Sorafenib: Rays of Hope in Thyroid Cancer

Abstract

Background:

Sorafenib (BAY 43-9006) is an inhibitor of multiple-receptor tyrosine kinases involved in tumor growth and angiogenesis, which can be advantageously administered orally. Initially used as monotherapy in advanced renal cell carcinoma, sorafenib was proven to increase progression-free survival while enhancing disease control. Clinical trials on sorafenib are at present ongoing for the treatment of various malignancies, including thyroid cancer (TC).

Summary:

Specifically, in two phase II studies recently conducted on papillary TC, although the respective results were not entirely compatible as regard partial response rate and progression-free survival, sorafenib demonstrated a relatively favorable benefit/risk profile. In another more recent phase II study, whose primary endpoint was the reinduction of radioactive iodine uptake at 26 weeks, although no reinduction of radioactive iodine uptake was observed, 59% had a beneficial response and 34% had stable disease. Sorafenib hence appears to be a valid alternative to conventional treatment of metastatic papillary TC refractory to radioiodine therapy.

Conclusions:

Further prospective investigations are required to define the characteristics of tumor response to the drug and the factors inducing resistance to treatment. A major issue demanding immediate attention involves optimization of sorafenib treatment: this concerns multidrug combination with different tyrosine kinase inhibitors or immunomodulating agents with the aim of reducing doses and thereby improving drug tolerability and antineoplastic capability.

“Life inevitably is discovered to be composed of life. We always think we have finally isolated the mechanism (cell, chromosome, gene, DNA…), only to find that the mechanism is an organism.”

—Jacob Needleman: A Sense of the Cosmos: The Encounter of Modern Science and Ancient Truth, Arkana Paperbacks, 1975, p. 64.

Introduction

T he fact that the life sciences are encountering philosophy by zeroing in on our “life composed of life” is evidenced by the impressive progress marked in genomics, transcriptomics, and proteomics over the last decade, these advances concurrently representing the driving force behind the expanding role of pharmacology within the field of oncology. Accumulating knowledge about tumor signaling pathways and metastases has greatly incentivized both researchers and industry, leading to the formulation of new molecular therapies targeted at the core of signaling pathways.

Signaling systems are of cardinal importance for tumor proliferation. One of the most important is the tyrosine kinase (TK) RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) pathway, a complex of protein–receptors that forms a highly conserved transduction system for growth factors and cytokines (1). Several tumors, such as papillary thyroid cancer (PTC), may initiate a cascade of transforming events along the TK pathway, resulting in tumor cell survival and proliferation. The acquisition of better insight into this process has enabled a novel multifaceted therapeutic approach via newly developed molecules targeting multiple signaling pathways (2). Accordingly, early clinical trials of targeted therapies have been initiated with encouraging first results that evidence an objective tumor response in up to 50% in medullary thyroid carcinoma (MTC) and differentiated thyroid carcinoma (DTC) patients (3).

In this line of evidence, sorafenib (BAY 43-9006), a multiple-receptor TK inhibitor (TKI), has recently been developed. Sorafenib is an oral antitumor compound that has been approved by the European Agency for the Evaluation of Medicinal Products and by the U.S. Food and Drug Administration for the treatment of metastatic renal cell carcinoma and hepatocellular carcinoma (3 –5). The drug blocks tumor growth by inhibiting both tumor cell proliferation and tumor angiogenesis. A possible role for sorafenib in the treatment of other malignancies is therefore under current investigation.

The aim of this review is to provide a concise evaluation of both the antitumor effects and the safety of sorafenib, followed by a detailed survey of the available studies on advanced TC, its potential combinatory therapeutic modes, and future prospects.

Tyrosine Kinases

TKs are proteins strongly involved in oncogenesis via aberrant expression of their receptors and reduced expression of their modulating enzymes, tyrosine phosphatases. These two pathways play key roles in both tumorigenesis and drug resistance mechanisms (6,7). While the RAS/RAF/MEK pathway mediates the cellular response to mitogenic signals, the mitogen-activated protein kinase (MAPK) and MEK/ERK are, together with the phospholidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), essential for regulation of cell proliferation and survival. RAS is a downstream effector of epidermal growth factor receptor (EGFR), which is mutationally overexpressed in numerous types of human cancer; RAF, a serine/threonine kinase, mutationally activates ERK/MAPK; concomitantly, ERK mutational activation promotes upregulation of EGFR constituting an autocrine growth loop crucial in tumor growth (8).

Growth and dissemination of tumors are heavily dependent on the vascular endothelial growth factor (VEGF) and the EGF, the ligand for the EGFR that drives VEGF expression (2,9). Conversely, upregulation of VEGF promotes resistance to EGF. Both factors therefore share common downstream signaling pathways. VEGF is secreted in pathological conditions by tumor cells and acts on the endothelial cells of the tumor blood vessels, thus initiating angiogenesis and migration (10). Its biological effects are mediated by two receptors, VEGF-1 and VEGF-2, which bind to the extracellular domain comprised of a transmembrane region and an intracellular TK domain.

Given that oxygen availability is crucial to the sustenance of pathologic angiogenesis, hypoxia, which results from a defective blood flow into the tumor mass, will act as a strong inducer of VEGF mRNA via the latter's ability to cause release of hypoxia-inducible factor, which in turn promotes transcription of several angiogenic genes, including VEGF (11 –13). It is hence evident that inhibition of both these factors is a prime objective for a large number of tumor types and several inhibitors are currently undergoing clinical testing.

TC and TK

The majority of patients with TC can be treated via total thyroidectomy and radioiodine ablation. However, about 2%–5% of DTC do not take up radioiodine, resulting in a poor prognosis (14). This is mainly due to reduced sodium iodide symporter (NIS) expression caused by loss of thyrotropin (TSH) receptor expression and/or aberrant activation of the ERK and AKT signaling pathways, both of which have been shown to impair NIS expression (15). PTC is strongly associated with activating mutations of RET, RAS, and BRAF, a downstream effector of RAS.

BRAF gene mutation is characterized by a substitution of valine-to-glutamate at residue 600 (V600E), generated by a thymine-to-adenosine transversion at position 1799 (16). The oncogene BRAF^V600E is associated with a high risk of recurrence and less differentiated PTC due to impairment of NIS-mediated ¹³¹I uptake and lower expression of both thyroperoxidase and NIS in PTC (17,18). The BRAF^V600E mutation, which is the most frequent genetic alteration in PTC, increases kinase activity, resulting in overactivation of the MEK/ERK/MAPK pathway and uncontrolled proliferation of cancer cells. In a recent study investigating the prognostic value of BRAF^V600E in 102 PTC patients with a median follow-up of 15 years, the mutation was found in 37.3% of the cases and correlated with the worst outcome for PTC patients (19). This strongly suggests that the introduction of inhibitors of Raf kinase activity, such as TKI, in TC cells with BRAF^V600E mutations may block growth of TC and provide clinical benefit in the treatment of various forms of PTC (20,21).

In contrast, TC cell lines with other MEK-ERK effector pathway gene mutations exhibit various response patterns to TKI, thus underlining the heterogeneity and complexity of the factors that determine the MEK-ERK activity and that appear fundamental to tumor survival. The fact that highly prevalent genetic alterations in receptor TK, PI3K/AKT, and MAPK pathways in anaplastic and follicular TC provide the genetic basis for the determinant role of these signaling pathways points to the therapeutic targets for management of these tumors (22).

A distinct pathogenetic role for BRAF, AKT1, and PIK3CA in patients with primary, advanced, and radioiodine refractory TC has recently been reported (23). BRAF mutations appear more frequent in patients with radioiodine refractory, 2-deoxy-2[¹⁸F]fluoro-D-glucose positron emission tomography positive, as well as anaplastic TC. Once detected in the primary samples, BRAF mutations will also be present in the metastases. Nevertheless, absence of PIK3CA/AKT1 mutations in one site does not exclude positivity at other sites, since these mutations may evolve during progression of disease. The AKT1_G49A mutation was revealed exclusively in metastatic disease and was documented for the first time in TC (23).

Sorafenib

Pharmacology: structure-related activity of sorafenib and a rationale for its use

A decade ago, in a medicinal chemistry program focused on selective RAF kinase inhibitors, ureas 2 and 3 were identified as potent, orally active inhibitors of the enzyme, both displaying broad in vivo antitumor activity. Chemical characteristic of these molecules are donor/acceptor motif and an acidic phenol flanked by two substitutions (24).

The synthetic compound sorafenib (BAY 43-9006 Onyx, Bayer; 4-[4-[3-(4-chlor-3-trifluormethylphenyl)ureido]phenoxy]pyridine carbonsauremethylamid [IUPAC]) is a potent derivative, which, having been isolated after an improved, four-step synthesis of urea, displayed antitumor activity (25). Sorafenib inhibited Raf-1 and suppressed both wild-type and V599E mutant B-Raf activity in cancer cell lines (26). Further, sorafenib demonstrated significant inhibitory activity against neovascularization and tumor progression factors such as VEGF receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR) beta, and the cytokine receptor c-KIT (26). In preclinical studies sorafenib exhibited broad-spectrum antitumor activity in various cancer xenograft models (26). Because of their pharmacodynamic pleiotropism, and more specifically due to their antagonistic activity upon the VEFGR, some among this class of small molecule-kinase inhibitors, such as sunitinib (27) and sorafenib itself, have also been confirmed as antiangiogenic drugs (28,29). On the basis of these encouraging results, sorafenib has been approved for treatment of unresectable hepatocellular carcinoma (5) as well as for advanced renal carcinoma (30).

Table 1.

Type of Thyroid Cancer, Number of Patients, and Percentage of Patient Response, Stable Disease, Partial Disease, and Progression-Free Survival in Phase II Trials of Sorafenib in Patients with Advanced Papillary Thyroid Cancer and Medullary Thyroid Carcinoma

Authors	Type	Patients	PR (%)	SD (%)	PD (%)	PFS (months)
Gupta-Abramson et al. (61)	PTC	30	23	53	3	19.8
Kloos et al. (62)	PTC^a	41	15	23	12	7.5
Hoftijzer et al. (63)	PTC	31	25	34	22	13.5
Lam et al. (65)	MTC	16	6.3	87.5	6.2	17.9

Classic PTC 73%; variants of PTC 27%.

MTC, medullary thyroid carcinoma; PD, partial disease; PFS, progression-free survival; PR, patient response; PTC, papillary thyroid cancer; SD, stable disease.

Kinetics and drug-to-drug interactions

Plasma-concentration–time profiles of sorafenib increase in a less than proportional fashion with increasing doses. Such variability in different individuals does not, however, seem correlated with drug-related adverse events (31). Steady-state concentrations of sorafenib are reached after 7 days of dosing, with no further substantial accumulation after this time, whereas its elimination half-life (t _1/2) is relatively long (32). Depending upon factors such as the liver status and the age of patients, sorafenib plasma levels are correspondingly variable and thus may to some degree influence the effectiveness and the safety of the drug. On the basis of the results of a study to establish safety and pharmacokinetics a dose of 400 mg bid was recommended (33).

Sorafenib is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzymes in the liver. Pharmacokinetics of sorafenib may as a consequence vary considerably when the drug is administered in concomitance with strong CYP3A4 inducers. Hence, the use of drugs such as dexamethasone, phenytoin, or rifabutin should be avoided in patients taking sorafenib because they may decrease drug plasma concentrations (34).

When sorafenib was administered with irinotecan in patients with advanced refractory solid tumors, the exposure to the latter was increased, probably due to inhibition of UGT1A1 pathway-mediated irinotecan metabolism. Patients should therefore be monitored for irinotecan-related toxicity symptoms (35).

In a study comprising 189 patients with advanced renal cancer, the subjects were assigned to sorafenib 400 mg twice daily or to subcutaneous interferon-alpha-2a, 9 million units, three times weekly. Patients treated with sorafenib exhibited greater rates of tumor size reduction, better quality of life and higher tolerability (36).

Side effects and toxicity of sorafenib

Although sorafenib is generally well tolerated, adverse effects, mostly mild-to-moderate, may occur during treatment. Based upon clinical studies, the most frequent drug-related adverse events include fatigue (40%), anorexia (35%), diarrhea and nausea (34%), and dermatologic reactions (25%) (37). Commonly observed dermatologic side effects are rash/desquamation (40%) and hand-foot skin reaction (30%), alopecia (27%), and pruritus (19%) (38). Hand-foot skin reactions and musculo-articular pain that are presented after 1–2 months tend to be particularly persistent and disruptive, while any gastrointestinal complications, which are usually reported at an early stage of treatment, improve after a few weeks (39). A recent trial demonstrated that patients who presented an early skin reaction to sorafenib had a higher tumor control rate (48.3%) as compared to those without cutaneous side effects (19.4%) (40). It was thus recommended that skin toxicity should be closely monitored as a surrogate marker of treatment efficacy (40).

Patients taking sorafenib also have an increased risk of developing eruptive keratoacanthoma-type squamous cell carcinomas, an adverse effect limited to this compound, which, however, is reversed with discontinuation of the drug (41). The pathogenesis is probably independent of TK inhibition and is likely linked to the effects of sorafenib on wild-type BRAF in the skin (42). Accordingly, physicians treating patients with sorafenib should be aware of these possibilities and monitor patients for skin lesions.

Reduction of therapy is often indicated as it alleviates the intensity of adverse reactions. Early intervention in the management of the side effects is important to improve compliance and to avoid interruption of treatment. Less frequently occurring adverse reactions have been reported and include cardiovascular effects, such as dysrythmias, congestive heart failure, infarction, and hypertension (43); endocrine/metabolic effects, such as weight loss, hypoalbuminemia, hypophosphatemia, and hypocalcemia (44); hepatic effects, such as conjugated hyperbilirubinemia and hepatic enzymes elevation (45); neurologic effects; psychiatric effects; renal effects; respiratory effects, such as dyspnea and pulmonary hemorrhage; and ophthalmic side effects presented as squamous blepharitis, or as dysfunctional tear-syndrome (46). Therefore, patients should be monitored for drug toxicity.

The quality of life has not as yet been systematically evaluated in patients taking sorafenib as compared to cytostatic (doxorubicin) or other TKIs drugs.

Finally, it is to be noted that the U.S. Food and Drug Administration has included sorafenib in Pregnancy category D, implying positive evidence of human fetal risk and therefore strongly recommending contraceptive measures. In addition, infant risk cannot be ruled out during breastfeeding.

Mode of action

Compounds that inhibit a distal effector in the MAPK pathway can block growth and tumorigenesis of human TC. Sorafenib targets the VEGFRs and PRGFR, which are key elements in tumor progression and tumorigenesis (47,48). VEGF is complemented by PDGF and treatment targeting VEGF consequently results in downregulation of both VEGF and PDGF and, hence, inhibition of tumor growth (48,49). Sorafenib blocks the activation of RAS by the VEGF/PDGF receptors autophosphorylation and the resultant phosphorylation and transactivation to RAF and MEK/ERK (Fig. 1). It thereby reduces tumor cell survival while impeding metastasis and tumor cell proliferation. Sorafenib may be particularly useful in the treatment of thyroid carcinomas harboring BRAF^V600E mutations that are refractory to conventional treatment by inducing apoptosis via suppression of the antiapoptotic proteins MCL-1 and BCL-2 (50). In a similar manner to some other TKIs, including sunitinib and motesanib, sorafenib, through targeting VEGFR-2 and inhibiting endothelial cells, is likely to exert a primarily direct antitumor action (51).

FIG. 1.

The mode of action of the multikinase inhibitor sorafenib. Sorafenib inhibits tumor growth via the blocking of RAF and Kit signaling as well as via inhibition of vascular endothelial growth factor receptor (VEGFR) (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). By blocking the downstream effectors of the signaling cascade, sorafenib demonstrates biologically significant inhibitory potential in tumor cell proliferation and metastasis.

Sorafenib inhibits the proliferation of anaplastic thyroid carcinoma (ATC) cells in vitro and reduces angiogenesis, through induction of endothelial cell apoptosis, in orthotopic ATC xenografts; as a result, sorafenib increases survival of mice, while decreasing the survival rate of tumor cells, due to its antiangiogenic effects (52).

TKIs are potentially involved in the functioning of the thyroid—via specific mechanisms for each single molecule—while sorafenib in particular is capable of interacting with TSH, although the scope and the precise mechanism of such interaction have not been elucidated as yet (53). Nevertheless, through its capacity to inhibit the RAF pathway, which has been demonstrated to be strongly implicated in the TSH signaling cascade, sorafenib is able to affect the TSH signal transduction pathway (54). In two cancer patients with a preexisting nodular goiter treated with another multitargeted TKI, sunitinib, achievement of a shrinkage of the thyroid gland and induction of clinical hypothyroidism was reported (55). It is therefore evident that thyroid morphological changes in patients under treatment with TKIs for gastrointestinal or renal-cell carcinomas are capable of serving as a biological marker of organ damage (56). However, since this thesis is at present controversial, another study having detected no changes in thyroid volume, the precise mechanism as yet eludes complete clarification (57,58).

Also noteworthy is the fact that in a recent study investigating the effects of sorafenib therapy on serum thyroid hormones in athyreotic patients, sorafenib was associated with increased type 3 deiodination (59). The serum-free thyroxine (T4) and triiodothyronine (T3) levels decreased by 11% and 18%, respectively, whereas serum T3/T4 and T3/rT3 ratios decreased in parallel, this probably indicating increased type 3 deiodination (60).

Both the implication of TKIs in thyroid metabolism and their observed negative impact on thyroid function point to the need for prospective thyroid function testing and evaluation of levo-T4 requirements for all patients starting therapy.

Sorafenib Studies in TC

TKI targeting of the RAS/RAF/MAPK and the VEGFR pathways represents a valid option for therapy in patients with radioiodine refractory PTC. Due to its unique dual action on the RAS-RAF pathway and on VEGFR-PDGFR expression, sorafenib constitutes an acceptably valid alternative to conventional treatment and represents a promising candidate drug for the treatment of advanced PTC.

Two phase II studies have been conducted with sorafenib in metastatic TC. The first study included 30 patients with iodine-refractory thyroid carcinoma treated with 800 mg sorafenib daily for 16 weeks: 7 patients (23%) had an objective partial response rate (PRR) of 18–84 weeks, 16 patients (53%) had stable disease (SD), whereas 95% of the patients showed a decrease of thyroglobulin (Tg) up to 70% (61). A PRR is defined as a decrease of 30% in the sum of the longest diameter measurements by response evaluation criteria in solid tumors. Evaluation by response evaluation criteria in solid tumors of the progression-free survival (PFS) as well as the best response yielded a median of 79 weeks.

In the second study, 41 patients were recruited of whom 6 (15%) had a PRR and 23 patients (56%) had SD lasting for a period of longer than 6 months (62). The median PFS was 15 months; the median PRR was 7.5 months. The Tg decline was >25%. Reduced levels of VEGF and ERK phosphorylation, as well as of VEGF expression, were observed in 4 tumor biopsies out of 10 during the course of treatment with sorafenib. In 52% of the patients, a dose reduction was necessary to ensure tolerability. In both studies the drug revealed clear clinical and biologic antitumor activity and was relatively well tolerated.

Another study has recently emerged reporting the effects of sorafenib, administered for 26 weeks, on the reinduction of radioiodine uptake and tumor progression in 31 patients with progressive metastatic or locally advanced radioiodine refractory DTC (63). A clinical response was observed in 59% of the patients; meanwhile, 25% registered a PRR, 34% had SD, and 22% had progressive disease, whereas the estimated PFS was 58 weeks. However, diagnostic body scan did not reveal any reinduction of radioactive iodine uptake and sorafenib results were clearly less effective in patients with bone metastases.

In another study reporting the M.D. Anderson experience with TKIs in 15 patients refractory to iodine DTC, those who received sorafenib (n = 13) showed up to 60% SD, 20% PRR, and 20% progressive disease (64). In the same trial, Tg, the tumor marker for DTC, promptly decreased in patients receiving sorafenib, this decrease preceding tumor shrinkage, as was shown via computed tomography; meanwhile, log Tg correlated with response to treatment (64). It is hence apparent that Tg represents a reliable biologic marker of response to treatment.

The relevant discrepancy with regard to PRR and PFS rates between the above mentioned studies may be due to differences in tumor characteristics, frequency of response evaluation and drug-resistance.

Of note, by targeting RET and VEGFR sorafenib also provides antitumor activity in MTC. This capacity has been demonstrated in a phase II clinical trial of sorafenib in patients with advanced MTC wherein PRR was achieved in 6.3% of 16 patients with sporadic MTC, whereas 87.5% had SD (65).

It is therefore probable that sorafenib, due to its demonstrated antitumor activity, may play a pivotal role in the treatment of iodine nonavid DTC, MTC, and ATC. The documented achievement of PR and SD rates up to 77% as well as PFS of 79 weeks reveals the potential of sorafenib as an adjunct to our arsenal of therapeutic practices.

However, the reported results so far clearly underline the necessity that patients must be carefully selected before starting treatment with TKIs, and as it has been stated in a recent editorial, only patients with rapidly progressive radioactive iodine-refractory metastatic disease should be candidate for treatment with TKIs (66).

Rationale of Combined Treatment with Sorafenib

Bearing in mind that VEGF complemented by PDGF exerts potent and specific effects on vessel formation and blood tumor supply, the hypothesis of direct antivascular effects of agents such as sorafenib, which specifically target VEGF, appears corroborated by the very encouraging results obtained in both animal models and human tumor studies. However, since tumors are often dependent on multiple signaling pathways that have been mutationally activated, the need for multiple-agent therapy covering many different targets is evident (67). Such combined treatment is particularly indicated given the tumor cellular heterogeneity, the complexity of molecular pathways, and the tenacity of the microenvironment to support survival and spread of solid tumors. Sorafenib has shown clinical effectiveness in various tumors when combined with other targeting or cytotoxic agents (68). This has been clearly demonstrated in experiments showing that sorafenib combined with the HIV protease inhibitor nelfinavir improved apoptosis. The latter is achieved by downregulating the antiapoptotic mitochondrial membrane protein MCL-1 and by inhibiting MCL-1 upregulation induced by nelfinavir, thereby resulting in enhanced nelfinavir activity (69).

In patients with advanced malignancies, including PTC and MTC, sorafenib was combined with the farnesyltransferase inhibitor tipifarnib in a 28-day cycle, that is, sorafenib daily and tipifarnib for 21 days (70). Prolonged SD or partial remission was seen in six out of eight patients with MTC, thus commending this mode of treatment for patients with advanced MTC. Sorafenib and sunitinib, both currently available TKIs, can be considered for treatment of patients with metastatic MTC, while other multikinase inhibitors will soon be available in single or combined treatment protocols (71,72).

Recent reports indicate that sorafenib used in the tuberous sclerosis complex in combination with the mTOR inhibitor rapamycin allows achievement of a more sustained tumor response than rapamycin alone (73). In fact, the mTOR is the downstream effector of the PI3K signaling cascade, which is often activated in TC and is considered responsible for tumor growth and proliferation (74).

In another study designed to investigate the in vivo antitumor activity on four patient-derived HCC xenografts, sorafenib inhibited tumor growth in a dose-dependent fashion (75). Combined treatment with sorafenib and rapamycin resulted in inhibition of VEGF-2 and PFGFR beta phosphorylation and increased apoptosis.

These results highlight the need to explore the efficacy of targeting the RAF/MEK/ERK and VEGF pathways, in combination with inhibitors of the mTOR pathway, as a therapeutic strategy in clinical trials in patients with advanced solid tumors and poorly DTC.

Conclusions

Targeting of VEGFR by TKIs constitutes an innovative mode of therapy in metastatic PTC. Among the newly developed TKIs investigated in recent studies, sorafenib is being regarded as a particularly attractive alternative to traditional treatment of PTC refractory to iodine. Nevertheless, additional studies are required to further elucidate the mechanisms of response and resistance to therapy as well as to define optimal duration of treatment, impact of dose reduction on toxicity, efficacy of the drug, and potential for its use in combination modules.

Footnotes

Acknowledgments

We wish to thank Dr. Guido Mangano and Dr. Nicole Ronsisvalle for their valuable assistance.

Disclosure Statement

The authors declare that no competing financial interests exist.

References

Krause

, Van Etten

. 2005. Tyrosine kinases as targets for cancer therapy. N Engl J Med, 353:172–187.

Tabernero

. 2007. The role of VEGF and EGFR inhibitor: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res, 5:203–220.

Fassnacht

, Kreissl

, Weismann

, Alolio

. 2009. New targets and therapeutic approaches for endocrine malignancies. Pharmacol Ther, 123:117–141.

Staehler

, Haseke

, Zilinberg

, Stadler

, Karl

, Siebels

, Duerr

, Siegert

, Jauch

, Bruns

, Stief

. 2010. Complete remission achieved with angiogenic therapy in metastatic renal cell carcinoma including surgical intervention. Urol Oncol, 28:139–144.

Llovet

, Ricci

, Mazzaferro

, Hilgard

, Gane

, Blanc

, de Oliveira

, Santoro

, Raoul

, Forner

, Schwartz

, Porta

, Zeuzem

, Bolondi

, Greten

, Galle

, Seitz

, Borbath

, Häussinger

, Giannaris

, Shan

, Moscovici

, Voliotis

, Bruix

. SHARP Investigators Study Group. 2008. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 359:378–390.

Cheng

, Kang

, Chen

, Tsao

, Qin

, Kim

, Luo

, Feng

, Ye

, Yang

, Xu

, Sun

, Liang

, Liu

, Wang

, Tak

, Pan

, Burock

, Zou

, Voliotis

, Guan

. 2009. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol, 10:25–34.

Melillo

, Castellone

, Guarino

, De Falco

, Cirafici

, Salvatore

, Caiazzo

, Basolo

, Giannini

, Kruhoffer

, Orntoft

, Fusco

, Santoro

. 2005. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest, 115:1068–1081.

Kumar

. 1998. Signaling by integrin receptors. Oncogene, 17:1365–1373.

Roberts

, Der

. 2007. Targeting the RAF-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26:3291–3310.

10.

Ferrara

, Gerber

, LeCouter

. 2003. The biology of VEGF and its receptors. Nat Med, 9:669–676.

11.

Ferrara

. 2004. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev, 25:581–611.

12.

Mori

, Sasaki

, Aoyama

, Sera

. 2010. Hypoxia-specific downregulation of endogenous human VEGF-A gene by hypoxia-driven expression of artificial transcription factor. Mol Biotechnol, 46:134–139.

13.

Carroll

, Ashcroft

. 2006. Role of hypoxia-inducible factor (HIF)-1 alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res, 66:6264–6270.

14.

Braga-Basaria

, Ringel

. 2003. Beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer. J Clin Endocrinol Metab, 88:1947–1960.

15.

Vadysirisack

, Venkateswaran

, Zhang

, Jhiang

. 2007. MEK signaling modulates sodium iodide symporter at multiple levels and in a paradoxical manner. Endocr Relat Cancer, 14:421–432.

16.

Davies

, Bignell

, Cox

, Stephens

, Edkins

, Clegg

, Teague

, Woffendin

, Garnett

, Bottomley

, Davis

, Dicks

, Ewing

, Floyd

, Gray

, Hall

, Hawes

, Hughes

, Kosmidou

, Menzies

, Mould

, Parker

, Stevens

, Watt

, Hooper

, Wilson

, Jayatilake

, Gusterson

, Cooper

, Shipley

, Hargrave

, Pritchard-Jones

, Maitland

, Chenevix-Trench

, Riggins

, Bigner

, Palmieri

, Cossu

, Flanagan

, Nicholson

, Ho

, Leung

, Yen

, Weber

, Seigler

, Darrow

, Paterson

, Marais

, Marshall

, Wooster

, Stratton

, Futreal

. 2002. Mutations of the BRAF gene in human cancer. Nature, 417:949–954.

17.

Riesco-Eizaquirre

, Gutierrez-Martinez

, Garcia-Cabezas

, Nistal

, Santisteban

. 2006. The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to impairment of Na+/I-targeting to the membrane. Endocr Relat Cancer, 13:257–269.

18.

Romei

, Ciampi

, Faviana

, Agate

, Molinaro

, Bottici

, Basolo

, Miccoli

, Pacini

, Pinchera

, Elisei

. 2008. BRAF V600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocr Relat Cancer, 15:511–520.

19.

Elisei

, Ugolini

, Viola

, Lupi

, Biagini

, Giannini

, Romei

, Miccoli

, Pinchera

, Basolo

. 2008. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab, 93:3943–3949.

20.

Ouyang

, Knauf

, Smith

, Zhang

, Ramsey

, Yusuff

, Batt

, Fagin

. 2006. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res, 12:1785–1793.

21.

Mitsiades

, Negri

, McMullan

, McMillin

, Sozopoulos

, Fanourakis

, Voutsinas

, Tseleni-Balafouta

, Poulaki

, Batt

, Mitsiades

. 2007. Targeting BRAFV600E in thyroid carcinoma: therapeutic implications. Mol Cancer Ther, 6:1070–1080.

22.

Liu

, Hou

, Ji

, Guan

, Studeman

, Jensen

, Vasko

, El-Naggar

, Xing

. 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. J Clin Endocrinol Metab, 93:3106–3116.

23.

Ricarte-Filho

, Ryder

, Chitale

, Rivera

, Heguy

, Ladanyi

, Janakiraman

, Solit

, Knauf

, Tuttle

, Ghossein

, Fagin

. 2009. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res, 69:4885–4893.

24.

Lackey

, Cory

, Davis

, Frye

, Harris

, Hunter

, Jung

, McDonald

, McNutt

, Peel

, Rutkowske

, Veal

, Wood

. 2000. The discovery of potent cRAF1 kinase inhibitors. Bioorg Med Chem Lett, 10:223–226.

25.

Bankston

, Dumas

, Natero

, Riedl

, Monahan

, Sibley

. 2002. A scalable synthesis of BAY 43-9600: a potent Raf kinase inhibitor for the treatment of cancer. Org Proc Res Dev, 6:777–781.

26.

Strumberg

. 2005. Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc), 41:773–784.

27.

Motzer

, Michaelson

, Redman

, Hudes

, Wilding

, Figlin

, Ginsberg

, Kim

, Baum

, DePrimo

, Li

, Bello

, Theuer

, George

, Rini

. 2006. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol, 24:16–24.

28.

Fabian

, Biggs

3rd , Treiber

, Atteridge

, Azimioara

, Benedetti

, Carter

, Ciceri

, Edeen

, Floyd

, Ford

, Galvin

, Gerlach

, Grotzfeld

, Hergard

, Insko

, Lai

, Leilas

, Mehta

, Milanov

, Velasco

, Wodicka

, Patel

, Zarrinkar

, Lockhart

. 2005. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol, 23:329–336.

29.

Clark

, Eder

, Ryan

, Lathia

, Lenz

. 2005. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res, 11:5472–5480.

30.

Escudier

, Eisen

, Stadler

, Szccylik

, Oudard

, Staehler

, Negrier

, Chevreau

, Desai

, Rolland

, Demkow

, Hutson

, Gore

, Anderson

, Hoflilena

, Shan

, Pena

, Lathia

, Bukowski

. 2009. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol, 27:3312–3318.

31.

Strumberg

, Clark

, Awada

, Moore

, Richly

, Hendlisz

, Hirte

, Eder

, Lenz

, Schwartz

. 2007. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist, 12:426–437.

32.

Awada

, Hendlisz

, Gil

, Bartholomeus

, Mano

, de Valeriola

, Strumberg

, Brendel

, Haase

, Schwartz

, Piccart

. 2005. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer, 92:1855–1861.

33.

Strumberg

, Richly

, Hilger

, Schleucher

, Korfee

, Tewes

, Faghih

, Brendel

, Voliotis

, Haase

, Schwartz

, Awada

, Voigtmann

, Scheulen

, Seeber

. 2005. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol, 23:965–972.

34.

Keating

, Santoro

. 2009. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs, 69:223–240.

35.

Mross

, Steinbild

, Baas

, Gmehling

, Radtke

, Voliotis

, Brendel

, Christensen

, Unger

. 2007. Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib. Eur J Cancer, 43:55–63.

36.

Escudier

, Szczylik

, Hutson

, Demkow

, Staehler

, Rolland

, Negrier

, Laferriere

, Scheuring

, Cella

, Shah

, Bukowski

. 2009. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cancer cell carcinoma. J Clin Oncol, 10:1280–1289.

37.

Welker

, Lubomierski

, Gog

, Hermann

, Engels

, Vogl

, Bechstein

, Zeuzem

, Trojan

. 2010. Efficacy and safety of sorafenib in advanced hepatocellular carcinoma under daily practice conditions. J Chemother, 3:205–211.

38.

Roberts

, Mateus

, Spatz

, Wechsler

, Escudier

. 2009. Dermatologic symptoms associated with the multikinase inhibitor sorafenib. J Am Acad Dermatol, 60:299–305.

39.

Lee

, Lee

, Chang

, Lee

, Kang

, Choi

, Moon

, Koh

. 2009. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol, 161:1045–1051.

40.

Vincenzi

, Santini

, Russo

, Addeo

, Giuliani

, Montella

, Rizzo

, Venditti

, Frezza

, Caraglia

, Colucci

, Del Prete

, Tonini

. 2010. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist, 15:85–92.

41.

Jantzem

, Dupre-Goetghebeur

, Spindler

, Merrer

. 2009. Sorafenib-induced multiple eruptive keratoacanthomas. Ann Dermatol Venereol, 136:894–897.

42.

Smith

, Haley

, Hamza

, Skelton

. 2009. Eruptive keratoacanthoma-type squamous cell carcinomas in patients taking sorafenib for the treatment of solid tumors. Dermatol Surg, 35:1766–1770.

43.

Izzedine

, Ederhy

, Goldwasser

, Soria

, Milano

, Cohen

, Khayat

, Spano

. 2009. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol, 20:807–815.

44.

Hutson

, Figlin

, Kuhn

, Motzer

. 2008. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist, 13:1084–1096.

45.

Miller

, Murry

, Owzar

, Hollis

, Kennedy

, Abou-Alfa

, Desai

, Hwang

, Vilalona-Calero

, Dees

, Lewis

, Fakih

, Edelman

, Millard

, Frank

, Hohl

, Ratain

. 2009. Phase I and pharmacokinetics study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol, 27:1800–1805.

46.

Basti

. 2007. Ocular toxicities of epidermal growth factor receptor inhibitors and their management. Cancer Nurs, 30:S10–S16.

47.

Takezawa

, Okamoto

, Yonesaka

, Hatashita

, Yamada

, Fukuoka

, Nakagawa

. 2009. Sorafenib inhibits non-small cell lung cancer growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res, 69:6515–6521.

48.

Wilhelm

, Carter

, Tang

, Wilkie

, McNabola

, Rong

, Chen

, Zhang

, Vincent

, McHugh

, Cao

, Shujath

, Gawlak

, Eveleigh

, Rowley

, Liu

, Adnane

, Lynch

, Auclair

, Taylor

, Gedrich

, Voznesensky

, Riedl

, Post

, Bollag

, Trail

. 2004. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res, 64:7099–7109.

49.

Bran

, Bran

, Hoermann

, Riedel

. 2009. The platelet derived growth factor receptor as a target for vascular endothelial growth factor-mediated anti-angiogenetic therapy in head and neck cancer. Int J Oncol, 34:255–261.

50.

Preto

, Gonçalves

, Rebocho

, Figueiredo

, Meireles

, Rocha

, Vasconcelos

, Seca

, Seruca

, Soares

, Sobrinho-Simões

. 2009. Proliferation and survival molecules implicated in the inhibition of BRAF pathway in thyroid cancer cells harbouring different genetic mutations. BMC Cancer, 9:387.

51.

Keefe

, Cohen

, Brose

. 2010. Targeting vascular endothelial growth factor receptor in thyroid cancer: the intracellular and extracellular implications. Clin Cancer Res, 16:778–783.

52.

Kim

, Yazici

, Calzada

, Wang

, Younes

, Jasser

, El-Naggar

, Myers

. 2007. Sorafenib inhibits the angiogenesis and growth of orthotropic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther, 6:1785–1792.

53.

Torino

, Corsello

, Longo

, Barnabei

, Gasparini

. 2009. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol, 6:219–228.

54.

Illouz

, Laboureau-Soares

, Dubois

, Rohmer

, Rodien

. 2009. Tyrosine kinase inhibitors and modifications of thyroid function tests: a review. Eur J Endocrinol, 160:331–336.

55.

Morshed

, Latif

, Davies

. 2009. Characterization of thyrotropin receptor antibody-induced signaling cascades. Endocrinology, 150:519–529.

56.

Rivas

, Santisteban

. 2003. TSH-activated signaling pathways in thyroid tumorigenesis. Mol Cell Endocrinol, 213:31–45.

57.

Rogiers

, Wolter

, Op de Beeck

, Thijs

, Decallonne

, Schöffski

. 2010. Shrinkage of thyroid volume in sunitinib-treated patients with renal-cell carcinoma: a potential marker of irreversible thyroid dysfunction? Thyroid, 20:317–322.

58.

Mannavola

, Coco

, Vannucchi

, Bertuelli

, Carletto

, Casali

, Beck-Peccoz

, Fugazzola

. 2007. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab, 92:3531–3534.

59.

Hershman

, Liwanpo

. 2010. How does sunitinib cause hypothyroidism? Thyroid, 20:243–244.

60.

Abdulrahman

, Verloop

, Hoftijzer

, Verburg

, Hovens

, Corssmit

, Reiners

, Gelderblom

, Pereira

, Kapiteijn

, Romijn

, Visser

, Smit

. 2010. Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination. J Clin Endocrinol Metab, 95:3758–3762.

61.

Gupta-Abramson

, Troxel

, Nellore

, Puttaswamy

, Redlinger

, Ransone

, Mandel

, Flaherty

, Loevner

, O'Dwyer

, Brose

. 2008. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol, 26:4714–4719.

62.

Kloos

, Ringel

, Knopp

, Hall

, King

, Stevens

, Liang

, Wakely

Jr. , Vasko

, Saji

, Rittenberry

, Wei

, Arbogast

, Collamore

, Wright

, Grever

, Shah

. 2009. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol, 27:1675–1684.

63.

Hoftijzer

, Heemstra

, Morreau

, Stokkel

, Corssmit

, Gelderblom

, Wejers

, Pereira

, Huijberts

, Kapiteijn

, Romijn

, Smit

. 2009. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol, 161:923–931.

64.

Cabanillas

, Waguespack

, Bronstein

, Williams

, Feng

, Hernandez

, Lopez

, Sherman

, Busaidy

. 2010. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M.D. Anderson experience. J Clin Endocrinol Metab, 95:2588–2595.

65.

Lam

, Ringel

, Kloos

, Prior

, Knopp

, Liang

, Sammet

, Hall

, Wakely

Jr. , Vasko

, Saji

, Snyder

, Wei

, Arbogast

, Collamore

, Wright

, Moley

, Vilalona-Calero

, Shah

. 2010. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol, 28:2323–2330.

66.

Fagin

, Tuttle

, Pfister

. 2010. Harvesting the low-hanging fruit: kinase inhibitors for therapy of advanced medullary and nonmedullary thyroid cancer. J Clin Endocrinol Metab, 95:2621–2624.

67.

Tortora

, Ciardiello

, Gasparini

. 2008. Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale, preclinical studies and clinical applications. Nat Clin Pract Oncol, 5:521–530.

68.

Takimoto

, Awada

. 2008. Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents: a review of clinical trials. Cancer Chemother Pharmacol, 61:535–548.

69.

Brüning

, Burger

, Vogel

, Gingelmaier

, Friese

, Burges

. 2010. Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib. Invest New Drugs, 28:535–542.

70.

Hong

, Sebti

, Newman

, Blaskovich

, Ye

, Gagel

, Moulder

, Wheler

, Naing

, Tannir

, Ng

, Sherman

, El Naggar

, Khan

, Trent

, Wright

, Kurzrock

. 2009. Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies. Clin Cancer Res, 15:7061–7068.

71.

Sherman

. 2009. Tyrosine kinase inhibitors and the thyroid. Best Pract Res Clin Endocrinol Metab, 23:713–722.

72.

Sugawara

, Geffner

, Martinez

, Hershman

. 2009. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes, 16:367–372.

73.

Lee

, Woodrum

, Nobil

, Rauktys

, Messina

, Dabora

. 2009. Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol, 9:8.

74.

Papewalis

, Wuttke

, Schinner

, Willenberg

, Baran

, Scherbaum

, Schott

. 2009. Role of the novel m TOR inhibitor RAD001 (everolimus) in anaplastic thyroid cancer. Horm Metab Res, 41:752–756.

75.

Huynh

, Ngo

, Koong

, Poon

, Choo

, Thng

, Chow

, Ong

, Chung

, Soo

. 2009. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med, 13:2673–2683.