Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo

The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC-cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 μM) was tested by WST-1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose-dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGF-A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation

Efficacy and safety of VEGFR inhibitors versus standard chemotherapy in Chinese patients with metastatic liver cancer: Results of a preliminary clinical trial

Purpose: To evaluate efficacy and safety of vandetanib with and without standard chemotherapy in Chinese patients with metastatic liver cancer. Methods: Patients with confirmed diagnosis of metastatic liver cancer were randomized to receive vandetanib (300 mg per day in 28 days cycle) intravenously or standard chemotherapy (FOLFOX4) plus best supportive care. Efficacy measures such as overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) were assessed after study drug treatment. Safety of vandetanib and FOLFOX4 was also assessed. Survival time with respect to disease progression was also assessed. Results: Vandetanib + standard chemotherapy-based regimens showed significantly higher OS benefit when compared to vandetanib and chemotherapy alone. Objective response rate (ORR) was also favorable among the patients treated with combination therapy when compared with monotherapy. A similar trend was noted for PFS; treatment with vandetanib + chemotherapy showed significantly longer PFS when compared to vandetanib and chemotherapy alone, respectively. Trial results demonstrated that vandetanib as a monotherapy or in combination with standard chemotherapy appears to be safe. Conclusion: The results of this trial may aid clinicians to select appropriate therapeutic intervention for patients with metastatic liver cancer. Keywords: Vandetanib, Metastatic liver cancer, Chemotherapy, FOLFOX4, VEGFR inhibitor

Tyrosine kinase inhibitors for the therapy of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is often incurable so new therapeutic approaches are needed. Tyrosine kinases inhibitors (such as imanitib, sunitinib or sorafenib) are under evaluation for the treatment of ATC. Other vascular disrupting agents, such as combretastatin A4 phosphate, and antiangiogenic agents, such as aplidin, PTK787/ZK222584 and human VEGF monoclonal antibodies (bevacizumab, cetuximab), have been evaluated. Small-molecule adenosine triphosphate competitive inhibitors directed intracellularly at EGFRs tyrosine kinase, such as erlotinib or gefitinib, are also studied. Furthermore, new molecules have been shown to be active against ATC, such as CLM94 and CLM3. However, more research is needed to finally identify therapies able to control and to cure this disease

Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency

The effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact FTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack FTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined

The safety and efficacy of vandetanib in the treatment of progressive medullary thyroid cancer

Introduction: Traditional therapies for advanced or metastatic progressive medullary thyroid cancer (pMTC) are poor effective. Several TKIs have been tested in clinical trials in pMTC patients. Areas covered: This paper reviews efficacy and safety of vandetanib in the treatment of pMTC. Expertcommentary: Vandetanib (trade name CAPRELSA® [Vandetanib]) has been shown to improve progression-free survival (30.5 vs 19.3&nbsp;months in controls) in pMTC patients. Vandetanib is approved by FDA and EMA for metastatic MTC in adults; in adolescents and children with metastatic or locally advanced MTC, vandetanib seems to be effective. The most common adverse events in vandetanib-treated patients are: diarrhea, rash, folliculitis, nausea, QTc prolongation, hypertension and fatigue. In patients with aggressive differentiated thyroid cancer, vandetanib has shown promising results. Further research is needed to determine the ideal targeted therapy, based on tumor molecular characterization and host factors, to obtain the best response in terms of survival and quality of life

Toxicity of cancer therapy: what the cardiologist needs to know about angiogenesis inhibitors

Clinical outcomes for patients with a wide range of malignancies have improved substantially over the last two decades. Tyrosine kinase inhibitors (TKIs) are potent signalling cascade inhibitors and have been responsible for significant advances in cancer therapy. By inhibiting vascular endothelial growth factor receptor (VEGFR)-mediated tumour blood vessel growth, VEGFR-TKIs have become a mainstay of treatment for a number of solid malignancies. However, the incidence of VEGFR-TKI-associated cardiovascular toxicity is substantial and previously under-recognised. Almost all patients have an acute rise in blood pressure, and the majority develop hypertension. They are associated with the development of left ventricular systolic dysfunction (LVSD), heart failure and myocardial ischaemia and can have effects on myocardial repolarisation. Attention should be given to rigorous baseline assessment of patients prior to commencing VEGFR-TKIs, with careful consideration of baseline cardiovascular risk factors. Baseline blood pressure measurement, ECG and cardiac imaging should be performed routinely. Hypertension management currently follows national guidelines, but there may be a future role forendothelin-1 antagonism in the prevention or treatment of VEGFR-TKI-associated hypertension. VEGFR-TKI-associated LVSD appears to be independent of dose and is reversible. Patients who develop LVSD and heart failure should be managed with conventional heart failure therapies, but the role of prophylactic therapy is yet to be defined. Serial monitoring of left ventricular function and QT interval require better standardisation and coordinated care. Management of these complex patients requires collaborative, cardio-oncology care to allow the true therapeutic potential from cancer treatment while minimising competing cardiovascular effects

Vandetanib-eluting radiopaque beads for chemoembolization: physicochemical evaluation and biological activity of vandetanib in hypoxia.

Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents

Role of vandetanib in the management of medullary thyroid cancer

Traditionally available treatments, like cytotoxic chemotherapy and external-beam radiation therapy, are limited and essentially ineffective for metastatic medullary thyroid carcinoma (MTC). In the last decade, small-molecule tyrosine kinase inhibitors (TKI) have been introduced in the field of thyroid cancer, after having been shown effective in a wide variety of other tumors. This review focuses on vandetanib (ZD6474, Zactima™; AstraZeneca) and its role in the treatment of MTC. Vandetanib is an oral TKI that targets VEGF receptors 2 and 3, RET, and at higher concentrations, the epidermal growth factor (EGF) receptor. This drug has been tested in two important phase II studies which demonstrated that both the 100 and 300 mg/day dosage of vandetanib have antitumor activity on advanced MTC. A phase III trial (ZETA trial) evaluating vandetanib in 331 patients with locally advanced or metastatic MTC showed a significant prolongation of PFS for patients receiving vandetanib compared with placebo. Toxicity surveillance in all studies reported high rates of adverse effects with diarrhea, rash, fatigue and nausea being the most commonly experienced by patients. Vandetanib is currently approved in the United States for unresectable locally advanced or metastatic MTC and has become a new standard of care in this rare and indolent pathology

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&lt;0.05). Proliferative effects associated with VEGF, FGF, and EGF were blunted in these cells pre-exposed to vandetanib (P&lt;0.05). The microcirculation pattern’s triple-negative breast cancer (TNBC) was suppressed by 1, 5 µM of vandetanib (P&lt;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&lt;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&lt;0.05). Conclusion: Vandetanib suppressed vasculogenic mimicry (VM) networking through blunting stemness properties, coincided with suppression of VE-cadherin in CSCs(Figure Presented).</p

Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

Purpose: The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination. Methods and Materials: LoVo cells were injected subcutaneously into the right hind limb (5x106 cells in 100μL phosphate-buffered saline) of athymic NCR NUM mice and tumors were grown to a volume of 200–300mm3 before treatment. Vandetanib was administered at 50 mg/kg daily orally for 14 days starting on Day 1. RT was given as three fractions (3x3 Gy) on Days 1, 2, and 3. CPT-11 was given at 15 mg/kg intraperitoneally on Days 1 and 3. Tumor volumes were measured on a daily basis and calculated by measuring tumor diameters with digital calipers in two orthogonal dimensions. Results: All three single treatments (vandetanib, CPT-11, and radiation) significantly slowed LoVo colorectal tumor growth. Vandetanib significantly increased the antitumor effects of CPT-11 and radiation when given in combination with either of these treatments. These treatment combinations resulted in a slow tumor growth rate during the 2 weeks of vandetanib administration. The triple combination of vandetanib, CPT-11, and radiation produced the most marked improvement in response as observed by measurable shrinkage of tumors during the first week of treatment. Conclusions: The tumor growth delay kinetics observed in this study of the LoVo colorectal model suggest concurrent and sustained post-sequencing of vandetanib with cytotoxic therapy may be beneficial in tumors of this type. Reprinted from International Journal of Radiation Oncology*Biology*Physics, Volume 75, Edition 3, Wachsberger P, Burd R, Ryan A, Daskalakis C, Dicker AP: “Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model”, pages 843-853, November 1, 2009