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Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, Ohio 45267-0547, USA

(Requests for offprints should be addressed to J A Fagin; Email: James.Fagin{at}uc.edu)

This article was presented at a symposium jointly sponsored by Journal of Endocrinology and Clinical Endocrinology at the BES meeting in Brighton, UK, 22–24 March 2004. Another paper from the same symposium has been published: Weetman AP 2004 Cellular immune responses in autoimmune thyroid disease. Clinical Endocrinology 61 405–413. CrossRef (http://dx.doi.org/10.1111/j.1365-2265.2004.02085.x).

	Abstract

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

 
Treatment of patients with thyroid cancer is usually successful, and most patients are cured of the disease. However, we do not have effective therapies for patients with invasive or metastatic thyroid cancer if the disease is not surgically resectable and does not concentrate radio-iodine. Conventional external beam radiotherapy and chemotherapy are of marginal benefit. In other types of cancer, new therapies are being developed that take advantage of our knowledge of cancer pathogenesis to interfere with the activity of specific oncoproteins believed to be important in disease causation. Because these approaches are being considered for thyroid cancer, I will briefly describe in this review examples of recent breakthroughs in medical therapy of certain hematological malignancies and some solid tumors using drugs that work in this fashion, focusing in particular on compounds that block the enzymatic activity of specific tyrosine kinase oncoproteins. It should be noted, however, that cancers commonly harbor mutations or other disruptions of many genes, each of which could conceivably play a role in disease pathogenesis. This makes the choice of molecular target a difficult and critical decision if these approaches are to succeed. Here I will argue that priority should be given to blocking the function of oncoproteins activated early in tumor development. We have a fairly good understanding of the genetic changes involved in thyroid cancer initiation, and hence these cancers may prove to be particularly well suited for oncoprotein-specific therapies.

	The emerging field of targeted cancer therapies

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

 
Targeted cancer therapies attempt to disrupt pathways that are inappropriately activated in cancer cells while leaving normal cells relatively unscathed. Although we still have limited clinical experience with these agents, there has been enough time to draw some useful conclusions. The most notable initial success has been with Gleevec (imanitib) in Philadelphia chromosome/BCR-ABL (+) chronic myelogenous leukemia (CML) (Druker et al. 2001). The BCR-ABL translocation results in expression of a BCR-ABL fusion protein, leading to constitutive activation of abl kinase activity and unregulated proliferation and survival of a primitive hematopoietic cell clone. Imanitib is a relatively selective inhibitor of abl kinase, and induces high rates of remission in patients with CML. Imanitib is also effective in patients with gastrointestinal stromal tumors, which are associated with activating mutations of the tyrosine kinase (TK) receptor C-KIT (Heinrich et al. 2000, Joensuu et al. 2001), and for metastatic dermatofibrosarcoma protuberans, believed to be dependent on the activity of the platelet-derived growth factor receptor kinase. In both cases, imanitib has been shown to have potent inhibitory activity on the activity of these receptor kinases, likely explaining the beneficial effects in patients with these conditions. Another success story in targeted therapies is that of patients with acute promyelocytic leukemia associated with a chromosomal translocation leading to expression of the PML-RAR fusion protein, leading to overexpression of the retinoic acid receptor . A significant proportion of these patients respond well to treatment with all-trans retinoic acid (ATRA) (Fenaux et al. 2000). Despite these favorable results, numerous other compounds have failed at early phases of clinical development, dampening some of the initial enthusiasm with targeted therapies (Katsnelson 2004). Some of the difficulties encountered likely stemmed from inappropriate choice of molecular targets, undesirable side effects or problems with trial design.

	Target selection: role of tumor-initiating events

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

 
A notable feature of some of the early successes in targeted therapies is that compounds such as imanitib and ATRA inhibit the activity of gene products believed to be early events in tumorigenesis. Thus, BCR-ABL and PML-RAR are thought to occur early in leukemogenesis (Brown et al. 1997). Their central role in leukemia development is demonstrated by their ability to induce myeloid proliferation when selectively overexpressed in myelocytes of transgenic mice. Recent studies in patients with CML who developed resistance to treatment with the abl kinase inhibitor imanitib showed that many of these had selected and/or acquired tumor clones with point mutations coding for substitutions within the imanitib-binding pocket of BCR-ABL, which interfered with binding and conferred resistance to the antagonist (Hochhaus et al. 2002, Shah et al. 2002). This illustrates two important points. First, that when placed under selective pressure, CML has potential for recurrence by reactivating the same pathway involved in tumor development (i.e. abl kinase activation) through acquisition of new somatic mutations. Secondly, that the abl kinase is indeed a major driving influence required for survival and expansion of the tumor clone. Because of these considerations, it is possible that oncoproteins implicated in tumor initiation may be particularly well suited as targets for development of inhibitory compounds. This is not to say that interfering with initiation events is all that will be needed, since it may ultimately be necessary to use combination therapies to block multiple pathways. We propose that oncoproteins activated by tumor-initiating mutations are likely to remain essential drivers of tumor expansion even after accumulation of numerous additional genetic changes. This premise, which has major implications for the potential effectiveness of targeted therapies, remains to be proven as a general principle, and in specific tumor types.

	Tumor-initiation events in thyroid cancer: the RET/PTC oncogenes

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

 
Thyroid cancers stand out among solid tumors because many of the tumor-initiating genetic events have been identified. Notable among them are the RET/PTC oncogenes, which are believed to play a causative role in the pathogenesis of a significant proportion of papillary carcinomas of the thyroid (PTC), in particular those arising after radiation exposure, and in pediatric cancers. Chromosomal rearrangements linking the promoter and N-terminal domains of unrelated gene/s to the C-terminal fragment of RET result in the aberrant production of a chimeric form of the receptor in thyroid cells that is constitutively active (Santoro et al. 2002). Several forms have been identified that differ according to the 5' partner gene involved in the rearrangement, with RET/PTC1 and RET/PTC3 being the most common. RET/PTC1 is formed by a paracentric inversion of the long arm of chromosome 10 leading to fusion of RET with a gene named H4/D10S170. RET/PTC3 is also a result of an intrachromosomal rearrangement and is formed by fusion with the RFG/ELE1 gene. Multiple lines of evidence point to RET/PTC as one of the key first steps in thyroid cancer pathogenesis (Fig. 1): (i) Thyroid-specific over-expression of either RET/PTC1 (Jhiang et al. 1996, Santoro et al. 1996) or RET/PTC3 (Powell et al. 1998) in transgenic mice leads to development of tumors with histological features consistent with papillary thyroid carcinoma, indicating that these oncoproteins can recreate the disease in an animal model. (ii) There is a high prevalence of RET/PTC expression in occult or microscopic PTC (Viglietto et al. 1995, Sugg et al. 1998, Corvi et al. 2001), pointing to the activation of this oncogene at early stages of tumor development. (iii) Exposure of cell lines (Ito et al. 1993) and fetal thyroid explants (Mizuno et al. 1997) to ionizing radiation results in expression of RET/PTC within hours, supporting a direct role for radiation in the illegitimate recombination of RET. (iv) The breakpoints in the RET and ELE1/RFG genes resulting in the RET/PTC3 rearrangements of radiation-induced pediatric thyroid cancers from Chernobyl are consistent with direct double-strand DNA break resulting in illegitimate reciprocal recombination (Nikiforov et al. 1999). Moreover, the H4 and RET genes, although lying at a considerable linear distance from each other within chromosome 10, are spatially juxtaposed during interphase in thyroid cells and presumably present a target for simultaneous double-strand breaks in each gene after ionizing radiation, thus giving rise to the RET/PTC1 rearrangement (Nikiforova et al. 2000). These data provide evidence that ionizing radiation, the major risk factor for development of papillary thyroid cancer, can directly induce RET recombination events, and link environmental events to tumor initiation through this genetic pathway.

View larger version (38K): [in this window] [in a new window]   Figure 1 RET/PTC rearrangements are involved in papillary thyroid carcinoma initiation. Several lines of evidence support the concept that RET/PTC is an early genetic event predisposing to development of papillary thyroid cancer. (A) Thyroid-specific expression of RET/PTC1 (Jhiang et al. 1996, Santoro et al. 1996) or RET/PTC3 (Powell et al. 1998) in transgenic mice result in development of tumors with cellular features resembling papillary thyroid carcinoma. (B) RET/PTC expression is detected in human thyroid micropapillary carcinomas (Viglietto et al. 1995, Sugg et al. 1998, Corvi et al. 2001). (C) External irradiation of human thyroid fetal explants and human carcinoma cell lines results in detectable RET/PTC rearrangements after short time intervals (Ito et al. 1993). Elements of this Figure are reproduced with permission from Powell et al.(1998) and Corvi et al.(2001).

	Mapping of signaling pathways used by RET/PTC to induce thyroid cell transformation provides clues for discovery of new thyroid oncogene

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

Buckwalter et al.(2002) investigated the contribution of these signaling pathways to RET/PTC1-induced thyroid tumor formation in vivo by characterizing transgenic mice expressing thyroid-targeted RET/PTC1 mutants with phenylalanine substitutions at either Y905, Y1015 or Y1062. Tumor formation was significantly decreased in all of the mutants, but in particular by RET/PTC1 Y905F. This points to significant contributions mediated by all of these pathways to RET/PTC-induced thyroid cell transformation. The interpretation of these experiments is complicated by the fact that RET/PTC expression in thyroid cells causes primary hypothyroidism through impaired expression of many of the specialized proteins required for thyroid hormonogenesis, and the degree of hypothyroidism and of the consequent thyrotropin elevation may have varied in severity between the mice expressing the different RET/PTC mutants. Nevertheless, this study indicates that none of these RET/PTC tyrosine residues alone is absolutely required for tumor formation, and all appear to contribute to some extent to the ultimate phenotype.

By contrast, in vitro data in thyroid cells point to an absolute requirement of Y1062 for RET/PTC-induced dedifferentiation, as determined by decreased expression of thyroid-specific gene products such as the sodium iodide symporter, thyroglobulin or PAX-8. RET/PTC-mediated dedifferentiation requires activation of Shc-RAS-RAF-MAP kinase (Knauf et al. 2003), thus providing a good rationale to explore the contribution of mutations of other effectors in this pathway to thyroid cancer pathogenesis (Fig. 2).

View larger version (22K): [in this window] [in a new window]   Figure 2 Mutations of three genes that signal in tandem implicate constitutive activation of the Ras-RAF-MAP kinase pathway in PTC pathogenesis. Several in vitro studies point to a critical role of RET Y1062, signaling via Ras and Raf, in cell transformation and thyroid cell dedifferentiation. Recent analysis of human papillary thyroid cancers demonstrate the presence of mutually exclusive mutations of either RET/PTC, RAS or BRAF, with little overlap between them, providing compelling genetic evidence for the critical role of this pathway in pathogenesis of these cancers.

	B-RAF: the most prevalent thyroid oncogene

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

The BRAF^T1796A mutation is the most common genetic change in PTC, and present in about 36–69% of cases (Cohen et al. 2003, Fukushima et al. 2003, Kimura et al. 2003, Namba et al. 2003, Nikiforova et al. 2003, Soares et al. 2003, Xu et al. 2003, Trovisco et al. 2004). BRAF^T1796A mutations are unique to PTC, and not found in any other form of well-differentiated follicular neoplasm arising from the same cell type. There is practically no overlap between PTC with RET/PTC, BRAF or RAS mutations, which altogether are found in about 70% of cases (Kimura et al. 2003, Soares et al. 2003). The lack of concordance for these mutations provides compelling genetic evidence for the requirement of this signaling system for transformation to PTC (Fig. 2). As these signaling proteins function along the same pathway in thyroid cells, this represents a unique paradigm of human tumorigenesis through mutation of three signaling effectors lying in tandem (Fig. 2). BRAF mutations can occur early in development of PTC, based on evidence that they are present in microscopic PTC (Nikiforova et al. 2003). Moreover, PTC with BRAF mutations have more aggressive properties, present more often with extrathyroidal invasion and at a more advanced clinical stage. The tall-cell variant papillary thyroid cancers, widely regarded as more aggressive, have a particularly high prevalence of BRAF mutations (Nikiforova et al. 2003). Undifferentiated or anaplastic carcinomas arising from preexisting papillary thyroid cancers have a significant prevalence of BRAF mutations, whereas those arising from preexisting follicular carcinoma do not (Namba et al. 2003, Nikiforova et al. 2003). These data indicate that BRAF mutations may be an alternative tumor-initiating event in papillary thyroid cancer, and that tumors with this genotype carry a less favorable prognosis. The role of oncogenic Braf as a tumor-initiating event has been confirmed in mice with targeted expression of BRAFV600E in thyroid cells. These animals develop papillary thyroid cancers with high penetrance early in life, and progress to dedifferentiation, capsular and microvascular invasion, confirming many of the features found in the human tumors (J A Knauf, N Mitsutake, L Zhang, Y E Nikiforov & J A Fagin, unpublished observations).

	Small molecule kinase inhibitors in thyroid cancer

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

 
Protein kinases are involved in transmitting intracellular signals that eventuate in all biological properties of cancer cells, including growth, survival, motility, invasion and metastasis. It is no surprise that these signaling effectors have been considered prime targets for interference by anticancer therapies. This approach, initially greeted with skepticism because of concerns of lack of specificity due to common catalytic mechanisms and structural similarity between kinases, has now shown clinical value with the emergence of the abl kinase inhibitor imanitib. Most of the protein kinase antagonists in development are directed towards the ATP-binding site. However, there are other potential approaches to inhibit specific kinases, by interfering with expression of the kinase, folding of the mature protein or interaction with substrates (Dancey & Sausville 2003). Among solid cancers, thyroid carcinomas represent a particularly promising paradigm for targeted therapy because some of the key oncogenic events are activating mutations of genes coding for TKs, and these occur early in cancer development.

RET is a logical target for selective inhibition in both medullary and papillary thyroid cancers. Several groups have published preclinical studies with compounds showing inhibitory effects on RET kinase activity at low nanomolar concentrations, and impairment of cell growth in vitro and in mouse xenografts (Carlomagno et al. 2002a, b, 2003, Lanzi et al. 2003, Strock et al. 2003) (Table 1). At least one of these compounds, ZD6474, originally developed as an anti-angiogenic agent through its inhibition of the vascular endothelial growth factor receptor KDR (Hartman et al. 2002), is now entering clinical trials for patients with medullary thyroid cancer. B-Raf represents an attractive target for treatment of papillary thyroid cancers because of its possible role in tumor initiation, its high prevalence, and its association with tumors presenting at an advanced stage. The compound BAY43–9006 is a potent and effective Raf inhibitor in vitro and in mouse xenografts, and is presently in clinical trials for other forms of cancer (Karasarides et al. 2004). Other Raf inhibitors, in the form of small molecule kinase inhibitors as well as antisense oligonucleotides, are also in development (Dancey & Sausville 2003). In due course it is likely that at least one of these compounds or others with similar properties will be tested in patients with advanced papillary thyroid cancer. It should be noted that other signaling pathways and molecular targets (Braga-Basaria et al. 2004), although not directly activated through genetic mutations, may prove to be crucial for thyroid cancer progression and thus appropriate for targeted inhibition.

	Conclusions

Top Abstract The emerging field of... Target selection: role of... Tumor-initiation events in... Mapping of signaling pathways... B-RAF: the most prevalent... Small molecule kinase inhibitors... Conclusions References

	Funding

 
This paper was supported in part by NIH grant CA50706. The author declares that there is no conflict of interest that would prejudice the impartiality of this scientific work.

	Acknowledgements

 
I am grateful to my fellows and other collaborators for contributing to many aspects of the original work which forms the basis for the topics discussed in this review, and in particular to Efisio Puxeddu for designing the graphics of Fig. 1.

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Received 7 July 2004
Accepted 16 August 2004
Made available online as an Accepted Preprint 26 August 2004

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