Medullary Thyroid Cancer Targeted Therapy
Definition
Targeted therapies in oncology are therapeutic treatments intended to target molecular aberrations driving tumor pathogenesis or progression. In contrast to conventional cytotoxic therapies, which are essentially guided by the site of patient’s tumor, targeted therapies are based on molecular features of the tumor. According to this approach, selective antibodies or rationally designed drugs are currently used to inhibit the function of proteins involved in biochemical pathways thought to be essential for survival or distant dissemination of tumor cells. Therapeutic targets can be expressed by either cancer cells (e.g., proteins encoded by oncogenes) or by stromal cells present in the tumor microenvironment including endothelial cells forming the tumor-associated vasculature.
Characteristics
Medullary thyroid cancer (MTC) is a neuroendocrine malignant tumor arising from parafollicular C-cells of the thyroid gland. It occurs sporadically in most cases, whereas in nearly 25% of cases, it is inherited in the context of the multiple endocrine 2 (MEN2) syndromes types 2A, 2B, and familial MTC. MTC represents the main cause of death in MEN2 patients. Surgery is the treatment of choice for both sporadic and hereditary MTC and the only curative modality available. Management of unresectable and advanced disease remains a challenge. Indeed, external radiation therapy has a limited role, and curative systemic treatments are not available. Only low rates (less than 20%) of partial, short-lasting, responses have been reported in patients receiving cytotoxic chemotherapeutics. The 10-year overall survival rate in patients presenting with locally advanced or metastatic disease is estimated in nearly 40%. Such a dismal prognosis prompts the preclinical and clinical research aimed at the identification of alternative, more effective, treatment options.
Advances in the knowledge of pathogenetic mechanisms of MTC, and emerging evidence ascribing to angiogenesis a critical role in maintenance and dissemination of solid tumors, have provided rational bases for testing new targeted agents. The first targeted therapeutic agents, vandetanib and cabozantinib, have been approved by the US Food and Drug Administration (FDA) for the treatment of MTC in patients with advanced disease. Additional targeted agents are currently being evaluated in clinical trials for their efficacy and safety in MTC therapy.
Molecular Therapeutic Targets in MTC
Among molecules identified as possible therapeutic targets, protein kinases have a primary role. This class of enzymes, which catalyzes protein phosphorylation reactions, functions in physiological signal transduction pathways, regulating cell proliferation, survival, differentiation, and migration. Several protein kinases can otherwise function aberrantly driving key processes, defined as “hallmarks of cancer” by Hanahan and Weinberg (2011) and Lemmon and Schlessinger (2010), which are critical in tumor development and progression. In MTC as in other malignancies, the dysregulated function of tyrosine kinases is thought to sustain tumor growth, angiogenesis, invasion, and metastasis. In particular, available data from preclinical research and clinical trials support a role for receptor tyrosine kinases (RTKs) encoded by the RET proto-oncogene and by genes implicated in angiogenesis as valuable therapeutic targets in MTC.
Ret and Angiogenesis-Related RTKs
The RET gene encodes a typical membrane RTK with extracellular, transmembrane, and cytoplasmic domains. Activation of the Ret receptor normally arises in the context of a complex including a co-receptor of the glial cell line-derived neurotrophic factor (GDNF) family receptor-α and requires the interaction with a ligand of the GDNF family. The ligand binding induces dimerization of Ret molecules and a mutual transphosphorylation (referred to as autophosphorylation) of tyrosine residues essential for the receptor signal transduction. Tyrosine phosphorylated residues form, in fact, the docking sites for adaptor and transducing proteins mediating the activation of downstream signaling pathways involving RAS/RAF/ERKs, PI3K/AKT, JNKs, ERK5, and PLCγ, which in turn lead to gene expression regulation and biological responses (Arighi et al. 2005). Gain-of-function mutations of RET, leading to aberrant, ligand-independent activation of the Ret receptor, are frequent oncogenic events in tumors of the thyroid gland, i.e., papillary thyroid cancer and MTC. In hereditary MTCs, germline RET mutations occur in the vast majority of patients and are recognized as the disease initiating events. In sporadic MTC cases, somatic RET mutations are present in 40–60% of patients. The most common mutation in sporadic MTC, M918T, whose prevalence is nearly 90%, has been associated with a more aggressive behavior and lower survival. Mutations in the intracellular TK domain, typical of sporadic MTC and MEN2B, induce constitutive enzyme activation. Mutations at cysteine residues in the extracellular domain, typical of MEN2A and FMTC, cause receptor activation by inducing constitutive dimerization.
Multi-kinase inhibitors currently undergoing clinical trials
| Drug | Company | Currently known targets | Phase of development |
|---|---|---|---|
| Vandetanibb, a (ZD6474) | Astra Zeneca | VEGFR2-3, EGFR, RET | II/III |
| Cabozantinibc, a (XL184) | Exelis | VEGFR2, RET, MET, KIT, TIE-2 | III |
| motesanibd (AMG706) | Amgen | VEGFR1-3, PDGFR, KIT, RET | II |
| Sorafenibe (BAY43-9006) | Bayer, Onyx | CRAF, BRAF,VEGFR2-3, PDGFR,FLT3, KIT, RET | II |
| Sunitinibf (SU11428) | Pfizer | VEGFR1-3, PDGFR, KIT, RET, FLT3, CSF1R | II |
| Axitinibg (AG013736) | Pfizer | VEGFR1-3, PDGFR, KIT | II |
| Pazopanibh (GW786034) | GlaxoSmithKline | VEGFR1-3, RET, MET,KIT | II |
| Lenvatinibi (E7080) | Eisai | VEGFR1-3, RET, KIT, PDGFR, FGFR1-4 | II |
Angiogenesis, the formation of new blood vessels from preexisting vessels, essential for both tumor growth and development of metastasis, provides additional relevant molecular targets for MTC therapy. Thyroid tumors have long been described as hypervascularized. In fact, MTC tends to metastasize early via hematogenous, in addition to lymphatic, route. However, little is known about the specific role of angiogenic factors in the pathogenesis or clinical course of MTC. Although the prognostic value of the angiogenic phenotype is debated, a few reports consistently showed overexpression of the vascular endothelial growth factor-A (VEGF-A) and its RTKs (VEGFR-1 and VEGFR-2) in sporadic and hereditary case series, supporting the idea that they are implicated in development and maintenance of MTC. VEGF-A-mediated pathway, which functions stimulating proliferation and survival of endothelial cells and increasing vascular permeability, is the major mediator of tumor angiogenesis. VEGF receptors are the most common targets shared by RTK inhibitors tested in the clinic in MTC patients. Other RTKs that play a relevant role in tumor angiogenesis, such as the receptors for the fibroblast growth factor (FGFR) and for the platelet-derived growth factor (PDGFR), are additional common targets for RTK inhibitors under clinical evaluation (Table 1).
Other Targets
The receptors of epidermal growth factor (EGFR) and hepatocyte growth factor ( Met) have been found overexpressed in the tumors of some MTC patients or in metastases compared to the matched primary tumors. Although the exact roles of EGFR and Met in MTC tumorigenesis have not been fully established, it is conceivable that co-targeting the cooperating or compensatory pathways mediated by these RTKs could be beneficial in subsets of MTC patients.
RTK Inhibitors
In the last years, multi-kinase inhibitors have entered clinical trials in patients with MTC (Table 1). Available data have confirmed the antitumor efficacy of the new therapeutic approach. Several agents have demonstrated promising activity with clinical responses (according to Response Evaluation Criteria of Solid Tumor) and stabilization of disease (>6 months), accounting for benefit in the majority of patients (Schlumberger et al. 2012).
To date, two drugs, vandetanib and cabozantinib, have received FDA approval based on the results of randomized placebo-controlled phase III trials. Vandetanib is an oral inhibitor of VEGFR2-3, Ret, and EGFR. In the phase III trial in patients with locally advanced or metastatic MTC, the median progression-free survival (PFS) was significantly prolonged from 19.3 months in the placebo arm to an estimated >30.5 months in the vandetanib arm. Partial responses were observed in 45% of patients. In this study, patients were not required to have progressive disease prior to entry. Cabozantinib is an oral inhibitor of VEGFR2, Ret, and Met. In the phase III trial in patients with radiographically confirmed progressive metastatic MTC, a significant prolongation in PFS was demonstrated with median PFS times of 4 and 11.2 months, in the placebo and cabozantinib arms, respectively. Partial responses were observed in 27% of patients.
Additional new promising multi-target therapeutic agents under clinical investigation for treatment of patients affected by MTC are reported in Table 1. Although side effects from targeted therapy are generally less severe than with conventional cytotoxic chemotherapy, it is important to note that clinical trials of all the above agents reported significant toxicities which could be serious and dose limiting in some cases, requiring expert managing.
Perspectives
Receptor tyrosine kinase inhibitors have shown promise in the treatment of advanced MTC and are revolutionizing management paradigms. Further research is now needed to understand the basis of tumor response, with particular reference to the relative contribution of the inhibition of each target. A deeper knowledge of the relevant targets and the identification of new, more effective, inhibitors are important objectives in the attempt to optimize treatments and to improve outcomes. To date, in fact, none of the new therapies have shown an impact on overall survival of MTC patients. Future efforts are also expected to address the development of new treatment modalities including rational drug combinations of different targeted therapeutics, or targeted and conventional drugs, designed to interact synergistically to improve efficacy without enhancing toxicity.
References
- Arighi E, Borrello MG, Sariola H (2005) Ret tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16:441–467PubMedCrossRefGoogle Scholar
- Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
- Lanzi C, Cassinelli G, Nicolini V, Zunino F (2009) Targeting RET for thyroid cancer therapy. Biochem Pharmacol 77:297–309PubMedCrossRefGoogle Scholar
- Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1133PubMedPubMedCentralCrossRefGoogle Scholar
- Schlumberger M, Massicotte MH, Nascimento CL, Chougnet C, Baudin E, Leboulleux S (2012) Kinase inhibitors for advanced medullary thyroid carcinoma. Clinics 67:125–129PubMedPubMedCentralCrossRefGoogle Scholar