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10.1245/s10434-006-9178-6
Annals of Surgical Oncology 14:719-729 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Anaplastic Thyroid Carcinoma: Expression Profile of Targets for Therapy Offers New Insights for Disease Treatment

Sam M. Wiseman1,2, Hamid Masoudi1,2, Paddy Niblock3, Dmitry Turbin2, Ashish Rajput2, John Hay3, Samuel Bugis1, Douglas Filipenko4, David Huntsman2 and Blake Gilks2

1 Department of Surgery, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada
2 Genetic Pathology Evaluation Center at the Prostate Research Center of Vancouver General Hospital, British Columbia Cancer Agency, and University of British Columbia, Vancouver, BC, Canada
3 Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
4 Department of Pathology, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada

Correspondence: Address correspondence and reprint requests to: Sam M. Wiseman; Department of Surgery, St. Paul’s Hospital, University of British Columbia, C303-1081 Burrard Street, Vancouver, BC, Canada V6Z-1Y6; E-mail: smwiseman{at}providencehealth.bc.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: Anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study. Little is known regarding the expression by anaplastic tumors of molecular targets for new human anticancer agents that have been studied in the preclinical or clinical setting. The objective of this work was to evaluate the expression profile of anaplastic thyroid tumors for molecular targets for treatment.

Methods: Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984–2004), 32 cases (34%) had adequate archival tissue available for evaluation. A tissue microarray was constructed from these anaplastic thyroid tumors and immunohistochemistry was utilized to evaluate expression of 31 molecular markers. The markers evaluated were: epidermal growth factor receptor (EGFR), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, ß-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin.

Results: A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort. The mean age of the anaplastic cohort was 66 years; 16 patients (51%) were females, and the median patient survival was 23 weeks. A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0–100%). The therapeutic targets most frequently and most strongly overexpressed by the anaplastic tumors were: ß-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%).

Conclusions: Anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability. This report is the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supports the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.

Key Words: Anaplastic • Thyroid, Cancer • Targeted therapeutics • EGFR


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Anaplastic thyroid carcinoma (ATC) is an uncommon endocrine malignancy. Its rare and rapidly fatal disease course has made it difficult to study in both clinical and laboratory settings. The majority of patients diagnosed with ATC will die from either suffocation, a consequence of locoregional disease extension or overwhelming distant metastatic disease.1–3 Over the past few decades there has been little improvement in the survival of ATC patients and today their mean survival is approximately 6 months.1–3 Currently, the most effective drug for treatment of ATC is doxorubicin that has been reported to have a response rate of 5–22%, and when combined with cisplatin, a further improvement of response to therapy has been observed.1,2 Tennvall et al. reported the results of three study protocols that combined doxorubicin, hyperfractionated radiotherapy, and surgery that were carried out on 55 Swedish subjects diagnosed with ATC.4 In this study, the median patient survival for these protocols ranged from 2 months to 4.5 months. In this cohort no treatment response was observed by distant metastatic disease and there was no evidence of local recurrence in the majority (60%) of ATC patients.4 A group from France recently reported results of prospective study evaluating another aggressive multimodal treatment protocol for ATC that included surgery, chemotherapy (doxorubicin and cisplatin), and hyperfractionated accelerated external beam radiotherapy.5 The overall 3-year survival rate in their group of 30 ATC patients was 27% and their median patient survival was 10 months.5 In this report, the cause of death was due to local disease progression, distant metastatic spread, or a combination of both in 5, 68, and 27% of the cases, respectively.5 Therefore, while current multimodal treatment protocols are able to control local disease in the majority of cases, individuals diagnosed with ATC rapidly die from their distant metastases.4,5 Other chemotherapeutic agents, which include bleomycin, cyclophosphamide, 5-fluororuracil, mitoxantrone, and paclitaxel, have been utilized with limited success for treatment of ATC.1–3 Thus, the identification of an effective systemic treatment for ATC, a disease in which greater than half of patients present with evidence of distant metastases, would represent a major advance in the management of this fatal thyroid cancer.

Recently, the development of molecular target-specific anticancer drugs has allowed for the emergence of new treatments for which the therapeutic benefit is maximized while the toxicity to normal tissues is limited. An example of a targeted anticancer drug is trastuzumab (Herceptin® Genentech Inc, San Francisco, CA), a monoclonal antibody that binds the type 1 growth factor receptor (T1GFR) family member HER2, shuts down signaling, and induces breast cancer regression.6 Target-specific anticancer drugs are now utilized for the treatment of and have led to improved outcomes for individuals diagnosed with a variety of malignancies, including breast cancer, colorectal cancer, lung cancer, and gastrointestinal stromal tumors (GISTs).6–9 Even for individuals with evidence of distant metastatic disease, targeted therapeutic drugs have led to improved outcomes.6–9 An ideal molecular target in cancer is either differentially expressed or differentially functional in malignant and normal tissues.10 Therefore, for many of these anticancer drugs the response of the tumor to therapy and the appropriateness of patient treatment with a specific targeting agent may be predicted by the expression of the molecular target by the tumor itself. Our study objective was to evaluate a large cohort of ATC for their expression of a panel of molecular targets for anticancer agents, which are currently in preclinical development, being studied in clinical trials, or have already become adopted into the clinical management of other human cancer types, in order to identify drugs that warrant further clinical evaluation for treatment of ATC. A secondary objective of this study was to review the ATC expression profile within the context of preclinical studies evaluating targeted therapeutics for ATC. In a population-based cohort of 32 ATC, utilizing a tissue microarray (TMA) approach, the expression of a panel of potential molecular targets for disease therapy was evaluated. The 31 molecular markers evaluated in the study of ATC population were: epidermal growth factor receptors (EGFR) (HER1), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, ß-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, MDM2, p53, p21, p27, Bcl-2, cyclin D1, cyclin E, calcitonin, MIB-1, TTF-1, and thyroglobulin (TG).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Sequential archival cases of ATC with available paraffin blocks that had been diagnosed and treated in British Columbia, Canada, over a 20-year period, were identified through the provincial tumor registry for TMA construction. This study was approved by the Research Ethics Board. The ATC pathologic diagnoses were confirmed by review of all cases by two endocrine pathologists. Hematoxylin and eosin (H&E)-stained sections of each tumor were examined and areas of ATC were marked on both the slide and the corresponding paraffin block for TMA construction. TMA construction was carried out in a manner that has been previously described.11 Adequate tissue was present for immunohistochemical staining of 32 ATC for the panel of 31 molecular markers summarized in Table 1Go. The antibodies utilized, and the antigen retrieval methodologies carried out are also summarized in Table 1Go. Sample cores of ATC stained for several potential therapeutic targets are presented in Fig. 1Go.


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  		TABLE 1. Characteristics of antibodies utilized for immunohistochemistry
 

Figure 1
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  		FIG. 1. Anaplastic thyroid carcinoma tissue cores exhibiting strong expression of: (A) EGFR, (B) Aurora A, (C) Cyclin E, (D) Cyclin D1, (E) ß-catenin, and (F) p53.

 
The scoring of the TMA sections stained for all markers evaluated was carried out in a semiquantitative manner. The scoring system types are summarized in Table 2Go and the scoring systems for all markers evaluated are summarized in Table 3Go. Whenever possible, scoring systems utilized were adapted from those applied to other tissues for therapeutic target selection (i.e., c-kit, EGFR, HER2). For the purpose of statistical analysis score data were binarized, using the cut-offs of 0 versus (1+) + if applicable (2+) + if applicable (3+) (for any expression) and (0) + (1+) versus (2+) + if applicable (3+) (for strong expression). All samples were evaluated and scored simultaneously by two pathologists who were blinded to all patient clinical data. Any interpathologist discrepancy in the scoring of a specific tissue core was immediately resolved. If there was a discrepancy in the scores assigned to the two cores from the same tumor, the tumor was assigned the higher score.


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  		TABLE 2. Scoring system types for markers evaluated
 

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  		TABLE 3. Scoring systems for markers evaluated
 
As has been previously described, all data was logged into a standardized score sheet matching each TMA section (Microsoft Excel Microsoft, Redmond, WA). The spreadsheet was then processed utilizing TMA-Deconvoluter 1.06 software that had been adapted for TMA analysis.12 Given the small sample size (n = 32), target expression was quantified as both the proportion of cases showing any target expression and the proportion of cases showing strong target expression (Table 4Go).


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  		TABLE 4. Proportion of cases expressing marker and expressing marker strongly for the entire anaplastic thyroid carcinoma cohort
 
All patient clinical data was retrospectively collected from hospital charts. All patients had newly diagnosed ATC. Clinicopathologic patient data collected included the following: age, sex, type of therapy, patient follow-up, and survival. A master database was created by incorporation of all deconvoluted marker data into the clinicopathologic patient database. Given the uniformly dismal prognosis of all individuals diagnosed with ATC, no attempt was made to evaluate the prognostic utility of the expression of any specific molecular marker. The potential targets for therapy were then stratified into three groups based on the proportion of tumors expressing the target and the strength of target expression (Table 4Go). Group 1 (poor target group) included tumors that expressed the target in only a minority of cases (<15%). Group 2 (possible target group) included targets expressed by an intermediate number of tumors (15–50%). Group 3 (promising target group) included targets expressed by the majority of ATC cases (>50%). The targets for therapy identified in Group 3 were then ranked based on the proportion of cases expressing the marker strongly.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Of the 94 cases of ATC diagnosed and treated in British Columbia, Canada, over a 20-year period (1984–2004), 32 cases (34%) had adequate tissue available for TMA construction. Immunohistochemistry revealed a single case that strongly expressed calcitonin, and this case was therefore diagnosed as a poorly differentiated medullary carcinoma and was excluded from further analysis. The histologic subtypes of the anaplastic tumors in the study cohort were: 18 epithelioid tumors, 11 spindle cell tumors, and 2 squamoid tumors. The study cohort was composed of 16 females and 15 males, and the median study patient age was 66 years (range 39–84 years). Four patients (13%) in the study cohort had a history of remote (>15 years prior to initial presentation) treatment of hyperthyroidism with radioactive iodine. No study patient had a history of head and neck irradiation, nor did any of the study patients have a personal or family history of thyroid carcinoma.

The most common treatment given to the study cohort, which was received by 15 patients (48%), was surgery (lobectomy or total thyroidectomy) and external beam radiotherapy; one patient (3%) was treated with surgery and chemotherapy; three patients (10%) received surgery, external beam radiotherapy, and chemotherapy; one patient (3%) received external beam radiotherapy and chemotherapy; five patients (16%) received external beam radiotherapy alone; three patients (10%) underwent surgery alone; and three patients (10%) did not undergo surgery, chemotherapy, or radiotherapy. The nine patients who did not undergo thyroid lobectomy or total thyroidectomy underwent an open biopsy for diagnosis. The median survival of the ATC cohort from their date of cancer diagnosis was 23 weeks (range 2–302 weeks) or less than 6 months. There was a single patient in the study population who did not die from ATC and has remained disease-free when recently evaluated at 302 weeks of clinical follow-up.

The expression patterns of the molecular targets evaluated in this study are summarized in Table 3Go. The five molecular targets expressed most frequently by the ATC cohort were: EGFR (87%), aurora C (90%), HER4 (93%), cyclin E (93%), and cyclin D1 (100%). The five molecular targets most frequently expressed strongly (scored >1+) by the ATC cohort were: ß-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%). The target groups are summarized in Table 4Go. Thus, the five most promising targets identified for treatment of ATC were: ß-catenin, aurora A, cyclin E, cyclin D1, and EGFR.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Due to the rarity of this malignancy, the majority of clinical studies of ATC have been historical retrospective case reviews, and the majority of the laboratory investigation of this disease have been ATC cell line (ATCCL)-based studies.13–15 Dozens of ATCCL, each with its own unique characteristics, have been developed from human ATC.16,17 Whether grown in culture or as xenografts in mice, ATCCLs have provided investigators with an experimental model to study both the disease biology and the effects of various treatments in vitro and in vivo.16,17 However, caution must be exercised when applying the results from these in vitro studies to the ATC patient. While tumor cells in culture may maintain many characteristics of the ATC from which they were derived, including radioresistance and invasive/ metastatic behavior, they also exhibit unique properties that arise as a consequence of immortalization.18,19 Onda et al. recently reported the expression profiles of 11 ATCCLs and 10 human ATC utilizing a cDNA microarray representing 25,344 genes.19 From a list of 12 genes that were significantly overexpressed by the ATCCL, 9 (75%) were also overexpressed by the human ATC.19 Of 15 genes underexpressed by the ATCCL only 3 (20%) were underexpressed by the human ATC.19 Thus, results from in vitro and in vivo studies of ATCCLs may generate hypotheses that warrant further clinical investigation but cannot be fully extrapolated to human beings.20,21 Studies evaluating ATC molecular marker expression have historically focused on panels of markers to reliably differentiate these tumors from medullary thyroid cancers and lymphomas.20,21 Few investigators have evaluated the expression of possible targets for therapy in a cohort of human ATC.22

The molecular markers evaluated in this study were selected based on their ability to assist in validating the expression profile of our ATC cohort and also based on their potential to serve as targets for anti-cancer drugs. With reference to the validation markers evaluated (TG, TTF-1, p53, and MIB-1), all were expressed at levels reported for ATC in the current literature. Thyroid tumor expression of TG and TTF-1 are suggestive of a more differentiated phenotype and are expressed by only a small proportion of ATC. The minority of tumors which expressed TG and TTF-1 in our ATC cohort (10% for each) and the weak marker expression observed (7% and 3%, respectively) is also consistent with the current literature.23,24 The TP53 tumor-suppressor gene has been extensively studied in thyroid cancer and is believed to play an important role in the development of ATC.25 In our study cohort, we observed expression of the p53 protein in 19 of 31 (61%) ATC cases which is also consistent with the current reports.25 ATC is characterized by a rapid rate of cellular proliferation.26 MIB-1 is an antibody that binds to the nuclear antigen Ki-67, and its expression correlates with measurements of cellular proliferation which include S-phase and bromodeoxyuridine uptake.27 The high proportion and strong staining of Ki-67 in our ATC cohort (90% and 100%, respectively) is also consistent with the current literature.26 Thus, the high level of Ki-67 and p53 protein expression that we observed in the ATC and the low levels of TG and TTF-1 expression we also observed in these cases, along with their clinical characteristics, make our study cohort similar to other ATC populations that have been previously described.

The clinical efficacy of a specific anticancer-targeted drug varies not only from tumor type to tumor type, but also from individual to individual, for tumors with identical gross and microscopic characteristics. Depending on the agent itself and the cancer type being treated, the selection of a cancer for therapy with a targeted drug is determined by evaluation of some alteration in the tumor’s DNA, RNA, or protein. For example, breast cancer treatment with trastuzumab is limited to those individuals whose tumors overexpress the HER2 protein by immunohistochemistry or exhibit an increase in the HER2 gene copy number by fluorescent in situ hybridization (FISH).28 In our study cohort, we utilized archival paraffin-embedded ATC specimens and evaluated protein expression by immunohistochemistry to identify potential targets for therapy.

The 13 therapeutic targets evaluated in the ATC cohort that made up the poor target group (target group 1) were: HER2, ER, PR, ILK, RET, clusterin, c-kit, IGF1-R, CA-IX , HER3 , AMF-R, aurora B, and E-cadherin. The lack of HER2 expression we observed in the ATC study cohort is consistent with the current literature and also suggests that trastuzumab treatment for ATC may be of limited value.29 Other potential molecular targets evaluated, which were also not found to be expressed by any of the ATC cases, were estrogen receptor (ER), progesterone receptor (PR), and integrin-linked kinase (ILK). ER and PR have previously been reported to be expressed at low levels by ATC and ATCCL.30 Younes et al. evaluated ILK as a potential therapeutic target in a cohort of 21 ATC and 5 ATCCL by immunohistochemistry.31 Unlike our ATC cases, 17 of their ATC cases (81%) and 4 (80%) of their ATCCL expressed ILK.31 In a series of experiments utilizing the ILK inhibitor QLT0267, they also demonstrated in vitro (ATCCL) and in vivo (mouse xenograft model) that ILK inhibition led to implanted tumor growth arrest and apoptosis.31 Clusterin, AMF-R, HER3, or CA-IX expression has previously not been reported for ATC, and the low level of expression they exhibit in the study cohort suggests a limited role for targeting them to treat this malignancy. Similar to our observations in the ATC study cohort, IGF1-R and E-cadherin expression have been previously reported to be expressed at low levels by ATC.32,33 It is also not surprising that the RET tyrosine kinase encoded by the RET proto-oncogene, which is frequently altered in thyroid cancer, was expressed by few ATC. Tallini et al. evaluated RET status by immunohistochemistry and reverse-transcription PCR in a group of 316 thyroid tumors.34 When compared with the differentiated thyroid cancers analyzed, the poorly differentiated thyroid tumors (15 cases) and ATC (17 cases) did not demonstrate RET activation.34 The conclusions of these investigators that RET/PTC-positive papillary carcinomas do not progress to more aggressive and less-differentiated tumor phenotypes are supported by the low level of RET expression exhibited by our ATC cohort.34 Aurora B is a member of the serine/threonine protein kinase subfamily that regulates several crucial mitotic activities including chromosome alignment, segregation, and cytokinesis.35 Sorrentino et al. recently reported strong aurora B expression in ATCCLs and 15 human ATC specimens.35 Utilizing RNA interference and a small molecule aurora kinase inhibitor in vivo (ATCCLs) and in vitro (mouse xenograft model) these investigators decreased the growth of their ATC cells/tumors.35 C-kit expression by ATC has been evaluated by a number of investigators because imatinib mesylate (Gleevec or STI571, Novartis, Annandale, NJ, USA), a drug which selectively inhibits the KIT, ABL, BCR-ABL, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are currently clinically utilized for the treatment of individuals diagnosed with chronic myeloid leukemia (CML) overexpressing the BCR-ABL mutant protein or for GISTs that harbor active forms of c-kit mutations.9 Podtchenko et al. demonstrated in vitro (ATCCLs) and in vivo (mouse xenograft model) significant anaplastic tumor growth inhibition by imatinib.36 Dziba et al. subsequently suggested that imatinib monotherapy for ATC be abandoned after they demonstrated in vitro that it had negligible antineoplastic activity against ATCCLs at therapeutically useful concentrations.37 The low level of c-kit expression we observed in our ATC cohort along with reported preclinical data suggests imatinib monotherapy for ATC would likely be of limited clinical benefit.

The five targets for therapy which we evaluated in the ATC study cohort and made up the possible target group (target group 2) were: MDM2, p21, p27, Bcl-2, and VEGF. The cell cycle represents a series of tightly integrated events that allow for cellular growth and proliferation.38 Not surprisingly, the ATC cell cycle is deranged with a short cellular doubling time and low apoptosis rate, and ATC cells display one of the most rapid growth rates of any solid tumor.39 Abnormality of the ATC cell cycle is suggested in the current study by the observed overexpression of the cyclin-dependent kinase inhibitors p21 and p27 and cyclin family members themselves (cyclins D1 and E). In a thyroid cancer cohort that included 13 ATC cases, Wang et al. reported cyclin D1 overexpression by ATC in the majority (76%) of cases.40 Numerous agents which target the cell cycle are in preclinical or clinical development and may warrant further investigation for treatment of ATC.38 Several authors have described alteration of the TP53 gene, a well-known tumor-suppressor gene that represents one of the most common sites for genetic abnormalities to be found in human cancer, to be commonly found in ATC.41 The TP53 gene product, the p53 protein (target group 3), is believed to have a dual role in protecting the cell from cancer development.41 The p53 protein causes cell cycle arrest, allowing damaged DNA to be repaired, and alternatively it helps prevent DNA damage from being passed on to the next cell generation by causing damaged cells to undergo apoptosis before division.41 Thus, cells that lack or only produce abnormal p53 protein are more susceptible to malignant transformation.41 In a review of 31 studies by Lam et al., 139 of 265 ATCs (52%) revealed either p53 protein or TP53 gene alterations when evaluated with a variety of molecular techniques.25 Several groups have reported in vitro (ATCCLs) and in vivo (mouse xenograft models) studies which have utilized gene therapy methodology to re-introduce wild-type p53 into anaplastic cells to induce a differentiated thyroid cancer phenotype.42–44 The proportion of ATC cases we observed to express the p53 protein is consistent with the current literature.25 The MDM2 oncoprotein interacts with the p53 protein in an auto-regulatory negative feedback loop to attenuate p53 cell cycle arrest and apoptosis functions.45 A number of agents that block the p53–MDM2 interaction leads to selective cancer cell death, and they sensitize cancer cells to chemotherapy and radiotherapy, which warrant future evaluation for treatment of ATC.45 Bcl-2 is an antiapoptotic molecule that is often overexpressed by cancer.46 Kim et al. have reported the ability of a Bcl-2 antisense oligonucleotide to increase drug sensitivity and enhance apoptosis in vitro (AT-CCL).46 Based on the overexpression of Bcl-2 that we observed in the ATC cohort and this preclinical work, further evaluation of agents that target Bcl-2 and allow selective killing of tumor cells by induction of apoptosis is another potentially important future-targeted treatment for ATC.47–51 Other groups have focused on evaluating antiangiogenic agents for treatment of ATC. Tumor neovascularization allows for continued growth and facilitates development of metastasis. Several agents have been investigated in vivo (ATCCL) and in vitro (mouse xenograft models), and they have been found to show promise for treatment of ATC. These agents include: combretastin A4 phosphate, aplidin, PTK787/ZK222584, and human VEGF monoclonal antibody.47–51 Preclinical data, along with observed VEGF expression by ATC, suggests future clinical investigation of antiangiogenic agents, such as bevacizumab (Avastin®, Genentech Inc., San Francisco, CA), a humanized monoclonal anti-VEGF antibody currently clinically utilized for treatment of human cancer, may also show future promise.52

The targets for therapy which we evaluated in our ATC cohort and made up the promising target group (target group 3) and have not yet been discussed include: HER4, uPA-R, aurora A, aurora C, ß-catenin, and HER1 (EGFR). In a cohort of 115 thyroid tumors, Kim et al. reported uPA-R overexpression by two of five (40%) ATC.53 Strategies that target the urokinase plasminogen activator system are currently in preclinical development.54 We have previously reviewed ß-catenin expression by ATC.55 Strategies targeting cancer cells that express ß-catenin, important for cell adhesion and Wnt pathway signaling, are also in preclinical development.56 Aurora A and C, like Aurora B, are members of the serine/threonine protein kinase subfamily, that are involved in regulation of cell cycle progression and are important for maintenance of genomic stability.57 Expression of aurora A and C has not been previously reported for human ATC and clinical trials evaluating aurora kinase inhibitors for human cancer are currently underway.58 HER4, like HER2 and HER3, is another T1GFR family member whose expression has not previously been reported for ATC and may also serve as a potential target for treatment of disease.59

Of all the targets we have evaluated, not only has EGFR been the most extensively studied preclinically for treatment of ATC, but there are also currently available several EGFR targeting drugs that are clinically utilized for treatment of human cancers. EGFR (HER1) is a transmembrane receptor tyrosine kinase which is also a member of the T1GFR family and is abnormally activated in many human tumors.60 The mechanism of EGFR activation that leads to it being overexpressed by cancer includes: EGFR gene amplification, activation of EGFR gene mutations, heterodimerization with other T1GFR family members, transactivation by heterologous signaling networks, and loss of mechanisms that regulate EGFR signaling.60 Abnormal EGFR activation leads to EGFR mRNA and/or protein overexpression, which stimulates excessive downstream signaling, and promotes cancer development and progression.60 Aberrant EGFR signaling leads to cellular proliferation, inhibition of apoptosis, angiogenesis, and the development of invasion and metastasis.60 Both human ATC and ATCCL have been reported to overexpress EGFR. 22,61 Bergstrom et al. reported EGFR expression by six ATCCLs. Similar to our study population, in a German cohort of ATC that was also evaluated by immunohistochemistry, Ensinger et al. reported EGFR expression by 20 of 25 (80%) cases.22

Drugs that are currently utilized clinically for the treatment of human cancer which targets EGFR can be classified as either monoclonal antibodies directed at its extracellular domain, such as cetuximab (Erbitux®, ImClone Systems Inc., N), or small-molecule adenosine triphosphate (ATP) competitive inhibitors directed intracellularly at EGFR’s tyrosine kinase, such as erlotinib (Tarceva®, Genentech Inc., San Francisco, CA), or gefitinib (Iressa®, AstraZeneca Pharmaceuticals, Wilmington, DE).60 Kim et al. recently reported the in vitro antiproliferative effects of cetuximab and irinotecan on an ATCCL and the in vivo effects of cetuximab and irinotecan in an orthotopic ATC mouse xenograft model.62 They observed in vivo cetuximab, irinotecan, and treatment with both agents resulted in 77, 79, and 93% tumor growth inhibition, respectively.62 They also observed that the incidence of nodal metastases, larynx invasion, and the tumor microvessel density were significantly decreased in the treated mice.62 Schiff et al. evaluated expression of EGFR in vitro (ATCCLs) and in vivo (xenograft mouse model) and the effect of gefitinib treatment alone and in combination with paclitaxel on anaplastic cells/tumors.63 In vitro they observed EGFR expression by ATCCL and that gefitinib was able to effectively block EGFR activation by EGF, inhibit anaplastic cellular proliferation, and induce apoptosis.63 In vivo gefitinib alone or given in combination with paclitaxel was able to reduce growth of anaplastic cells/tumors.63 Nobuhara et al. carried similar preclinical work evaluating EGFR expression in vitro (ATCCLs) and in vivo (xenograft mouse model), and they evaluated the effect of gefitinib treatment on these cells/tumors.64 They observed that gefitinib inhibited EGFR transmitted proliferation by anaplastic cells/tumors.64

The development of drugs that have multiple therapeutic targets and the utilization of multiple cancer-targeting agents are both emerging strategies for cancer treatment.65 A preclinical study evaluated the activity of a dual inhibitor of EGFR and VEG, NVP-AEE788 (AEE788, Novartis Pharma AG, Basel, Switzerland), alone and in combination with paclitaxel for treatment of ATC.66 They evaluated the effect of NVP-AEE788 in vitro (ATCCL) and in vivo (mouse xenograft model).66 These investigators found that NVP-AEE788 administration alone and in combination with paclitaxel inhibited xenograft growth by 44% and 69%, respectively.66 Kurebayahi et al. recently reported a preclinical study evaluating the impact of simultaneous treatment with imatinib and gefitinib in vitro (one poorly differentiated thyroid cancer cell line and two ATCCLs) and in vivo (mouse xenograft model).67 They found in vitro that each agent induced apoptosis and combined therapy-enhanced apoptosis with the downstream regulation of antiapoptotic proteins, Bcl-2 and Bcl-xL.67 Combined treatment with imatinib and gefitinib inhibited the growth of anaplastic xenografts in mice.67


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Utilizing a TMA-based approach, we have evaluated the expression profile of 31 human ATC for a panel of 31 molecular markers with the aim of identifying molecular targets for treatment of ATC. We selected the most promising markers as those that were expressed strongly and by a large proportion of the anaplastic tumors. Controversy currently exists as to how the patients diagnosed with a specific cancer type should be selected for treatment with a specific targeted agent.68 Regardless of whether this selection process is based on protein expression or overexpression, gene amplification, mutational analysis, gene expression profile, or some other tumor characteristic, it needs to be validated and reproduced in human beings in the setting of a clinical trial. Therefore, even the targets which we have classified as poor should not be abandoned, as protein expression is not the only method that can be utilized to guide target selection. For a rare malignancy like ATC, targets for therapy that are expressed by a small proportion of tumors might work for some individuals diagnosed with this cancer but would be virtually impossible to clinically validate. Therapeutic target validation for ATC treatment will require a multicenter clinical trial that includes collection of tissues for clinical–molecular correlates. Many questions currently remain unanswered when considering application of targeted therapeutic drugs for treatment of ATC. The ability of these targeted agents, selected based on molecular characteristics of the anaplastic primary tumor, and not the metastases that must also respond to therapy, is currently unknown. ATC also exhibits considerable molecular heterogeneity which is reflected by the diverse origins of this cancer that may include papillary carcinoma, follicular carcinoma, and Hurthle cell cancer.13 Pre-clinical studies utilizing ATCCLs and xenograft models may therefore not truly reflect the complexity of this disease. Challenges that will be faced when targeted agents are utilized clinically for treatment of ATC include determining the most appropriate method for evaluating tumor response to treatment and the limitations of targeted therapy that may arise due to the development of drug resistance.

From a survey of the therapeutic targets that we have evaluated in this study, it is apparent that ATC cells exhibit considerable derangement of their cell cycle regulation and multiple important signal transduction pathways that ultimately lead to uncontrolled cellular growth, proliferation, and the development of genomic instability. Review of the preclinical ATC-targeted therapeutic studies, the expression profile of the study ATC cohort, along with consideration of currently clinically utilized targeted therapeutic drugs, supports the development of clinical trials with anticancer agents that target EGFR and the aurora kinases. New drugs that target these and other important molecular characteristics of ATC and other human cancers, such as agents that target the cell cycle and angiogenesis, also warrant evaluation as they are developed and become adopted into clinical practice. The treatment of ATC with targeted therapeutics alone, in combination, or as an adjuvant to traditional cytotoxic chemotherapy and radiation therapy, warrants further clinical study and may offer new hope for individuals diagnosed with this fatal thyroid malignancy.


   ACKNOWLEDGMENTS
 
Dr Wiseman and Dr Huntsman are Michael Smith Foundation for Health Research Scholars.

Received for publication March 21, 2006. Accepted for publication June 5, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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