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Chief, Endocrine Section Washington Hospital Center Washington, D.C. 20010 and Professor, Departments of Medicine Georgetown University Medical Center Washington, D.C. and Uniformed Services University of the Health Sciences Bethesda, Maryland 20814
Address all correspondence and requests for reprints to: Kenneth Burman, Chief, Endocrine Division, 110 Irving Street, Northwest, Washington, D.C. 20010. E-mail: Kenneth.Burman{at}Medstar.net.
Thyroid cancer is becoming an increasingly frequent problem. It has been estimated that in 2003 there will be 22,000 new cases of thyroid cancer, with 16,300 occurring in women and 5,700 occurring in men. Thought partly related to improved detection, but also probably related to undefined pathogenetic factors, new cases of thyroid cancer have been increasing at a rate of about 3% yearly. Approximately 292,555 individuals in the United States have had the diagnosis of thyroid cancer [American Cancer Society and the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute database].
There are four major types of thyroid cancer: papillary, follicular, medullary, and anaplastic (1). Differentiated thyroid cancer (i.e. papillary and follicular) is the most common type; primary treatment is generally a total thyroidectomy followed by radioactive iodine 131I therapy. Patients are monitored for recurrent disease by physical examinations, scintographic and radiologic studies and monitoring of serum thyroglobulin concentrations (1). Although the majority of patients with differentiated thyroid cancer are cured by these procedures, a significant percentage of individuals have persistent or recurrent disease. This group of patients requires the development of innovative therapeutic modalities to help decrease the progression of their disease and to decrease mortality rates. The pathophysiologic mechanism(s) leading to persistence, recurrence, and/or progression of thyroid cancer are largely unknown. It is thought that one mechanism relates to loss of capacity to respond to 131-I therapy, probably because of decreased function of the sodium-iodide symporter. These patients are sometimes considered to have poorly differentiated thyroid cancer (1). Although this term is vague and ambiguous, in general parlance it suggests that the tumor does not respond to 131I, synthesizes and secretes thyroglobulin poorly, and/or that the cytologic or histologic characteristics have changed such that the cells appear less differentiated.
It is this problematic group of patients with poorly differentiated carcinoma that Schoenberger et al. (2) address in their present study. The foundation of their study relies on the knowledge that vascular endothelial growth factors (VEGFs) acting through stimulation of tyrosine kinase play an important role in neoangiogenesis in thyroid tumor growth (3, 4, 5). Accordingly, they used an orally active agent [PTK787/ZK222584 (PTK/ZK)] to inhibit VEGF-induced tyrosine kinase activation and thereby decrease thyroid cancer growth. Their study is innovative, well performed, and potentially clinically relevant. They cultured ML-1 follicular thyroid cancer cell lines and injected these cells sc into 8-wk-old nude mice that subsequently, as expected, developed solid tumors within 1–2 months. These solid tumors were then transplanted into the flank of a different set of 8-wk-old nude mice. One group of mice received 75 mg/kg of PTK/ZK, and a control group of mice received saline, both administrated via nasogastric tube daily. After a month of treatment, the animals were killed and their tumors studied. Tumor volume in the PTK/ZK-treated mice decreased by 41% and the tumor implants showed earlier necrosis. Using CD31 staining, PTK/ZK-treated tumors also demonstrated decreased angiogenesis and vascularization. Total collagen content in the PTK/ZK-treated tumors was decreased and serum thyroglobulin levels were decreased from 179.6 ng/ml in the control mice to 53.6 ng/ml in the PTK/ZK-treated group (P < 0.05). PTK/ZK was well tolerated, and there was no evidence of increased bleeding or thrombotic events, although caution must be used regarding this conclusion because the frequency of thrombotic events may depend on the dose of agent used as well as the tumor being studied (6). Therefore, in these preliminary studies, it would appear that PTK/ZK is a potentially beneficial treatment for selected patients with poorly differentiated thyroid cancer.
However, there are several comments to be made regarding this study. The authors used the ML-1 human follicular thyroid carcinoma line (7), and the results obtained may not be applicable to more well studied cell lines such as NPA (papillary thyroid cancer) or WRO (follicular thyroid cancer) and, of course, may also not be applicable to anaplastic thyroid cancer (ARO) or to medullary thyroid cancer (TT) cell lines. Medullary thyroid cancer and anaplastic thyroid cancer are generally considered more aggressive tumors, and innovative therapies obviously need to be applied to these cell types as well (1). Furthermore, their cell line and animal model may not have direct correlates with spontaneously occurring thyroid cancer in humans. There are other issues. For example, as noted above, the term "poorly differentiated thyroid cancer" is ambiguous, and the authors note that the ML-1 cell line traps glucose, and iodine and secretes T3 and thyroglobulin. Thus, it retains many of the characteristics of differentiated thyroid follicular cells and, as a result, the conclusions made may not be applicable to "poorly differentiated" recurrent or persistent thyroid cancers in humans. Another issue is that the authors use a nude mouse xenotransplant model that, in general, may not have direct clinical application because of the decreased ability of the mice to immunologically respond to the tumor presence. Most importantly, although the potential benefits of PTK/ZK on thyroid tumor size in this study seem unequivocal, unfortunately, during the time frame of the study, there was not complete regression of the tumor. It is unknown whether additional regression would be observed during a longer time frame or whether PTK/ZK would have synergistic benefit when used with other modalities such as external radiation, 131I and/or chemotherapy. Lastly, most of the results in the present study are derived from immunofluorescent studies. Although it appears the studies are well performed and the conclusions well founded, immunofluorescence is somewhat subjective in nature and it would be appropriate to extend these studies to include more quantitative and confirmatory studies, such as with Western blots.
There are wider implications of this study in regard to the treatment of various types of carcinoma. There are many circumstances when standard chemotherapeutic regimens may be relatively unsuccessful. A novel paradigm employing antineoplastic agents that are specifically targeted against carcinogenic biochemical or molecular pathways represents a new frontier and holds great promise as an innovative approach to cancer treatment (8). For example, as employed by Schoenberger et al. (2), angiogenesis has been a major target of directed cancer therapy. VEGF has been found to have possible prognostic significance in node-negative breast cancer, ovarian neoplasm, renal cell carcinoma, and thyroid carcinoma (9, 10, 11, 12, 13, 14). VEGF antibody has been used successfully to treat thyroid cancer xenotransplants in animals (15, 16). VEGF tyrosine kinase inhibition has been demonstrated to decrease tumor growth, metastases, and tumor vascularization in murine renal cell carcinoma (13). Combretastatin or combretastatin A4 prodrug disrupts the cellular integrity of immature endothelial cells and has shown preliminary promise in the treatment of medullary thyroid cancer, chronic lymphocytic leukemia, gliomas, Kaposi’s sarcoma, non-Hodgkins’ lymphoma, and colon cancer (9, 17, 18, 19, 20, 21, 22). Most of these studies are preclinical and represent animal or in vitro analyses.
C-ABL is a ubiquitous non-receptor-associated tyrosine kinase that participates in normal and stressed cell cycle events (23, 24, 25). For example, c-ABL kinase activates MAPK activation induced by integrin or platelet derived growth factor. The tyrosine kinase inhibitor, STI571, the prototypical agent for this new paradigm, selectively suppresses the activity of anaplastic thyroid cancer in vitro, an effect likely mediated through mutated p53 (24). This action is a matter of discussion, especially as relating to the possible serum levels obtainable in humans (26). In human clinical studies, STI571 has shown antitumor activity in chronic myelogenous leukemia, small cell lung cancer, and gastrointestinal stromal tumors (27, 28, 29, 30, 31). There is significant enthusiasm for the utility of this agent, but it has been tempered to some extent by the development of drug resistance. The mechanism of resistance is being actively studied and seems multifactoral. She et al. (32) have suggested that resistance to epidermal growth factor receptor (EGFR)-selective tyrosine kinase inhibition may be related to PTEN loss and subsequent uncoupling of the Akt signaling pathway. Kirschner and Baltensperger (33) have demonstrated that erythropoietin plays a role in the development of resistance to the deregulation of tyrosine kinase in patients with chronic myeloid leukemia. Bakalova et al. (23) suggest that resistance to tyrosine kinase inhibition relates to enhanced alternate signaling pathways with activation of telomerase
Besides angiogenesis, other novel approaches have been applied to the interruption of cell cycle events involved in neoplastic cell growth. Various agents have been devised to target signaling molecules. Antisense agents that modify elements of the Ras pathway may inhibit tumor cell growth either in vitro or in animal transplant models (34). Ras activation requires farnesylation, and farnesyl transferase inhibitors have also been suggested to inhibit cancer progression (35). In other studies, Raf-mediated MAPK kinase activation is known to be important in cell growth, and c-Raf antisense inhibits malignant cell growth in vitro and in animal models (36, 37). Modulation of members of the EGFR superfamily (Her1, Erb1, or EGFR; her2/neu or ErB2; Her3 or ErB3) may represent an alternative approach (38).
A multitude of other approaches have also been used mainly targeting intracellular proteins thought to be important in mediating cellular growth such as mammalian target of rapamycin (39). Of course, modulation of apoptosis has also been studied and has preliminarily shown beneficial responses. Enhancement of TNF-related apoptosis-inducing ligand activity or suppression of Bcl-2 activity enhances apoptosis and possibly decreases tumor cell growth in vitro, as well as in preliminary human studies in patients with melanoma and prostate cancer (40, 41).
Inhibition of heat shock protein 90 activity by 17-N-allylamino-17-demethoxy-geldanamycin (17-AAG), and the use of histone deacetylase inhibitors also show some promise (42, 43). Attempts at gene therapy with, for example, p53 or with transfection of a functional sodium-iodide symporter, have largely been restricted to in vitro studies and will require much further investigation before being used in human studies (44).
These approaches show great promise to affect tumor growth and propagation in a variety of different tumors and, hopefully, will be shown to be beneficial in human disease. However, it is difficult to know which specific avenue should be vigorously pursued and which approach has the highest likelihood of being successful. It is also unknown which type of in vitro and animal studies will have the greatest prognostic ability for humans. These characteristics may vary between tumors. However, as regards thyroid cancer, the general approach taken by Schoenberger et al. (2) seems appropriate. Studies assessing thyroid cancer must be specific for each type of tumor (i.e. papillary, follicular, medullary and anaplastic) and relevant animal models that spontaneously produce thyroid cancer must be developed and studied. Ying et al. (45) have recently published an important study showing that mice harboring a knock-in mutation of the thyroid hormone receptor ß spontaneously develop thyroid follicular carcinoma including vascular invasion and distant metastases. They are now studying this model to assess factors that modulate or mediate tumor progression and, for example, have recently demonstrated that peroxisome proliferator-activated receptor 
suppression is associated with carcinogenesis. This exciting development may allow development of a rationale approach to thyroid cancer treatment that may have more rapid and direct clinical implications. Relevant specific areas in follicular thyroid carcinoma research appear to relate to modulation of the oncogenic potential of the translocation fusion between the DNA binding domain of the thyroid transcription factor paired box gene (PAX8) and the peroxisome proliferator-activated receptor receptor (46). Ret/PTC and TRK rearrangements and more recently, BRAF mutations, appear important in papillary thyroid carcinoma propagation (47).
In addition to primarily studying thyroid tumor progression, it also is important to understand the mechanism(s) of metastasis. Ringel et al. (48) have recently studied a human tumor metastasis suppressor, KiSS-1, whose product, metastin acts an endogenous agonist for a novel Gq/11 metastin receptor. Metastin mRNA and receptor were infrequently expressed or noted in normal or benign thyroid samples, but enhanced levels were detected in papillary thyroid cancer, a tumor type that infrequently has distant metastasis. In contrast, follicular thyroid cancer, which has a higher tendency for distant metastasis, only infrequently had mRNA metastin or receptor expression (48). In a broader sense and in a variety of circumstances, the chemokine receptor CXCR4 has been shown to play a role in the mediation of metastasis (49).
In summary, the study by Schoenberger et al. (2) is an important step in advancing the concept that the formulation of targeted antineoplastic therapeutic agents based on known biochemical or oncogene abnormalities is a beneficial new frontier. Despite potential limitations as noted, this general approach is expected to lead to important new developments in cancer therapy across a wide span of diseases.
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Received December 3, 2003.
Accepted for publication December 8, 2003.
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during thyroid carcinogenesis. Cancer Res 63:5274–5280 rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab 88:4440–4445
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