Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy.

The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

Vandetanib as a prospective anti-inflammatory and anti-contractile agent in asthma.

Background: Vandetanib is a small-molecule tyrosine kinase inhibitor. It exerts its therapeutic effects primarily in a range of lung cancers by inhibiting the vascular endothelial growth factor receptor 2. However, it remains unclear whether vandetanib has therapeutic benefits in other lung diseases, particularly asthma. The present study investigated the pioneering use of vandetanib in the treatment of asthma. Methods: In vivo experiments including establishment of an asthma model, measurement of airway resistance measurement and histological analysis were used primarily to confirm the anticontractile and anti-inflammatory effects of vandetanib, while in vitro experiments, including measurement of muscle tension and whole-cell patch-clamp recording, were used to explore the underlying molecular mechanism. Results: In vivo experiments in an asthmatic mouse model showed that vandetanib could significantly alleviate systemic inflammation and a range of airway pathological changes including hypersensitivity, hypersecretion and remodeling. Subsequent in vitro experiments showed that vandetanib was able to relax the precontracted rings of the mouse trachea via calcium mobilization which was regulated by specific ion channels including VDLCC, NSCC, NCX and K+ channels. Conclusions: Taken together, our study demonstrated that vandetanib has both anticontractile and anti-inflammatory properties in the treatment of asthma, which also suggests the feasibility of using vandetanib in the treatment of asthma by reducing abnormal airway contraction and systemic inflammation.

Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC.

RET fusion is an oncogenic driver in 1-2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.

The VEGFs/VEGFRs system in Alzheimer's and Parkinson's diseases: Pathophysiological roles and therapeutic implications.

The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer's (AD) and Parkinson's (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.

Crystal structure and Hirshfeld surface analysis of a salt of antineoplastic kinase inhibitor vandetanib.

A salt of vandetanib, namely, 4-({4-[(4-bromo-2-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}methoxy)-1-methylpiperazin-1-ium 2-(butylamino)-4-phenoxy-6-sulfamoylbenzoate acetonitrile monosolvate, C22H25BrFN4O2+·C17H19N2O5S-·C2H3N, composed of kinase inhibitor vandetanib and sulfamyl diuretic bumetanide in a 1:1 molar ratio, is reported. There is proton transfer between the piperidine ring of vandetanib and the carboxyl group of bumetanide to form the salt. In the vandetanib cation, the arene and pyrimidine rings are not coplanar, their planes subtending a dihedral angle of 60.47 (14)°. The roles of the intermolecular interactions in the crystal packing were clarified using Hirshfeld surface analysis, and two-dimensional fingerprint plots indicate that the most important contributions to the crystal packing are from H...H (40.5%), O...H/H...C (20.7%), C...H/ H...C (18.8%) and N...C/C...N (9.0%) contacts.

Remission of Ectopic Cushing Syndrome Secondary to Medullary Thyroid Cancer With Vandetanib and Selpercatinib.

Medullary thyroid cancer (MTC) is a neuroendocrine tumor associated with activating mutations of the rearranged during transfection (RET) proto-oncogene. These tumors may rarely secrete adrenocorticotropin or corticotropin-releasing hormone, resulting in a paraneoplastic ectopic Cushing syndrome (ECS). Paraneoplastic ECS carries a high risk of mortality, and management is difficult due to the lack of response to antiadrenal therapies. We report on a 37-year-old man who was diagnosed with metastatic MTC and reported symptoms of cortisol excess with laboratory testing in keeping with ECS. He began treatment with vandetanib, a multitargeted tyrosine kinase inhibitor, which resulted in decreased tumor burden as well as clinical and biochemical resolution of ECS. Due to progressive structural disease 10 months later, he was switched to the selective RET inhibitor selpercatinib, which was followed by a rapid reduction of cortisol nearing the threshold of adrenal insufficiency. Tumor markers were also improved, and repeat imaging showed decreased tumor burden. Our case highlights the efficacy of tyrosine kinase inhibitors in the management of paraneoplastic ECS. Selective RET inhibitors may emerge as preferred targeted treatment options due to better efficacy and toxicity profiles compared to multitargeted inhibitors. Clinicians should monitor for adrenal insufficiency with the use of selective RET inhibitors.

RSV Induces Activation of Intracellular EGFR on the Mitochondrial Membrane for Virus Propagation.

Respiratory syncytial virus (RSV) infects people of all ages and is one of the most common causative agents of lower respiratory tract infections, such as pneumonia, especially in infants under one year of age. However, no direct treatment has been developed for RSV infections. Maintenance of mitochondrial homeostasis and epidermal growth factor receptor (EGFR) activity is important for human cell growth. This study reported that RSV infection maintained the total cellular ATP levels and promoted the intracellular activity of EGFR to replicate RSV. RSV activates the intracellular EGFR-mediated cell survival signaling cascade and maintains mitochondrial EGFR expression for viral production during early events after infection. The approved EGFR inhibitor, vandetanib, markedly reduces RSV propagation, suggesting that EGFR is an attractive host target for RSV therapeutics. Our results suggest that RSV infection maintains cellular ATP levels and promotes the activation of intracellular EGFR in the mitochondrial membrane, significantly contributing to robust RSV propagation.

Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.

BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

Vandetanib alters the tumoricidal capacity of human breast cancer stem cells via inhibiting vasculogenic capacity.

Introduction: The inhibition of vascularization into tumor stroma as well as dynamic cell growth is the center of attention. Here, we aimed to examine the role of vandetanib on angiogenesis capacity of breast cancer stem cell (CSCs). Methods: MDA-MB-231 cells were exposed to different doses of vandetanib and survival rate was monitored. Stimulatory effects of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) were evaluated in vandetanib-treated MDA-MB-231 cells. In vitro tubulogenesis capacity was studied on the Matrigel surface. The synergistic effects of vandetanib on cell survival were also assessed after PI3K and/or Wnt3a inhibition. Vascular endothelial (VE)-cadherin, matrix metalloproteinase-2 (MMP-2), -9, Wnt3a, and p-Akt/Akt ratio were measured using western blotting. Results: Vandetanib reduced survival rate in a dose-dependent manner (P<0.05). Proliferative effects associated with VEGF, FGF, and EGF were blunted in these cells pre-exposed to vandetanib (P<0.05). The microcirculation pattern's triple-negative breast cancer (TNBC) was suppressed by 1, 5 µM of vandetanib (P<0.05). Hence 1, 5 µM of vandetanib potentially decreased the population of CD24- cells. 1 and 5 µM of vandetanib inhibited cell proliferation by blocking PI3K and Wnt3a pathways and decreased the p-Akt/Akt ratio, Wnta3 protein levels (P<0.05). 1 and 5 µM vandetanib combined with PI3K inhibitor diminished metastatic markers including, MMP-2, and MMP-9. The concurrent treatment (PI3K, inhibitor+ 1, 5 µM vandetanib) also considerably reduced epithelial-mesenchymal transition (EMT) markers such as VE-cadherin (P<0.05). Conclusion: Vandetanib suppressed vasculogenic mimicry (VM) networking through blunting stemness properties, coincided with suppression of VE-cadherin in CSCs.

Vandetanib.

Vandetanib is an anti-cancer drug called an antineoplastic kinase inhibitor. The FDA authorized vandetanib on April6, 2011 for the treatment of nonresectable, locally progressed, or metastatic medullary thyroid carcinoma in adults. Because Vandetanib can make the Q-T interval last longer, it shouldn't be given to people with serious heart problems like congenital long QT syndrome or heart failure that hasn't been fixed yet. This chapter provides an overview of Vandetanib's physical and molecular properties, mode of action, pharmacokinetics, and common applications. In furthermore, a detailed summary of the reported techniques of Vandetanib measurement will be provided to assist analysts in selecting the most practical approach for its estimation in routine analysis. This chapter will also explain the synthesis methods developed in the preparation of vandetanib as well as pharmacology of its. In addition, this section summarizes the analytical and characterization techniques utilized to characterize vandetanib row material.

Investigating the effect of vandetanib and celecoxib combination on angiogenesis.

Objective: Angiogenesis plays an important role in various physiological and pathological conditions and is essential for tumor growth and metastasis. The aim of this study was to evaluate the effect of a combination of vandetanib and celecoxib on angiogenic tube formation and its effect on angiogenic genes (MMP-2 and MMP-9) using an in vitro model of human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were cultured and verified by flow cytometry. HUVECs were then treated with vandetanib, celecoxib, and the combination of both drugs. Then, we investigated cell viability and cell apoptosis by MTT assays and flow cytometry. The process of angiogenesis was analyzed by tube formation assays, and the effect on angiogenic genes was determined by RT-qPCR. Results: HUVECs were positive for CD144 and negative for CD14. Vandetanib, celecoxib, and their combination inhibited HUVEC viability in a dose-dependent manner (p < 0.001). The rate of apoptosis was 13.1%, 9%, and 23.7% (p < 0.001) when treated with vandetanib, celecoxib, or the combination of both drugs, respectively. Vandetanib inhibited tube formation by 43.7%, celecoxib by 21%, and their combination by 77.3% (p < 0.001), respectively. RT-qPCR revealed that both vandetanib and celecoxib reduced the expression levels of MMP-2 and MMP-9, and their combination resulted in an even greater extent of reduction in expression levels (p < 0.001). Conclusion: Celecoxib enhanced the effect of vandetanib in inhibiting in vitro angiogenesis and the combination of these two drugs led to even greater extents of inhibition than vandetanib alone.

Cabozantinib, Vandetanib, Pralsetinib and Selpercatinib as Treatment for Progressed Medullary Thyroid Cancer with a Main Focus on Hypertension as Adverse Effect.

This manuscript investigates cabozantinib, vandetanib, pralsetinib, and selpercatinib, four tyrosine kinase inhibitors (TKIs), which are used to treat advanced and/or metastatic medullary thyroid cancer (MTC). Data on efficacy and safety are presented with the main focus on treatment-related hypertension, a well-known adverse effect (AE) of these TKIs. Taken together, TKI-induced hypertension is rarely a dose-limiting side effect. However, with increasing survival times of patients under treatment, hypertension-associated complications can be expected to be on the rise without proper medication.

Vandetanib downregulates type 2 deiodinase in fibro/adipogenic progenitors.

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity. This occurs in the diffused population of fibro/adipogenic progenitors, which reside in different tissues - including the muscles - and normally express D2. Given the widespread diffusion of mesenchymal cells within the body, our results may explain at least partially the alterations in thyroid hormone levels that occur in vandetanib-treated patients. Our findings represent a step forward into the understanding of the mechanisms by which TKIs induce hypothyroidism and identify a resident cell population in which such an effect takes place.

The Role of Tyrosine Kinase Inhibitors in Reduction of Mortality from Non-small Cell Lung Cancer: A Meta-analysis.

BACKGROUND: Tyrosine kinase inhibitors are widely used in the treatment of non-small cell lung cancer. However, the exact role of these inhibitors, particularly in the reduction of mortality of non-small cell lung cancer, is unclear so far. As a result, we used RevMan 5 to conduct a meta- analysis of accessible data from randomised clinical trials. METHODS: The studies were categorised based on the inclusion and exclusion criteria after being collected from PubMed using appropriate MeSH terms. The fixed or random effect model was used based on heterogeneity among studies. The overall estimate was estimated as an odd ratio with a confidence interval of 95%. The heterogeneity among studies was calculated by I2 and Cochrane Q test. The qualitative analysis of publication bias was done using a funnel plot. RESULTS: The overall estimate measures [OR 1.02 (0.83, 1.25)] have shown non-significant role of tyrosine kinase inhibitors in reduction of deaths of non-small cell lung cancer patients as compared to non-tyrosine kinase inhibitors group. The subgroup analysis of individual tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, osimertinib and vandetanib) has also shown similar findings. CONCLUSION: Based on available data, there is no significant role played by tyrosine kinase inhibitors in the reduction of deaths of non-small cell lung cancer patients.

A Novel Green Micellar HPLC-UV Method for the Estimation of Vandetanib in Pure Form, Human Urine, Human Plasma and Human Liver Microsomes Matrices with Application to Metabolic Stability Evaluation.

Vandetanib (Caprelsa®; VNB) is a prescription medicine that is used for the treatment of medullary thyroid cancer that has disrupted other body parts or that cannot be removed by surgery. It is considered a tyrosine kinase inhibitor (TKI). Fast, sensitive and validated HPLC-UV was established for VNB quantification in pure human biological fluids (urine and plasma) and human liver microsomes (HLMs). This analytical methodology was applied also to the metabolic stability assessment of VNB. This method was performed using a phenyl column (250 mm × 4.6 mm id, 5 µm particle size). A sodium dodecyl sulphate solution (0.05 M, pH 3.0 using 0.02 M orthophosphoric acid) containing 0.3% triethylamine and 10% n-butanol was used as a mobile phase and was pumped isocratically at a flow rate of 0.7 mL/min and at a 260 nm detection wavelength. The total elution time was 6 min with an injection volume of 20 µL. The linearity of the established methodology ranged from 30 to 500 ng/mL in pure form and 50 to 500 ng/mL (r2 ≥ 0.9994) in human biological fluids and HLMs. No significant interference from the matrix components was observed. The proposed methodology revealed the benefits of being green, reliable and economic.

Disseminated medullary thyroid cancer - an alternative therapeutic approach.

Not required for Clinical Vignette.

Daily Management of Patients on Multikinase Inhibitors' Treatment.

In a minority of differentiated thyroid cancer (TC) cases and in a large percentage of poorly differentiated TCs (PDTCs) and anaplastic TCs (ATCs), the prognosis is poor due to the lack of response to conventional treatments. In the last two decades, multikinase inhibitor (MKI) compounds have been developed and demonstrated to be very effective in these aggressive cases. Besides the great efficacy, several adverse events (AEs) have been reported in virtually all patients treated with MKIs, largely overlapping between different compounds and including hypertension, diarrhea, anorexia, decreased weight, fatigue, and proteinuria. Most grade 3-4 adverse reactions occur during the first 6 months of treatment and require dosage reduction and/or drug discontinuation. Due to severity of the AEs related to the treatment with MKIs, a multidisciplinary team is definitely required for the daily management of these patients, for the evaluation of the disease status, and the psychophysical condition. Moreover, it is crucial that the patients could have a facilitated access to reach either specialist doctors or nurses who must have been trained to follow them for their individual clinical complications. The follow-up visits should take place at monthly intervals until the sixth month and then every 1-2 months until the completion of the first year of treatment. The flow chart followed at our tertiary center is reported in the present review as a real-life-based example for the follow-up of patients with advanced TC on MKI treatment.

Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin type-B receptor 4.

The oncogenic role of ephrin type-B receptor 4 (EPHB4) has been reported in many types of tumors, including chronic myeloid leukemia (CML). Here, we found that CML patients have a higher EPHB4 expression level than healthy subjects. EPHB4 knockdown inhibited growth of K562 cells (a human immortalized myelogenous leukemia cell line). In addition, transient transfection of EPHB4 siRNA led to sensitization to imatinib. These growth defects could be fully rescued by EPHB4 transfection. To identify an EPHB4-specific inhibitor with the potential of rapid translation into the clinic, a pool of clinical compounds was screened and vandetanib was found to be most sensitive to K562 cells, which express a high level of EPHB4. Vandetanib mainly acts on the intracellular tyrosine kinase domain and interacts stably with a hydrophobic pocket. Furthermore, vandetanib downregulated EPHB4 protein via the ubiquitin-proteasome pathway and inhibited PI3K/AKT and MAPK/ERK signaling pathways in K562 cells. Vandetanib alone significantly inhibited tumor growth in a K562 xenograft model. Furthermore, the combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib-resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via targeting EPHB4.