bauer et al. 2003, Lin et al. 2003) due to recent availability of potent and specific inhibitors of angiogenesis in the clinic. In order for tumors to grow and metastasize, they must acquire angiogenic capability (Gullino 1978) to provide their own blood supply. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are among the potent angiogenic factors that are implicated in pathogenesis of a variety of cancers including thyroid cancers (Fig. 2). VEGF binds to a family of membrane-bound receptor tyrosine kinases, VEGF receptors (VEGFRs) 1–4, resulting in subsequent down-stream signaling and release of angiogenic factors with subsequent new blood vessel formation.

View larger version (119K): [in this window] [in a new window]   Figure 2 Tumor angiogenesis. Reprinted by permission from Macmillan Publishers Ltd: Cristofanilli M, Charnsangavej C & Hortobagyi GN 2002 Nature Reviews. Drug Discovery 1 415–426, copyright (2002).

	Preclinical studies

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

Sorafenib, a multi-kinase inhibitor targeting BRAF, VEGFR, PDGFR, and RET, was shown to suppress BRAF signaling and cell/tumor growth when tested in vitro and in xenograft models (Salvatore et al. 2006). Knockdown of BRAF by small inhibitory duplex RNA inhibited the MAP kinase signaling and the growth of ATC cells. Similar inhibition was achieved with sorafenib at half-maximal inhibitory concentrations (IC₅₀) of 0.5–1 mmol/l in thyroid carcinoma cells but not in normal thyrocytes. ATC xenografts were significantly smaller in nude mice treated with sorafenib than in control mice. This inhibition was associated with suppression of phospho-MAP kinase levels. Subsequently, RET kinase was reported to be a target in multi-kinase inhibitor spectrum of sorafenib based on its testing in pre-clinical models of RET mutated PTC and MTC (Carlomagno et al. 2006). Sorafenib inhibited oncogenic RET kinase activity at IC₅₀ of <50 nM in oncogenic RET-transfected NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts transformed by oncogenic RET and of thyroid carcinoma cells, human TPC1 (PTC cell line), and TT (MTC cell line), that harbor spontaneous oncogenic RET alleles. After 3 weeks of treatment with oral sorafenib, the volume of TT cell xenografts was reduced from 72 to 44 mm³, whereas in vehicle-treated mice, mean tumor volume increased to 408 mm³ (P=0.02). This inhibition paralleled a decrease in RET phosphorylation. Another study targeting the BRAF expression using a small inhibitory RNA construct in thyroid cancer cell lines induced a comparable reduction of viability in both wild-type BRAF and BRAF^V600E mutant cancer cells (Mitsiades et al. 2007). Furthermore, AAL881, BRAF kinase inhibitors, inhibited MEK and ERK phosphorylation, and induced apoptosis preferentially in BRAF^V600E-harboring cells over wild-type cells.

Vandetanib (ZD 6474)

Vandetanib is an anilinoquinazoline multi-tyrosine kinase inhibitor targeting VEGFR and EGFR signaling. Like sorafenib, this drug also inhibits the RET oncoprotein making it an interesting targeted therapy for both PTC and MTC. It has been shown that vandetanib blocks the enzymatic activity of RET-derived oncoproteins at IC₅₀ of 100 nM (Carlomagno et al. 2002). Vandetanib also blocked in vivo phosphorylation and signaling of the RET/PTC3 and RET/MEN2B oncoproteins and of an EGF-activated EGFR/RET chimeric receptor. Furthermore, vandetanib prevented the growth of two human PTC cell lines that carry spontaneous RET/PTC1 rearrangements and blocked the formation of tumors after injection of NIH-RET/PTC3 cells into nude mice.

Sunitinib

Sunitinib is another multi-tyrosine kinase inhibitor that targets VEGFR, PDGFR, and c-kit. It has also been shown to target RET/PTC, both blocking proliferation of TPC-1 cells that harbor RET/PTC1 rearrangement and causing morphologic reversal of transformed NIH-RET/PTC3 cells (Kim et al. 2006).

Gefitinib

Gefitinib is a tyrosine kinase inhibitor targeting an EGFR, which blocks its auto-phosphorylation and signal transduction. EGFR is overexpressed in ATC cell lines in vitro and in vivo as well as human ATC specimens (Schiff et al. 2004). Gefitinib inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of subcutaneous implant of ATC. This has been confirmed in another preclinical study, where gefitinib was combined with imatinib, a tyrosine kinase inhibitor targeting c-abl/PDGF-R (Kurebayashi et al. 2006). In this study, the combination therapy demonstrated enhanced apoptosis associated with the down-regulation of antiapoptotic proteins, Bcl-2 and Bcl-xL, and inhibited the growth of KTC-3 xenografts.

Combretastatin

Combretastatin is a microtubule inhibitor, which has been shown to destabilize vasculature, making it an attractive anti-tumor agent. Combretastatin displayed significant cytotoxicity in eight human ATC cell lines and in xenograft tumors from four ATC cell lines when injected in athymic nude mice (Dziba et al. 2002). Furthermore, it can also significantly enhance tumor response to both cisplatinum and radiation (Chaplin et al. 1999). In a nude mouse xenograft model with ARO and KAT-4 cells, combretastatin and paclitaxel in combination with manumycin or carboplatin demonstrated significant antitumor activity (Yeung et al. 2007). Blebbing/budding of endothelial cells into capillary lumens and autophagy of tumor cells in combretastatin-treated xenografts confirms its vascular disrupting activity. Nelkin & Ball (2001) showed improvement in doubling time of MTC tumors in nude mice model from 12 to 29 days when treated with combretastatin and doxorubicin.

Bortezomib

In vitro, a proteasome inhibitor bortezomib alone or in combination with chemotherapy has been shown to induce apoptosis in MTC and ATC cells by inhibiting NF-B, increasing p53, p21, and jun expression, and inducing caspase-dependent apoptosis (Mitsiades et al. 2006).

17-AAG

17-AAG is a heat shock protein (Hsp) 90 inhibitor that has been identified as a potential therapeutic agent in thyroid cancer. Hsp 90 specifically has been found to be important to the signaling kinases Akt and RAF as well as formation of the PTC1 protein, which is the most common RET/PTC chimeric oncoprotein seen in PTC (Smida et al. 1999). In preclinical studies, 17-AAG was found to reduce RET/PTC1 protein levels, induce cell death and increase the uptake of radioactive iodine into thyroid cancer cells (Marsee et al. 2004). It has also been shown that levels of Hsp 90, rather than histologic subtype, determine the cytotoxic response to the agent in thyroid cancer cell lines (Braga-Basaria et al. 2004).

Histone deacetylase inhibitors

Depsipeptide (romidepsin, FK228) has been shown to increase sodium–iodine symporter expression and uptake of I¹²⁵ (Kitazono et al. 2001, Furuya et al. 2004). In the FTC and ATC cell lines, a very low concentration of depsipeptide increased histone acetylation and expression of both thyroglobulin (Tg) and the Na(+)/I(–) symporter (NIS) mRNAs (Kitazono et al. 2001).

In preclinical studies using thyroid cancer cell lines, suberoylanilide hydroxamic acid (SAHA) was found to induce growth arrest in ATC and MTC cell lines through p21-mediated inhibition of Rb phosphorylation (Mitsiades et al. 2005). In these studies, SAHA was also found to sensitize thyroid cancer cells to caspase-mediated death-receptor mediated cell death as well as to augment anti-tumor activity of doxorubicin.

DNA methylation inhibitors

Decitabine appears to work through inhibition of DNA methyltransferases, and causes reversible DNA damage to malignant cells (Palii et al. 2008). In preclinical studies, decitabine also has been shown to increase iodine uptake in ATC and poorly DTC cell lines (Provenzano et al. 2007). Thyroid carcinoma cell lines DRO and 2–7 had high levels of DNA methylation (74 and 80%) compared with normal thyroid tissue (6%; P<0.05). This finding correlated with low levels of NIS expression in the untreated thyroid carcinoma cell lines. Combination treatment with the epigenetic-modifying agents 5-aza-2'-deoxycytidine and sodium butyrate resulted in increases in NIS mRNA levels, global histone acetylation, and 8-to 9-fold increases in I¹²⁵ uptake for the DRO and 2–7 cells.

3-Phosphoinositide-dependent kinase-1 inhibitors

OSU-03012 (2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide) is a derivative of celecoxib, which was formulated to be a more potent inhibitor of 3-phosphoinositide-dependent kinase (PDK)-1. When exposed to OSU-03012, prostate cancer cells were shown to have dephosphorylation of Akt and subsequent apoptosis (Zhu et al. 2004). OSU-03012 was also found in thyroid cancer cells to directly inhibit p-21 activated kinases, downstream effectors of PDK-1, which are important in cell motility and proliferation (Porchia et al. 2007).

Peroxisome proliferator-activated receptor-gamma agonist

CS-7017, a thiazolidinedione class peroxisome proliferator-activated receptor (PPAR) gamma agonist, alone or in combination with paclitaxel inhibited the proliferation of the human ATC cell line DRO and inhibited the growth of the DRO in nude rats in a dose-dependent manner (Copland et al. 2006, Shimazaki et al. 2008).

Chemotherapeutic agents

Capecitabine is a tumor-activated fluoropyrimidine carbamate which is converted to 5-FU in target tissues by thymidine phosphorylase, causing high drug levels inside tumors while sparing normal tissues. 5-FU interferes with DNA synthesis by blocking thymidylate synthetase, and is inactivated by dihydropyrimidine dehydrogenase. Because of its mechanism of action, it is suspected that high levels of thymidine phosphorylase and low thymidylate synthetase and dihydropyrimidine dehydrogenase would predict response to capecitabine. In one study looking at immunohistochemistry of thyroid tumors, 43% of PTC and 25% of FTC had favorable characteristics (Patel et al. 2004).

Irinotecan, a topoisomerase I inhibitor, prevents the relaxation of DNA supercoiling during DNA replication (Garcia-Carbonero & Supko 2002). A preclinical study in a mouse model of ATC showed that the combination of irinotecan and cetuximab, a chimeric monoclonal antibody to EGFR, inhibited tumor growth, invasion, and angiogenesis (Kim et al. 2006). In the same study, at the end of a 3 week treatment period, this combination decreased mean tumor volume by 97%, while doxorubicin decreased tumor volume by 7% (Kim et al. 2006). In a study using a mouse model of MTC, irinotecan was found to be highly effective (Strock et al. 2006).

	Clinical trials in DTC

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
Clinical trials are studies designed to find new and better ways to treat patients with cancer. Through clinical trials, scientists and clinicians break new ground in the development of anti-cancer treatment. The definitions of phases of clinical trials and key points in response criteria in solid tumors (RECIST) are described in Tables 1 and 2. In the last 5 years, dramatic advances have occurred in development of clinical trials for thyroid cancer (Table 3). Table 4 outlines summary of results of published phase II trials of kinase inhibitors, however, caution must be taken in comparing these results, as patient population tested was variable among these trials.

Sorafenib has been approved through the FDA for patients with metastatic renal cell carcinoma and hepatocellular carcinoma, and is the first compound of its class to show promising anti-tumor activity in patients with advanced DTC (Kloos et al. 2005, 2008). Our group conducted a National Cancer Institute (NCI)-sponsored phase II trial of sorafenib that enrolled 58 patients with advanced non-MTCs (Kloos et al. 2005, 2008, Gupta-Abramson et al. 2008). Sorafenib was administered at an initial dose of 400 mg orally twice each day, and was dose-reduced in 52% of patients. Of 33 cytotoxic chemonaive PTC patients, 5 patients had partial responses (PRs; 15%; 95% confidence interval (CI) 5–32) and 19 patients had stable disease (SD) lasting >6 months (57%). The Kaplan–Meier estimate of median progression free survival (PFS) was 16 months (95% CI, 8–27.5). Objective response was seen even in the eight patients who had previously received cytotoxic chemotherapy, with 13% PR and 50% SD >6 months duration. While no PRs were noted, SD >6 months was noted in 54 and 25% of patients in FTC/hurthle (n=11) or ATC (n=4) respectively. We noted dramatic sustained decreases in serum Tg levels in some patients with PRs and SDs, however, neither baseline Tg nor Tg response consistently correlated with degree or duration of objective response. Common (>10%) grade 3 adverse event (AE)s included hand–foot skin reaction, musculoskeletal pain, and fatigue. Rare events of keratoacanthoma, bowel perforation, and bleeding (hemoptysis in patients with central chest tumor lesions) were also observed. BRAF mutation (BRAF^V600E or BRAF^K601E) was detected in 17 of 22 (77%) patients with PTC. Four of ten paired tumor biopsies from PTC patients performed pre-treatment and at 8 weeks on treatment showed a reduction in levels of pVEGFR, pERK and increase VEGF expression in response to sorafenib. Tumor perfusion was decreased with sorafenib as evaluated by dynamic contrast enhanced magnetic resonance imaging in 10 of 14 evaluable PTC patients. While decreases in SUV_max and metabolic volume had been observed in index lesions with sorafenib, no clear correlation was noted between fluorodeoxyglucose positron emission tomography (PET) response and objective response.

In a single center phase II study of sorafenib in 30 patients with advanced thyroid cancer, Gupta-Abramson et al. (2008) reported 7 (23%) PRs and 16 (53%) SDs and a median PFS of 19.7 months. A majority of these patients were PET scan positive (93%) and had either PTC (n=18) or FTC/Hurthle cell variant (n=9). Only 5 of 30 patients (17%) had received prior chemo- or investigational-therapy. While sorafenib was delivered at 400 mg orally twice daily in this study as well, dose reduction was required in 47% of the patients. Common treatment-related AEs included palmar-plantar erythema, rash, musculoskeletal pain, pruritus, hypertension, diarrhea, fatigue, weight loss, stomatitis/mucositis, alopecia, abdominal bloating, and mood changes.

Objective response rates and median PFS in the above studies of sorafenib vary despite similar dosing schedule. While there is no clear explanation for such differences, it may be due to differences in patient characteristics such as prior therapy, overall tumor burden, and rate of progressive disease at the study entry, as well as tumor characteristics including BRAF mutation and tumor vascularity. Based on the promising data noted in these phase II studies, the authors recommend the use of sorafenib 400 mg orally twice daily under proper supervision in high-risk patients with metastatic PTC who have progressed despite standard surgery and ¹³¹I and do not have the option to participate in clinical trials. In 2008, The National Comprehensive Cancer Network (NCCN; http://www.nccn.org/professionals/physician_gls/PDF/thyroid.pdf) also endorsed the use of sorafenib in the management of clinically progressive or symptomatic iodine-refractory PTC.

Axitinib (AG-013736)

Like sorafenib, axitinib is an oral multi-targeted tyrosine kinase inhibitor, but with a selectivity and potency against VEGFRs. Clinical responses have been observed in renal cell carcinoma (Rixe et al. 2007). In a multicenter phase II study of 60 patients with advanced thyroid cancer using 5 mg daily dosing of axitinib, 18 (30%) PRs and 23 (38%) SD of >4 months duration were observed (Cohen et al. 2008b). Median PFS was 18 months (95% CI, 12.1 to not estimable). Among 30 PTC patients on this study, 8 (27%) achieved PRs and 12 (40%) experienced SD. While no definitive conclusions were made in serum Tg response in this study, significant decreases in mean serum VEGFR-2 and -3 concentrations were noted compared with baseline. The most common treatment-related AEs occurring in >20% of patients included fatigue, diarrhea, nausea, anorexia, hypertension, stomatitis, weight loss, and headache.

Motesanib (AMG-706)

Motesanib is a multi-targeted tyrosine kinase inhibitor that targets the VEGFRs, PDGFR, and c-kit (Polverino et al. 2006). In an open-label multicenter international phase II trial of motesanib in 93 patients with radioiodine-resistant, progressive DTC, motesanib was administered orally at a dose of 125 mg orally daily (Sherman et al. 2008). Objective response included 14% PRs, 67% SD and a 35% SD >6 months duration. The Kaplan–Meier estimate of the median duration of the response was 8 months (95% CI, 6–not estimable) and median PFS was 10 months (95% CI, 8–12.5). Among 75 patients in whom Tg analysis was performed, 81% had decreased serum Tg concentrations during treatment as compared with baseline, and significant correlation was noted between serum Tg response and RECIST response. The most common (>40%) treatment-related AEs were diarrhea, hypertension, fatigue, and weight loss. Grade 3 AEs occurred in 55% of patients that included diarrhea, hypertension, abdominal pain, anorexia, fatigue and rare gall bladder toxicity, hemorrhage, and thromboembolic events. Of note, hypothyroidism was noted in 12% of the patients. Of 25 patients with PTC, 10 had the mutant BRAF^V600E genotype, and 4 had mutations in RAS genes.

Sunitinib (SU 011248)

Sunitinib is approved through the FDA for patients with metastatic renal cell carcinoma or imitanib-refractory gastrointestinal stromal tumors. In an NCI-sponsored phase II study of sunitinib in 37 patients with iodine-refractory progressive DTC (Cohen et al. 2008a), treatment consisted of 6 week cycles of sunitinib malate 50 mg orally each day on a 4-week-on/2-week off schedule. Of 31 evaluable DTC patients who completed 12 weeks of treatment, the best response was PR in 13%, SD in 68%, and progressive disease in 10%, with 13% of patients not evaluable. The most common (>40%) drug related AEs included fatigue, diarrhea, palmar-plantar erythrodysesthesia, neutropenia, and hypertension. Results are awaited for other ongoing phase II trials of sunitinib in patients with iodine-refractory DTC and metastatic MTC (Goulart et al. 2008, Ravaud et al. 2008).

Gefitinib

Gefitinib is extensively studied in patients with non-small cell lung cancer. In a single institution phase II study in patients with advanced thyroid cancer, gefitinib was administered orally at dose of 250 mg daily in a total of 27 patients, 67% of whom had DTC (Pennell et al. 2008). No objective responses were observed, and five (18%) patients (2 PTC, 3 FTC) had SDs associated with minor (>10%) decrease in serum Tg compared with the baseline that was maintained for at least 3 months. Two of these patients had a >50% decline in the Tg levels. However, median PFS on the study was 4 months suggesting only limited potential benefit from the drug.

Vorinostat

Our group conducted NCI-sponsored phase II study to assess objective response to vorinostat (SAHA) in patients with advanced thyroid cancer (Woyach et al. 2008). Of the total of 19 patients, 16 had DTC that had progressed after standard therapy. Patients received oral vorinostat at a starting dose of 200 mg twice daily with dose adjustments allowed as necessary for toxicity. Patients were treated for 2 weeks followed by 1 week off therapy (3-week cycle) until disease progression or study withdrawal. No patient achieved a PR or CR. Grade 3 AEs consisted of fatigue, dehydration, ataxia, pneumonia, bruises, and deep vein thrombosis. Grade 3–4 thrombocytopenia was seen in seven patients and was associated with minor bleeding or bruises. This study shows that vorinostat at this dose/schedule is not an effective treatment for advanced thyroid cancer. Our study did not examine potential effect of vorinostat on re-expression of NIS gene.

Romidepsin

In a phase II clinical trial of romidepsin in patients with iodine-refractory, progressive, measurable DTC, romidepsin was administered at a dose of 13 mg/m² IV on day 1, 8, and 15, every 28 days (Su et al. 2006). In preliminary report, 14 DTC patients out of a target accrual of 21 were enrolled. One grade 5 AE of sudden death was noted. Grade 3 AEs included fatigue, dysphagia, and dyspnea. No PR or CR was observed. Clinically, significant restoration of ¹³¹I avidity was observed in one PTC patient who subsequently was given treatment-dose ¹³¹I with a dramatic ¹³¹I avidity by post-therapy whole body scan. Although this restoration of ¹³¹I avidity is promising, the noted serious AE raises the question of safety of this drug.

A phase I trial of romidepsin using an alternate dosing schedule where romidepsin was administered on days 1, 3, and 5 was performed with a goal of enhancing gene expression and evaluating ¹³¹I uptake in patients with ¹³¹I-refractory DTC (Pierkarz et al. 2008). Twenty-six patients with solid tumors on this phase I study received doses ranging from 1 to 9 mg/m². Nine of 26 patients on this study had thyroid cancers and received a median of eight cycles (range 1–24). Hypoxia, nausea, and vomiting were considered as dose-limiting toxicities. Grade 3 AEs included cytopenias, anorexia, nausea, and vomiting. Six of nine patients with thyroid cancer had SDs for a median of 3 months. None of the four DTC patients who underwent the follow-up ¹³¹I scans had increased ¹³¹I uptake. Evaluation of histone acetylation in peripheral blood mononuclear cells (PBMCs) demonstrated a >2-fold increase.

Decitabine

Decitabine (5-aza-2'-deoxycytidine) is a demethylating agent that is approved through the FDA for myelodysplastic syndrome (MDS). An NCI-sponsored multi-institutional phase II study of decitabine is currently examining whether DNA demethylation can induce re-expression of the NIS, and thus ¹³¹I avidity, in thyroid cancer. The study was designed in patients with iodine-refractory DTC whose tumor lesions were <1 cm, and iodine avidity is measured by diagnostic iodine scan after two cycles of decitabine. Twelve patients in the first stage of the two-arm study have been enrolled and currently results are being analyzed.

Celecoxib

Our group led a NCCN-sponsored two-center phase II trial of single agent celecoxib, a selective COX-2 inhibitor, in patients with progressive metastatic DTC (Mrozek et al. 2006). Patients were treated with celecoxib 400 mg orally twice a day for 12 months. The primary endpoint was PFS at 12 months using RECIST and/or serum Tg response. Twenty-three of 32 patients experienced progressive disease or stopped therapy due to toxicity, thus fulfilling the intent-to-treat study endpoint for celecoxib failure. One patient achieved PR, and one patient completed 12 months of therapy progression-free. The study was terminated early due to lack of efficacy and new data regarding cardiotoxicity. Celecoxib failed to halt progressive metastatic DTC in most patients. COX-2 protein expression studies were performed in tumor tissue obtained from two responders and three randomly selected non-responder PTC patients. High COX-2 expression was observed in both responders with overall scores of +3. In two of the three non-responders examined, COX-2 expression was largely negative with overall scores of +1. However, the third non-responder patient had an overall score of +2 to +3.

Thalidomide and lenalidomide

Thalidomide and its analogue lenalidomide are potent anti-inflammatory, anti-angiogenic, and immunomodulatory drugs, successfully used for the treatment of multiple myeloma. Ain et al. (2007) studied the activity of both of these agents in a single institution phase II trials in patients with radioiodine-unresponsive progressive (tumor volumes increasing 30% per year before entry assessed by radiographic studies) thyroid cancer. A phase II study to assess efficacy of thalidomide enrolled 29 patients with DTC and 7 patients with MTC. Daily thalidomide was administered at 200 mg, increasing over 6 weeks to 800 mg or maximum tolerated dose. Among 28 evaluable patients, five PRs (18%; 95% CI: 6–37) and nine SD (32%; 95% CI: 12–42) were observed. Median PR duration was 4 months (range, 2–6), and SD duration was 6 months (range, 2–14). Median survival was 23.5 months for responders (PR+SD) and 11 months for non-responders. Half of the patients with objective response discontinued thalidomide due to toxicity. Common AEs included fatigue, somnolence, peripheral neuropathy, constipation, dizziness, and infection. Pericardial effusion and pulmonary embolus were also seen as rare, but serious AEs.

An open-label phase II trial of single agent lenalidomide enrolled 21 patients with I¹³¹-unresponsive DTC (Ain et al. 2008). Lenalidomide was administered orally at a dose of 25 mg daily. Preliminary results show 22% PRs and 44% SDs in 18 evaluable patients. Treatment was well tolerated with myelosuppression responding to dose reduction being the most commonly reported AE. Of note, response criteria were based on tumor volume and not standard RECIST and response rate analysis was not done as intent-to-treat analysis in either of these studies.

Bortezomib (PS-341)

In an NCI-sponsored multicenter phase II trial of the bortezomib in patients with metastatic ¹³¹I-refractory DTC, the drug was administered at a dose of 1.3 mg/m² i.v. on days 1, 4, 8, and 11 in a 3-week cycle (Brierley et al. 2006). At the time of preliminary report, ten patients had been enrolled. Among six evaluable patients, four (67%) patients had SDs as best response with one of these responses lasting more than 12 months. However, serum Tg levels increased in all four patients with SD by a median of 506%. Grade 3–4 AEs included pulmonary embolism (n=1) and motor neuropathy (n=1).

Cytotoxic chemotherapy

Irofulven, a novel DNA binding agent of the acylfulvene class, demonstrated anti-tumor activity in a variety of chemoresistant tumors. A phase I trial of an irofulven in combination with capecitabine conducted based on positive preclinical data in solid tumors showed PRs in two thyroid cancer patients (Alexandre et al. 2003). Subsequently, an international multicenter 2-stage, phase II trial was conducted to evaluate the objective response rate of combination cytotoxic chemotherapy in patients with advanced thyroid cancer (Droz et al. 2006). Patients were treated with irofulven at a dose of 0.4 mg/kg given over 30 min as an i.v. infusion on days 1 and 15 and capecitabine orally 2000 mg/m² daily from day 1 to 15 every 28 days. At the time of preliminary report, 23 patients (14 DTC, 5 MTC, and 4 ATC) had been treated. No objective responses were observed and SD was seen in 11 (79%) of DTC patients with a median duration of 4.8 months. Two of these patients had 14 and 19% decreases in tumor size respectively. The main AEs reported were thrombocytopenia, neutropenia, nausea, and asthenia.

	Clinical trials in MTC

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
Vandetanib

A multicenter phase II trial of vandetanib was performed which included patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC harboring a RET germline mutation (Wells et al. 2007). Thirty patients received initial treatment with vandetanib 300 mg orally daily and at the time of preliminary report, the median duration of treatment was 6 months. Six of 30 patients (20%) experienced a PR with duration of response ranging from 1.9 to 8.6 months and 9 patients (30%) had SD disease >6 months duration. In 19 patients, plasma calcitonin levels showed a >50% decrease from baseline that was maintained for at least 6 weeks. Common AEs (>50%) included rash, diarrhea, fatigue, and nausea. QTc prolongation was uncommon (16%) and asymptomatic.

Another phase II clinical trial evaluated efficacy of vandetanib in patients with hereditary MTC when administered at 100 mg orally daily (Haddad et al. 2008). Patients were allowed to increase the dose to 300 mg orally daily at time of progression. Among 19 patients, 2 (10%) PRs and 6 (42%) SD >6 months have been noted.

Based on promising preliminary results of these small size phase II trials in hereditary MTC, an international phase III trial of vandetanib in sporadic and hereditary MTC was recently completed and the results are eagerly awaited.

Motesanib (AMG 706)

Motesanib is an oral multi-tyrosine kinase inhibitor targeting VEGF-R, PDGF-R, and c-kit, which has been studied in patients with DTC as well as MTC. In a multicenter international open label phase II trial of motesanib in MTC, patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib diphosphate 125 mg daily for up to 12 months or until unacceptable toxicity or disease progression (Schlumberger et al. 2007). Among 91 patients, 2 patients (2%) achieved PRs (95% CI, 0.3–7.7), and 43 (47%) had SDs of >6 months duration. The Kaplan–Meier estimate of median PFS was 12 months (95% CI, 10.7–14). The most common treatment-related AEs were diarrhea (41%), fatigue (41%), hypertension (27%), anorexia (27%), and nausea (26%). Interestingly, plasma motesanib trough concentrations were reduced compared with previous monotherapy studies at the same dose level, which may impact efficacy.

XL-184

XL-184 is an oral multi-kinase inhibitor targeting RET, MET and VEGFR2. In a phase I clinical trial of XL-184, 14 patients with MTC were enrolled (Salgia et al. 2008). Three PRs were noted among ten evaluable MTC patients, and 56–96% reductions in serum calcitonin and 5–80% reductions in serum CEA were noted in all ten evaluable MTC patients. Based on promising anti-tumor activity of XL-184 in MTC, this pilot trial was expanded to MTC cohort using a specific phase II dose of XL-184. An international phase 3 study of XL-184 versus placebo in patients with advanced MTC has recently begun.

Imatinib (STI-571)

Based on in vitro inhibition of RET receptor tyrosine kinase by imatinib, phase II open label trials using imatinib in metastatic MTC were conducted by two groups. In the first study, among nine MTC patients (one hereditary, eight sporadic) with unresectable, measurable, and progressive metastases, imatinib was administered at a dose of 600 mg orally daily (Frank-Raue et al. 2007). Best response was SD >6 months in five patients and >12 months in one patient. The median PFS was 6 months. Common AEs included mild–moderate nausea, edema, diarrhea, and skin rash. In another phase II study of imatinib using same dosing for up to 12 months, 4 of 15 metastatic MTC patients showed SD >2 years duration (de Groot et al. 2007). Serious AEs included hypothyroidism (n=9) and laryngeal edema in patients with history of recurrent laryngeal nerve palsy (n=2). Other AEs were fatigue, malaise, nausea, and skin rash. The absence of objective response and potential for serious toxicities possibly associated with imatinib do not justify its further use in patients with MTC.

Radioimmunotherapy

In radioimmunotherapy, a radionuclide is targeted to tumor sites using an antibody or antibody fragment. For less radiosensitive tumors, tumor tissue uptake can be enhanced by ‘pretargeting’, a two-step approach where the immune recognition of the tumor site and delivery of the therapeutic radionuclide occur sequentially. This approach has been studied in MTC in an attempt to take advantage of the CEA-positive nature of this type of tumor (Chatal et al. 2006, Martins et al. 2006). In a French Endocrine Oncology Group study, 29 patients with advanced, progressive MTC (serum calcitonin doubling times of <5 years) received an anti-CEA/anti-diethylenetriamine pentaacetic acid-indium bispecific monoclonal antibody, followed 4 days later by a ¹³¹I-labeled bivalent hapten. When compared with 39 matched controls, overall survival was significantly longer in high risk treated patients than in untreated patients (110 vs 61 months; P<0.030). Toxicity was mainly hematologic and related to bone/bone-marrow tumor metastasis. Five (17%) patients had grade 4 thrombocytopenia, four (15%) experienced grade 4 neutropenia and one patient (3%) developed MDS. While a significant difference in overall survival is noted, this study is limited by the use of historic controls as a comparison group. Furthermore, prolonged duration of myelosuppression and occurrence of MDS make this treatment less attractive in patients with MTC.

	Clinical trials in ATC

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
Conducting clinical trials in ATC poses several challenges due to the following factors: rare incidence; extremely aggressive clinical course in a vast majority of patients resulting in poor performance status and/or organ dysfunction; poor prognosis and short life expectancy; lack of knowledge about oncogenic targets; and lack of multi-disciplinary teams for care of ATC patients at most cancer centers. While these challenges have limited clinical trials in ATC in the past, the current era is very exciting due to the initiation of phase I-III clinical trials.

Combretastatin

Based on anti-tumor activity of combretastatin against ATC in pre-clinical studies and safety noted in a phase I trial, a phase II trial was conducted in 18 patients who had metastatic ATC, good performance status, and no prior therapy for disseminated disease (Cooney et al. 2006). Combretastatin at a dose of 45 mg/m² was administered as 10-min i.v. infusion on days 1, 8, and 15 every 28 days until progressive disease was noted. While therapy was well tolerated, no objective responses were seen. Six patients had SDs while rest of the patients progressed. Median PFS was 1.8 months (range, 0.5–21); with 28% of patients progression free >3 months. Median survival was 5 months. Based on these results, an international phase III study of paclitaxel and carboplatin with or without combretastatin is ongoing.

	Conclusions

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
With the development of targeted small molecule kinase inhibitors, the treatment of advanced thyroid cancer is changing dramatically. No longer is supportive care the standard, as there are clinical trials underway, which have the potential to revolutionize the field. Because of the well-described pathogenetic targets such as RET, RET/PTC, RAS, BRAF, c-Met, and VEGFR, this field will likely continue to see an explosion of new targeted agents. Besides these known targets, there still remains the opportunity to discover novel pathways important in the development of thyroid carcinoma. It also remains to be seen whether combinations of targeted therapies with other small molecular therapies, with chemo- or radio-therapy will improve response rates. The results of the clinical trials presented, as well as new agents in development, will likely greatly improve the lives of patients with advanced thyroid carcinoma.

	Declaration of interest

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
Dr Manisha Shah had consultant role for Exelixis and BAYER pharmaceuticals in the past two years. Dr Jennifer Woyach has no conflict of interest.

	Funding

 
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

	References

Top Abstract Background Novel insights in the... Preclinical studies Clinical trials in DTC Clinical trials in MTC Clinical trials in ATC Conclusions Declaration of interest References

 
Ain KB, Lee C & Williams KD 2007 Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid 17 663–670.[CrossRef][Web of Science][Medline]

Ain KB, Lee C, Holbrook K, Dziba JM & Williams KD 2008 Phase II study of lenalidomide in distantly metastatic, rapidly progressive, and radioiodine-unresponsive thyroid carcinomas: preliminary results. Journal of Clinical Oncology 26 Supplement abstract 6027.

Alexandre J, Berthault-Cvitkovic F, Hilgers W, Yovine A, Weems G & Herait P 2003 Phase I and pharmacokinetic (PK) study of irofulven (IROF) and capecitabine (CAP) in combination using an intermittent schedule in advanced solid tumors. Proceedings of the American Society of Clinical Oncology 22 abstract 615.

Argiris A, Agarwala SS, Karamouzis MV, Burmeister LA & Carty SE 2008 A phase II trial of doxorubicin and interferon alpha 2b in advanced, non-medullary thyroid cancer. Investigational New Drugs 26 183–188.[CrossRef][Web of Science][Medline]

Bauer AJ, Patel A, Terrell R, Doniparthi K, Saji M, Ringel M, Tuttle RM & Francis GL 2003 Systemic administration of vascular endothelial growth factor monoclonal antibody reduces the growth of papillary thyroid carcinoma in a nude mouse model. Annals of Clinical and Laboratory Science 33 192–199.[Abstract/Free Full Text]

Belfiore A, Gangemi P, Costantino A, Russo G, Santonocito GM, Ippolito O, Di Renzo MF, Comoglio P, Fiumara A & Vigneri R 1997 Negative/low expression of the Met/hepatocyte growth factor receptor identifies papillary thyroid carcinomas with high risk of distant metastases. Journal of Clinical Endocrinology and Metabolism 82 2322–2328.[Abstract/Free Full Text]

Bergstrom JD, Hermansson A, Diaz de Stahl T & Heldin NE 1999 Non-autocrine, constitutive activation of Met in human anaplastic thyroid carcinoma cells in culture. British Journal of Cancer 80 650–656.[CrossRef][Web of Science][Medline]

Bergstrom JD, Westermark B & Heldin NE 2000 Epidermal growth factor receptor signaling activates met in human anaplastic thyroid carcinoma cells. Experimental Cell Research 259 293–299.[CrossRef][Web of Science][Medline]

Braga-Basaria M, Hardy E, Gottfried R, Burman KD, Saji M & Ringel MD 2004 17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels. Journal of Clinical Endocrinology and Metabolism 89 2982–2988.[Abstract/Free Full Text]

Brierley J, Tsang R, Glisson B, Kies M, Kane M, Haugen B, Litofsky D & Sherman S 2006 Bortezomib in patients with metastatic differentiated thyroid cancer: preliminary results of a multicenter phase II study. Thyroid 16 858.

Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A & Santoro M 2002 ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Research 62 7284–7290.[Abstract/Free Full Text]

Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM & Santoro M 2006 BAY 43-9006 inhibition of oncogenic RET mutants. Journal of the National Cancer Institute 98 326–334.[Abstract/Free Full Text]

Chaplin DJ, Pettit GR & Hill SA 1999 Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Research 19 189–195.[Web of Science][Medline]

Chatal JF, Campion L, Kraeber-Bodere F, Bardet S, Vuillez JP, Charbonnel B, Rohmer V, Chang CH, Sharkey RM, Goldenberg DM et al. 2006 Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. Journal of Clinical Oncology 24 1705–1711.[Abstract/Free Full Text]

Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW & Sidransky D 2003 BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute 95 625–627.[Abstract/Free Full Text]

Cohen E, Needles B, Cullen K, Wong S, Wade J, Ivy S, Villaflor V, Seiwert T, Nichols K & Vokes E 2008a Phase 2 study of sunitinib in refractory thyroid cancer. Journal of Clinical Oncology 26 Supplement abstract 6025.

Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P et al. 2008b Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. Journal of Clinical Oncology 26 4708–4713.[Abstract/Free Full Text]

Cooney M, Savvides P, Agarwala S, Wang D, Flick S, Bergant S, Bhakta S, Lavertu P, Ortiz J & Remick S 2006 Phase II study of combretastatin A4 phosphate (CA4P) in patients with advanced anaplastic thyroid carcinoma (ATC). In ASCO Annual Meeting, p 5580.

Copland JA, Marlow LA, Kurakata S, Fujiwara K, Wong AK, Kreinest PA, Williams SF, Haugen BR, Klopper JP & Smallridge RC 2006 Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1. Oncogene 25 2304–2317.[CrossRef][Web of Science][Medline]

Davies L & Welch HG 2006 Increasing incidence of thyroid cancer in the United States, 1973–2002. Journal of the American Medical Association 295 2164–2167.[Abstract/Free Full Text]

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W et al. 2002 Mutations of the BRAF gene in human cancer. Nature 417 949–954.[CrossRef][Medline]

De Besi P, Busnardo B, Toso S, Girelli ME, Nacamulli D, Simioni N, Casara D, Zorat P & Fiorentino MV 1991 Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. Journal of Endocrinological Investigation 14 475–480.[Medline]

Droz J, Baudin E, Medvedev V, Delord J, Kane M, Kloos R, Ringel M, Kahatt C, Weems G & Shah M 2006 Activity of irofulven (IROF) combined with capecitabine (CAPE) in patients (pts) with advanced thyroid carcinoma: phase II international multicenter study (preliminary results). Journal of Clinical Oncology 24 Supplement abstract 15511.

Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R & Talpaz M 2001 Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. New England Journal of Medicine 344 1038–1042.[Abstract/Free Full Text]

Dvorakova S, Vaclavikova E, Sykorova V, Vcelak J, Novak Z, Duskova J, Ryska A, Laco J, Cap J, Kodetova D et al. 2008 Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas. Molecular and Cellular Endocrinology 284 21–27.[CrossRef][Web of Science][Medline]

Dziba JM, Marcinek R, Venkataraman G, Robinson JA & Ain KB 2002 Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors. Thyroid 12 1063–1070.[CrossRef][Web of Science][Medline]

Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, Agate L, Vivaldi A, Faviana P, Basolo F et al. 2008 Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. Journal of Clinical Endocrinology and Metabolism 93 682–687.[Abstract/Free Full Text]

Frank-Raue K, Fabel M, Delorme S, Haberkorn U & Raue F 2007 Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. European Journal of Endocrinology 157 215–220.[Abstract/Free Full Text]

Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, Sekikawa K, Hagiwara K & Takenoshita S 2003 BRAF mutations in papillary carcinomas of the thyroid. Oncogene 22 6455–6457.[CrossRef][Web of Science][Medline]

Furuya F, Shimura H, Suzuki H, Taki K, Ohta K, Haraguchi K, Onaya T, Endo T & Kobayashi T 2004 Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology 145 2865–2875.[Abstract/Free Full Text]

Garcia-Carbonero R & Supko JG 2002 Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clinical Cancer Research 8 641–661.[Abstract/Free Full Text]

Gottlieb JA & Hill CS Jr 1974 Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. New England Journal of Medicine 290 193–197.[Web of Science][Medline]

Goulart B, Carr L, Martins R, Eaton K, Kell E, Wallace S, Capell P & Mankoff D 2008 Phase II study of sunitinib in iodine refractory, well-differentiated thyroid cancer (WDTC) and metastatic medullary thyroid carcinoma (MTC). Journal of Clinical Oncology 26 Supplement abstract 6062.

de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ, de Vries MM, Links TP, Lips CJ & Voest EE 2007 A trial of imatinib therapy for metastatic medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 92 3466–3469.[Abstract/Free Full Text]

Gullino PM 1978 Angiogenesis and oncogenesis. Journal of the National Cancer Institute 61 639–643.[Web of Science][Medline]

Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K, Mandel SJ, Flaherty KT, Loevner LA, O'Dwyer PJ et al. 2008 Phase II trial of sorafenib in advanced thyroid cancer. Journal of Clinical Oncology 26 4714–4719.[Abstract/Free Full Text]

Haddad RI, Krebs A, Vasselli J, Paz-Ares L & Robinson B 2008 A phase II open-label study of vandetanib in patients with locally advanced or metastatic hereditary medullary thyroid cancer. Journal of Clinical Oncology 26 Supplement abstract 6024.

Hoelting T, Siperstein AE, Clark OH & Duh QY 1994 Epidermal growth factor enhances proliferation, migration, and invasion of follicular and papillary thyroid cancer in vitro and in vivo. Journal of Clinical Endocrinology and Metabolism 79 401–408.[Abstract]

Hou P, Liu D, Shan Y, Hu S, Studeman K, Condouris S, Wang Y, Trink A, El-Naggar AK, Tallini G et al. 2007 Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clinical Cancer Research 13 1161–1170.[Abstract/Free Full Text]

Hundahl SA, Fleming ID, Fremgen AM & Menck HR 1998 A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995 (see comments). Cancer 83 2638–2648.[CrossRef][Web of Science][Medline]

Ivan M, Bond JA, Prat M, Comoglio PM & Wynford-Thomas D 1997 Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells. Oncogene 14 2417–2423.[CrossRef][Web of Science][Medline]

Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY, Xing S & Ledent C 1996 Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137 375–378.[Abstract]

Jiang W, Hiscox S, Matsumoto K & Nakamura T 1999 Hepatocyte growth factor/scatter factor, its molecular, cellular and clinical implications in cancer. Critical Reviews in Oncology/Hematology 29 209–248.[Web of Science][Medline]

Kebebew E, Greenspan FS, Clark OH, Woeber KA & McMillan A 2005 Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 103 1330–1335.[CrossRef][Web of Science][Medline]

Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park SH, Hwang JH, Rha SY, Kweon GR et al. 2006 An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. Journal of Clinical Endocrinology and Metabolism 91 4070–4076.[Abstract/Free Full Text]

Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE & Fagin JA 2003 High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Research 63 1454–1457.[Abstract/Free Full Text]

Kitazono M, Robey R, Zhan Z, Sarlis NJ, Skarulis MC, Aikou T, Bates S & Fojo T 2001 Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(–) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. Journal of Clinical Endocrinology and Metabolism 86 3430–3435.[Abstract/Free Full Text]

Kloos R, Ringel M, Knopp M, Heverhagen J, Hall N, Weldy L, Arbogast D, Collamore M & Shah M 2005 Preliminary results of phase II study of RAF/VEGF-R kinase inhibitor, BAY 43-9006 (sorafenib), in metastatic thyroid carcinoma. 13th International Thyroid Congress, Buenos Aires, Oct 30-Nov 4, 2005.

Kloos R, Ringel M, Knopp M, Hall N, King M, Stevens R, Liang J, Wakely P, Vasko V, Saji M et al. 2008 Phase II clinical trial of the multi-kinase inhibitor, Sorafenib, in metastatic thyroid cancer. Journal of Clinical Oncology 27 1675–1684.[CrossRef][Web of Science]

Knauf JA, Ma X, Smith EP, Zhang L, Mitsutake N, Liao XH, Refetoff S, Nikiforov YE & Fagin JA 2005 Targeted expression of BRAF^V600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Research 65 4238–4245.[Abstract/Free Full Text]

Kurebayashi J, Okubo S, Yamamoto Y, Ikeda M, Tanaka K, Otsuki T & Sonoo H 2006 Additive antitumor effects of gefitinib and imatinib on anaplastic thyroid cancer cells. Cancer Chemotherapy and Pharmacology 58 460–470.[CrossRef][Web of Science][Medline]

van der Laan BF, Freeman JL & Asa SL 1995 Expression of growth factors and growth factor receptors in normal and tumorous human thyroid tissues. Thyroid 5 67–73.[Medline]

Lennard CM, Patel A, Wilson J, Reinhardt B, Tuman C, Fenton C, Blair E, Francis GL & Tuttle RM 2001 Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 129 552–558.[CrossRef][Web of Science][Medline]

Lewy-Trenda I & Wierzchniewska-Lawska A 2002 Expression of vascular endothelial growth factor (VEGF) in human thyroid tumors. Polish Journal of Pathology 53 129–132.[Medline]

Lin SY, Wang YY & Sheu WH 2003 Preoperative plasma concentrations of vascular endothelial growth factor and matrix metalloproteinase 9 are associated with stage progression in papillary thyroid cancer. Clinical Endocrinology 58 513–518.[CrossRef][Medline]

Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, El-Naggar AK & Xing M 2008 Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. Journal of Clinical Endocrinology and Metabolism 93 3106–3116.[Abstract/Free Full Text]

Marsee DK, Venkateswaran A, Tao H, Vadysirisack D, Zhang Z, Vandre DD & Jhiang SM 2004 Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells. Journal of Biological Chemistry 279 43990–43997.[Abstract/Free Full Text]

Martins RG, Rajendran JG, Capell P, Byrd DR & Mankoff DA 2006 Medullary thyroid cancer: options for systemic therapy of metastatic disease? Journal of Clinical Oncology 24 1653–1655.[Free Full Text]

Mesa C Jr, Mirza M, Mitsutake N, Sartor M, Medvedovic M, Tomlinson C, Knauf JA, Weber GF & Fagin JA 2006 Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. Cancer Research 66 6521–6529.[Abstract/Free Full Text]

Mitsiades CS, Poulaki V, McMullan C, Negri J, Fanourakis G, Goudopoulou A, Richon VM, Marks PA & Mitsiades N 2005 Novel histone deacetylase inhibitors in the treatment of thyroid cancer. Clinical Cancer Research 11 3958–3965.[Abstract/Free Full Text]

Mitsiades CS, McMillin D, Kotoula V, Poulaki V, McMullan C, Negri J, Fanourakis G, Tseleni-Balafouta S, Ain KB & Mitsiades N 2006 Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro. Journal of Clinical Endocrinology and Metabolism 91 4013–4021.[Abstract/Free Full Text]

Mitsiades CS, Negri J, McMullan C, McMillin DW, Sozopoulos E, Fanourakis G, Voutsinas G, Tseleni-Balafouta S, Poulaki V, Batt D et al. 2007 Targeting BRAFV600E in thyroid carcinoma: therapeutic implications. Molecular Cancer Therapeutics 6 1070–1078.[Abstract/Free Full Text]

Mrozek E, Kloos RT, Ringel MD, Kresty L, Snider P, Arbogast D, Kies M, Munden R, Busaidy N, Klein MJ et al. 2006 Phase II study of celecoxib in metastatic differentiated thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 91 2201–2204.[Abstract/Free Full Text]

Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T & Yamashita S 2003 Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. Journal of Clinical Endocrinology and Metabolism 88 4393–4397.[Abstract/Free Full Text]

Nelkin BD & Ball DW 2001 Combretastatin A-4 and doxorubicin combination treatment is effective in a preclinical model of human medullary thyroid carcinoma. Oncology Reports 8 157–160.[Web of Science][Medline]

Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A et al. 2003 BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. Journal of Clinical Endocrinology and Metabolism 88 5399–5404.[Abstract/Free Full Text]

Paes JE & Ringel MD 2008 Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia. Endocrinology and Metabolism Clinics of North America 37 375–387, (viii–ix).[CrossRef][Web of Science][Medline]

Palii SS, Van Emburgh BO, Sankpal UT, Brown KD & Robertson KD 2008 DNA methylation inhibitor 5-Aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Molecular and Cellular Biology 28 752–771.[Abstract/Free Full Text]

Patel A, Pluim T, Helms A, Bauer A, Tuttle RM & Francis GL 2004 Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults. Cancer Chemotherapy and Pharmacology 53 409–414.[CrossRef][Web of Science][Medline]

Pennell NA, Daniels GH, Haddad RI, Ross DS, Evans T, Wirth LJ, Fidias PH, Temel JS, Gurubhagavatula S, Heist RS et al. 2008 A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid 18 317–323.[CrossRef][Web of Science][Medline]

Pierkarz R, Luchenko V, Draper D, Wright J, Figg W, Fojo A & Bates S 2008 Phase I trial of romidepsin, a histone deacetylase inhibitor, given on days one, three and five in patients with thyroid and other advanced cancers. Journal of Clinical Oncology 26 Supplement abstract 3571.

Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, Bready J, Estrada J, Cattley R, Kaufman S et al. 2006 AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Research 66 8715–8721.[Abstract/Free Full Text]

Porchia LM, Guerra M, Wang YC, Zhang Y, Espinosa AV, Shinohara M, Kulp SK, Kirschner LS, Saji M, Chen CS et al. 2007 2-Amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phe nyl} acetamide (OSU-03012), a celecoxib derivative, directly targets p21-activated kinase. Molecular Pharmacology 72 1124–1131.[Abstract/Free Full Text]

Provenzano MJ, Fitzgerald MP, Krager K & Domann FE 2007 Increased iodine uptake in thyroid carcinoma after treatment with sodium butyrate and decitabine (5-Aza-dC). Otolaryngology – Head and Neck Surgery 137 722–728.[CrossRef][Web of Science]

Ravaud A, de la Fouchardière C, Courbon F, Asselineau J, Klein M, Nicoli-Sire P, Bournaud C, Delord J, Weryha G & Catargi B 2008 Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial. Journal of Clinical Oncology 26 Supplement abstract 6058.

Di Renzo MF, Olivero M, Ferro S, Prat M, Bongarzone I, Pilotti S, Belfiore A, Costantino A, Vigneri R, Pierotti MA et al. 1992 Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene 7 2549–2553.[Web of Science][Medline]

Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J et al. 2007 Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncology 8 975–984.[CrossRef][Web of Science][Medline]

Salgia R, Sherman S, Hong D, Ng C, Frye J, Janisch L, Ratain M & Kurzrock R 2008 A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). Journal of Clinical Oncology 26 Supplement abstract 3522.

Salvatore G, De Falco V, Salerno P, Nappi TC, Pepe S, Troncone G, Carlomagno F, Melillo RM, Wilhelm SM & Santoro M 2006 BRAF is a therapeutic target in aggressive thyroid carcinoma. Clinical Cancer Research 12 1623–1629.[Abstract/Free Full Text]

Santarpia L, El-Naggar AK, Cote GJ, Myers JN & Sherman SI 2008 Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. Journal of Clinical Endocrinology and Metabolism 93 278–284.[Abstract/Free Full Text]

Santoro M, Rosati R, Grieco M, Berlingieri MT, D'Amato GL, de Franciscis V & Fusco A 1990 The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene 5 1595–1598.[Web of Science][Medline]

Schiff BA, McMurphy AB, Jasser SA, Younes MN, Doan D, Yigitbasi OG, Kim S, Zhou G, Mandal M, Bekele BN et al. 2004 Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer, and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer. Clinical Cancer Research 10 8594–8602.[Abstract/Free Full Text]

Schlumberger M, Elisei R, Sherman S, Bastholt L, Wirth L, Martins R, Licitra L, Jarzab B, Pacini F, Daumerie C et al. 2007 Initial results from a phase II trial of motesanib diphosphate (AMG 706) in patients with medullary thyroid cancer. 89th Annual Meeting of the Endocrine Society (ENDO 07): Toronto, ON.

Shaha AR, Shah JP & Loree TR 1997 Differentiated thyroid cancer presenting initially with distant metastasis. American Journal of Surgery 174 474–476.[CrossRef][Web of Science][Medline]

Shan L, Nakamura M, Nakamura Y, Utsunomiya H, Shou N, Jiang X, Jing X, Yokoi T & Kakudo K 1998 Somatic mutations in the RET protooncogene in Japanese and Chinese sporadic medullary thyroid carcinomas. Japanese Journal of Cancer Research 89 883–886.[CrossRef][Web of Science][Medline]

Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, Licitra L, Eschenberg MJ, Sun YN, Juan T et al. 2008 Motesanib diphosphate in progressive differentiated thyroid cancer. New England Journal of Medicine 359 31–42.[Abstract/Free Full Text]

Shimaoka K, Schoenfeld DA, DeWys WD, Creech RH & DeConti R 1985 A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 2155–2160.[CrossRef][Web of Science][Medline]

Shimazaki N, Togashi N, Hanai M, Isoyama T, Wada K, Fujita T, Fujiwara K & Kurakata S 2008 Anti-tumour activity of CS-7017, a selective peroxisome proliferator-activated receptor gamma agonist of thiazolidinedione class, in human tumour xenografts and a syngeneic tumour implant model. European Journal of Cancer 44 1734–1743.[CrossRef][Web of Science][Medline]

Smida J, Salassidis K, Hieber L, Zitzelsberger H, Kellerer AM, Demidchik EP, Negele T, Spelsberg F, Lengfelder E, Werner M et al. 1999 Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. International Journal of Cancer 80 32–38.[CrossRef][Web of Science][Medline]

Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Maximo V, Botelho T, Seruca R & Sobrinho-Simoes M 2003 BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22 4578–4580.[CrossRef][Web of Science][Medline]

Strock CJ, Park JI, Rosen DM, Ruggeri B, Denmeade SR, Ball DW & Nelkin BD 2006 Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 91 79–84.[Abstract/Free Full Text]

Su Y, Tuttle R, Fury M, Ghossein R, Singh B, Herman K, Venkatraman E, Stambuk H, Robbins R & Pfister D 2006 A phase II study of single agent depsipeptide (DEP) in patients (pts) with radioactive iodine (RAI)-refractory, metastatic, thyroid carcinoma: preliminary toxicity and efficacy experience. Journal of Clinical Oncology 24 Supplement abstract 5554.

Tanaka K, Kurebayashi J, Sonoo H, Otsuki T, Yamamoto Y, Ohkubo S, Yamamoto S & Shimozuma K 2002 Expression of vascular endothelial growth factor family messenger RNA in diseased thyroid tissues. Surgery Today 32 761–768.[CrossRef][Web of Science][Medline]

Trovisco V, Vieira de Castro I, Soares P, Maximo V, Silva P, Magalhaes J, Abrosimov A, Guiu XM & Sobrinho-Simoes M 2004 BRAF mutations are associated with some histological types of papillary thyroid carcinoma. Journal of Pathology 202 247–251.[CrossRef][Web of Science][Medline]

Uchino S, Noguchi S, Yamashita H, Sato M, Adachi M, Yamashita H, Watanabe S, Ohshima A, Mitsuyama S, Iwashita T et al. 1999 Somatic mutations in RET exons 12 and 15 in sporadic medullary thyroid carcinomas: different spectrum of mutations in sporadic type from hereditary type. Japanese Journal of Cancer Research 90 1231–1237.[CrossRef][Web of Science]

Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, Visconti R, Mastro A, Santoro M & Fusco A 1995 RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 11 1207–1210.[Web of Science][Medline]

Weinstein IB 2002 Cancer. Addiction to oncogenes – the Achilles heal of cancer. Science 297 63–64.[Free Full Text]

Weinstein IB & Joe A 2008 Oncogene addiction. Cancer Research 68 3077–3080, (discussion 3080).[Abstract/Free Full Text]

Wells S, Gosnell J, Gagel R, Moley J, Pfister D, Sosa J, Skinner M, Krebs A, Hou J & Schlumberger M 2007 Vandetanib in metastatic hereditary medullary thyroid cancer: follow-up results of an open-label phase II trial. In 2007 ASCO Annual Meeting, Abst no. 6018.

Williams SD, Birch R & Einhorn LH 1986 Phase II evaluation of doxorubicin plus cisplatin in advanced thyroid cancer: a Southeastern Cancer Study Group Trial. Cancer Treatment Reports 70 405–407.[Web of Science][Medline]

Woyach J, Kloos R, Ringel M, Arbogast D, Collamore M, Zwiebel J, Grever M, Villalona-Calero M & Shah M 2008 Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 94 164–170.[CrossRef][Medline]

Xing M 2005 BRAF mutation in thyroid cancer. Endocrine-Related Cancer 12 245–262.[Abstract/Free Full Text]

Xing M, Vasko V, Tallini G, Larin A, Wu G, Udelsman R, Ringel MD, Ladenson PW & Sidransky D 2004 BRAF T1796A transversion mutation in various thyroid neoplasms. Journal of Clinical Endocrinology and Metabolism 89 1365–1368.[Abstract/Free Full Text]

Xu X, Quiros RM, Gattuso P, Ain KB & Prinz RA 2003 High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Research 63 4561–4567.[Abstract/Free Full Text]

Yeung SC, She M, Yang H, Pan J, Sun L & Chaplin D 2007 Combination chemotherapy including combretastatin A4 phosphate and paclitaxel is effective against anaplastic thyroid cancer in a nude mouse xenograft model. Journal of Clinical Endocrinology and Metabolism 92 2902–2909.[Abstract/Free Full Text]

Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, Shaw YJ, Kulp SK & Chen CS 2004 From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Cancer Research 64 4309–4318.[Abstract/Free Full Text]

This Article Abstract Full Text (PDF) All Versions of this Article: ERC-08-0335v1 16/3/715    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Woyach, J. A Articles by Shah, M. H PubMed PubMed Citation Articles by Woyach, J. A Articles by Shah, M. H