Vandetanib In Medullary Thyroid Cancer Research Articles

YAP confers resistance to vandetanib in medullary thyroid cancer

Medullary thyroid cancer (MTC) is the third most common thyroid cancer. RET (Rearranged in Transformation) gene mutations are considered as one of the major drivers of MTC. Vandetanib suppresses RET activity, and has shown promise in clinical trials. Unfortunately, acquired resistance to vandetanib has been observed in MTC, although the mechanism was largely unknown. We investigated the critical role of YAP (Yes-Associated Protein) on vandetanib resistance in MTC. For this, TT cells (medullary thyroid cancer cells) were treated with vandetanib for 3 months to generate a vandetanib-resistant cell line (TT-R). We investigated the role of YAP on vandetanib-resistance in TT-R cells by performing cell proliferation and colony formation assays, and examined the antitumor effects of YAP inhibitor and vandetanib in a mouse model of xenografted MTC. The TT-R cells displayed 6-fold higher IC50 to vandetanib than the TT cells. Overexpression of YAP resulted in resistance to vandetanib, whereas knockdown of YAP re-sensitized the TT-R cells to vandetanib. The YAP inhibitor synergized with vandetanib on tumor inhibition. Our results suggest that YAP plays an important role in acquired resistance to vandetanib in MTC, providing basis for combating MTC with YAP inhibitor and vandetanib.

Comparative efficacy and safety of tyrosine kinase inhibitors for thyroid cancer: a systematic review and meta-analysis.

The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57-81 and 19 months, 95% CI: 9-29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25-56 and 31 months, 95% CI: 19-43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.

The treatment landscape in thyroid cancer: a focus on cabozantinib.

Although patients with thyroid cancer generally fare well, there is a subset for which this is not necessarily true. Progress in understanding the molecular aberrations in thyroid cancer has led to a change in the management of these cases. Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer – cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer. This change in the treatment landscape has raised challenges for practitioners who may not be familiar with the use of MKIs or with the treatment and natural history of advanced thyroid cancer in general. This article reviews the epidemiology, molecular drivers, and initial treatment of patients with thyroid cancer and offers practical guidance to assist with the determination of when to appropriately start an MKI. As an example, cabozantinib and its efficacy are discussed in detail. Close monitoring is required for all patients on targeted agents to assess for adverse effects and response to therapy. An approach to managing drug-related adverse events is detailed. Since these drugs are not curative and have not yet proven to prolong overall survival, it is critical to weigh the risks and benefits of treatment at every visit. The potential value of changing to a different agent following failure of an MKI is also addressed.

Selective use of vandetanib in the treatment of thyroid cancer.

Vandetanib is a once-daily orally available tyrosine kinase inhibitor that works by blocking RET (REarranged during Transfection), vascular endothelial growth factor receptor (VEGFR-2, VEGFR-3), and epidermal growth factor receptor and to a lesser extent VEGFR-1, which are important targets in thyroid cancer (TC). It is emerging as a potentially effective option in the treatment of advanced medullary thyroid cancer (MTC) and in dedifferentiated papillary thyroid cancer not responsive to radioiodine. The most important effect of vandetanib in aggressive MTC is a prolongation of progression-free survival and a stabilization of the disease. Significant side effects have been observed with the vandetanib therapy (as fatigue, hypertension, QTc prolongation, cutaneous rash, hand-and-foot syndrome, diarrhea, etc), and severe side effects can require the suspension of the drug. Several studies are currently under way to evaluate the long-term efficacy and tolerability of vandetanib in MTC and in dedifferentiated papillary TC. The efficacy of vandetanib in patients with MTC in long-term treatments could be overcome by the resistance to the drug. However, the effectiveness of the treatment could be ameliorated by the molecular characterization of the tumor and by the possibility to test the sensitivity of primary TC cells from each subject to different tyrosine kinase inhibitor. Association studies are evaluating the effect of the association of vandetanib with other antineoplastic agents (such as irinotecan, bortezomib, etc). Further research is needed to determine the ideal therapy to obtain the best response in terms of survival and quality of life.

Patterns of thyroid hormone levels in pediatric medullary thyroid carcinoma patients on vandetanib therapy.

BackgroundTyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect. Prior studies of vandetanib in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement. We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of vandetanib for medullary thyroid cancer (MTC)MethodsData from 13 patients with multiple endocrine neoplasia type 2B (MEN 2B) and MTC were analyzed [6 M, 7 F, median age 13.0 y (9.1-17.3)] Eleven patients (85%) had undergone prior thyroidectomy and all received single-drug therapy with vandetanib for > 6 months. Confirmed compliance with vandetanib (67–150 mg/m2/day) and LT was a necessary inclusion criterion.ResultsWhile on vandetanib treatment, all 11 athyerotic patients exhibited significantly increased TSH levels. The baseline TSH level was 4.37 mclU/ml (0.08 - 23.30); in comparison, the first peak TSH concentration on vandetanib was 15.70 mclU/ml (12.50 - 137.00, p = 0.0010). The median time to reach the initial peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range. An increase from a baseline LT dose of 91 mcg/m2/day (±24) to 116 mcg/m2/day (±24) was required in order to resume normative TSH levels (p = 0.00005), equal to an increase of 36.6% (±16.56) in the dosage of LT in mcg/day. For the 2 patients with intact thyroid glands, free T4 and TSH remained normal over a combined 6 patient years of follow up.ConclusionsIn our cohort of pediatric MTC patients, athyreotic patients with preexisting hypothyroidism developed increased TSH and reduced free T4 during the first few months of treatment with vandetanib, necessitating an increase in LT dosage. Additional patients with normal thyroid function before treatment and intact glands (n = 2) maintained normal thyroid function tests during treatment. Elevated TSH in athyreotic patients may be due to an indirect effect of vandetanib on the metabolism of thyroid hormone, or to altered TSH sensitivity at the pituitary. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs.Trial registrationClinicalTrials.gov Identifier: NCT00514046

Progress in Molecular Targeted Therapy for Thyroid Cancer: Vandetanib in Medullary Thyroid Cancer

Progress in Molecular Targeted Therapy for Thyroid Cancer: Vandetanib in Medullary Thyroid Cancer

Vandetanib in metastatic hereditary medullary thyroid cancer: Follow-up results of an open-label phase II trial

6018 Background: Medullary thyroid cancer (MTC) is the most common cause of death in patients with hereditary syndromes caused by activating mutations in the RET protooncogene. RET activation is the initial oncogenic event, with the activity of other receptor tyrosine kinases, including VEGFR and EGFR, likely to contribute to tumor growth and metastasis. Vandetanib (ZD6474) is a once- daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. Methods: Eligible patients had unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation. Patients received vandetanib 300 mg/day until disease progression or any other withdrawal criteria. The primary objective was to assess the objective tumor response (RECIST every 3 months). Secondary assessments included disease control rate, biochemical response (determined by decrements in plasma levels of calcitonin, a tumor marker for MTC) and safety and tolerability. Results: Thirty patients (21 female; median age 50 years) received initial treatment with vandetanib 300 mg. At data cut-off (20 Nov 2006), the median duration of treatment was 172 days. Based on site investigator assessments, 20% (6/30) of patients experienced a partial response (duration of response 59–260 days) and another 30% (9/30) of patients experienced stable disease =24 weeks, yielding a disease control rate of 50% (15/30). Centralized independent confirmation of response is planned. In 19 patients, plasma calcitonin levels showed a =50% decrease from baseline that was maintained for at least 6 weeks. Adverse events (AEs) occurring in >50% of patients were rash (73%), diarrhea (67%), fatigue (57%) and nausea (53%). Most AEs were grade 1 or 2; grade 3 AEs included asymptomatic QTc prolongation (n=5), rash and diarrhea (both n=3), all of which were manageable. Conclusions: Vandetanib has demonstrated clinical activity in this phase II study in metastatic hereditary MTC, and the safety profile is generally consistent with previous vandetanib monotherapy studies. Accrual is now complete (30 patients), and an updated analysis will be performed in April 2007. An international, randomized, placebo-controlled phase II trial of vandetanib in MTC is now recruiting patients. # No significant financial relationships to disclose.