Evolving Strategies for Targeted Cancer Therapy—Past, Present, and Future

Samuel A. Wells, Joseph R. Nevins
Medullary thyroid carcinoma occurs most often as a sporadic malignancy, although in approximately 30% of cases, it occurs as part of the multiple endocrine neoplasia type 2 (MEN2) syndromes MEN2A and MEN2B or the related disease, familial medullary thyroid carcinoma. These three syndromes, inherited as autosomal dominant traits, are clinically characterized by near complete penetrance but variable expressivity. The thyroid malignancy is present in virtually all patients with MEN2A, MEN2B, and familial medullary thyroid carcinoma, and it is the most common cause of death in affected patients. Medullary thyroid carcinoma cells secrete the hormone calcitonin, and elevated plasma levels of this polypeptide, either basally or following provocation with intravenous calcium and pentagastrin, indicate the presence of medullary thyroid carcinoma, even though the tumor may not be clinically evident. The test is especially useful for evaluating patients after removal of the thyroid gland. Recently, it was discovered that mutations in the RET protooncogene are causative of MEN2A, MEN2B, and familial medullary thyroid carcinoma (1–3). Subsequently, it was found that approximately 30% of patients with sporadic medullary thyroid carcinoma have a RET mutation in the medullary thyroid carcinoma cells but not in germline DNA (4). Furthermore, in patients with papillary thyroid carcinoma, the most common endocrine malignancy, the RET gene is activated secondary to a chromosomal rearrangement, resulting in fusion of the portion of the RET gene encoding tyrosine kinase to an upstream region derived from one of several genes expressed in normal thyroid follicular cells (5). RET expression is driven by the promoters of the fused genes, resulting in constitutive activation of the kinase. Patients with medullary thyroid carcinoma are cured only by total thyroidectomy, performed when the disease is confined to the thyroid gland. Since the malignancy is not responsive to standard chemotherapeutic regimens or to conventional doses of external beam radiotherapy, early diagnosis and treatment are essential. Patients who seek medical advice because of a thyroid nodule are usually incurable because the cancer has already metastasized to regional lymph nodes or distant sites. Conversely, kindred members at direct risk for MEN2A, MEN2B, or familial medullary thyroid carcinoma can be identified as having inherited a mutated RET allele by direct DNA analysis early in life. Total thyroidectomy, performed prior to clinical or biochemical evidence of medullary thyroid carcinoma, is curative in a high percentage of patients. Papillary thyroid carcinoma is also treated by thyroidectomy; however, most patients with persistent or recurrent distant disease can be effectively treated with radioactive iodine. If this

treatment fails, patients may succumb to disease. Thus, for many patients with hereditary or sporadic medullary thyroid carcinoma, and for some patients with papillary thyroid carcinoma who are not cured by total thyroidectomy and other adjuvant therapies, there is no effective treatment. In this issue of the Journal, Cuccuru et al. (6) report antitumor activity of the RET inhibitor, RPI-1, in MEN2A-associated medullary thyroid carcinoma. This activity coincides with the ability of the drug to inhibit tumor cell proliferation as well as anchorage-independent growth and reflects the inhibition of the tyrosine kinase activity of the receptor. Similarly, Carlomagno et al. (7) earlier reported that the quinazoline ZD6474 was a potent inhibitor of RET oncoproteins, which exerted powerful growthinhibitory effects on thyroid carcinoma cell lines with RET/ papillary thyroid carcinoma rearrangements. ZD6474 also inhibited angiogenesis and thus exhibited a dual antitumor effect. These two studies, based on an understanding of the oncogenic process, support the “targeted therapy” approach for patients with diseases characterized by RET activation and offer the possibility of a successful interventional therapy when conventional pharmacologic and radiotherapeutic regimens have failed. A major success story in the development of targeted therapeutics is the use of imatinib mesylate (Gleevec STI571), which inhibits Abl tyrosine kinase (8 –12), for treating chronic myelocytic leukemia. This successful therapy also emphasizes the challenges of treating advanced-stage disease, because tumors that are initially sensitive to the action of a given drug often develop resistance to that drug over time. Thus, understanding the complexity of the oncogenic process to then design and apply additional therapies will be critical to long-term success. In the case of RET, one approach might rely on the development of multiple targeted drugs as described by Cuccuru (6) and Carlomagno (7). Tumors that develop resistance to one agent, particularly in those instances of RET mutations that block drug interaction, may retain sensitivity to another drug. A second approach to managing resistance might take advantage of combinational therapy that targets multiple steps in the oncogenic process. It is clear from the history of oncology that tumors arise as a result of the acquisition of large numbers of genetic alterations, particularly during the advanced stages of

Affiliation of authors: Duke University Medical Center, Durham, NC. Correspondence to: Samuel A. Wells, MD, Duke University Medical Center, P.O. Box 3627, Durham, NC 27710 (e-mail: wells029@surgerytrials.duke.edu) DOI: 10.1093/jnci/djh214 Journal of the National Cancer Institute, Vol. 96, No. 13, © Oxford University Press 2004, all rights reserved.

Journal of the National Cancer Institute, Vol. 96, No. 13, July 7, 2004

disease. This complexity may make mono-specific therapeutics relatively ineffective. Although much attention has been paid to the use of combinational therapy, in which pathway-specific drugs are combined with cytotoxic agents or combinations of pathway-specific agents are used, the major limitation currently is gathering information that can guide the formulation of the most effective combinations. An example of one strategy to guide the rational use of combinational therapy can be seen in recent studies based on knowledge of known pathway interactions. Prior work has shown that BCR/ABL transformation required the activation of ERK and PI3K pathways (13,14), leading to the speculation that combining an ABL inhibitor with a PI3K pathway inhibitor might be more effective than either one alone. Indeed, there was a synergistic response to imatinib and the mTOR inhibitor rapamycin combined, providing one example of the potential value in targeting multiple pathways affected in the oncogenic process (15). Advances in genomic profiling of tumors by using DNA microarray data may offer a more comprehensive and powerful approach to the selection of combinational therapies. The power of gene expression profiles to uncover subtle aspects of tumor biology that predict clinical outcome has now been demonstrated in a number of instances. Equivalent analyses of protein patterns, as well as other molecular profiles, promise to expand this capability. Similar approaches have also been applied to the study of specific oncogenic signaling pathways, identifying gene expression signatures that reflect the deregulation of Ras, Myc, Rb, and cyclin-dependent kinases (16 –18). Given the availability of drugs that have been developed to target components of these pathways, it is conceivable that new therapeutic strategies, using various combinations of pathway-specific drugs, could be driven by an understanding of the profile of pathway deregulation within a given tumor. Thus, the development of therapeutic protocols, whether for patients with metastatic thyroid carcinoma or other advanced-stage cancers, will likely be based on predictors of response to a specific drug or on an understanding of the state of pathway function within an individual tumor. The application of specially designed combinational therapies, dependent on the unique characteristics of the individual patient and his or her malignancy, may become the standard therapeutic strategy in patients with incurable solid tumors.

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Journal of the National Cancer Institute, Vol. 96, No. 13, July 7, 2004