Inhibition of IRAK1/4 enhances the antitumor effect of lenvatinib in anaplastic thyroid cancer cells.
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ABSTRACT:
SUBMITTER: Kawamura Y
PROVIDER: S-EPMC8586669 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need.Patients and methodsThis phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate.ResultsAt data cutoff, 17 patients with ATC were enrolled. All experienced ≥1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%.ConclusionIn this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC.ClinicaltrialsgovNCT01728623.
| S-EPMC5331066 | biostudies-literature
Project description:Anaplastic thyroid carcinoma (ATC) is a malignant tumor of the thyroid gland, infrequent but with a very poor prognosis, as it rapidly causes death (mean survival of about 6 months). ATC treatment includes a multimodal protocol consisting of surgery, chemotherapy (doxorubicin and cisplatin), and hyperfractionated accelerated external beam radiotherapy (median patient survival of 10 months). For this reason, the identification of an effective systemic treatment for ATC would be a major advance in the management of this deadly thyroid cancer. The opportunity to test the sensitivity to different drugs of primary cells from ATC (pATC) cultures, obtained from each patients, could improve the effectiveness of the treatment. Then, the administration of inactive therapeutics could be avoided. Our aim is to investigate the antineoplastic effect of two tyrosine kinase inhibitors (TKIs; lenvatinib, vandetanib) in pATC obtained both from biopsy (biop-pATC), and from fine needle aspiration (FNA-pATC). The antiproliferative activity of lenvatinib and vandetanib was evaluated in 6 ATC patients, on biop-pATC, such as on FNA-pATC. A significant reduction of proliferation (obtained by WST-1 assay) vs. control was shown with lenvatinib and vandetanib in FNA-pATC, as well as in biop-pATC. The percentage of apoptosis in FNA-pATC, or biop-pATC, increased with both compounds dose-dependently. pATC cells from FNA, or biopsy, had a similar sensitivity to lenvatinib and vandetanib. In conclusion, primary cells (biop-pATC or FNA-pATC) have a similar sensitivity to TKIs, and lenvatinib and vandetanib are effective in reducing cell growth, increasing apoptosis in ATC. The possibility to test the sensitivity to different TKIs in each patient could open the way to personalized treatments, avoiding the administration of ineffective, and potentially dangerous, drugs.
| S-EPMC6305332 | biostudies-other
Project description:Anaplastic thyroid cancer (ATC) is a rare neoplasia with a poor prognosis. Proliferation and apoptosis assays were performed on ATC cell lines (8305C, 8505C) exposed to vinorelbine, lenvatinib, as well as to concomitant combinations. ABCB1, ABCG2 and CSF-1 mRNA expression was evaluated by real time PCR. The relative levels of pospho Akt were investigated as part of a human phospho-kinase array analysis, and CSF-1 and VEGFR-2 protein levels were measured by ELISA. The intracellular concentration of lenvatinib in ATC cells was measured by combined reversed-phase liquid chromatography-tandem mass spectrometry. An ATC subcutaneous xenograft tumor model in nude mice was treated with vinorelbine, lenvatinib, or vinorelbine plus lenvatinib. After treatment with vinorelbine, lenvatinib, a significant antiproliferative effect in ATC cell lines was observed. The concomitant treatment of vinorelbine and lenvatinib revealed synergism for all the fractions of affected cells. A decrease in ABCB1 expression was reported in both ATC cell lines treated with the lenvatinib plus vinorelbine combination, as was an increase in the intracellular concentration of lenvatinib. The combination caused a decrease in Akt, GSK3α/β, PRAS40 and Src phosphorylation, and in both CSF-1 mRNA and protein levels. In the subcutaneous tumor model, the combination reduced the tumor volume during the treatment period. Our results establish the synergistic ATC antitumor activity of a vinorelbine and lenvatinib combination.
| S-EPMC8011355 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC) is a very rare disease with a poor prognosis and with no established effective drug therapy. The present study aimed to report the outcomes of lenvatinib single-agent therapy as an initial drug treatment in ATC, and to investigate its safety and efficacy. This retrospective cohort study included 56 patients with unresectable primary ATC, of whom 36 were treated with lenvatinib and 12 with weekly paclitaxel, and 8 patients who refused any drug treatment who received palliative care. The average survival in the lenvatinib group was 5.8 months, which was significantly longer than 2.0 months in the paclitaxel group (P=0.005). The efficacy of lenvatinib in the 36 patients with ATC, whose primary tumors were unresectable, was evaluated. The response rate was 33% and the median overall survival time was 5.0 months. A safety review indicated that lenvatinib should be used under the careful observation of local findings. Two patients, who showed a reduction with lenvatinib, underwent conversion surgery, which prolonged the prognosis in terms of avoiding events, such as asphyxia, fistula and hemorrhage due to tumor growth; however, the surgical margins were positive, indicating that complete remission was impossible even if surgical resection was performed. Therefore, starting with lenvatinib treatment and identifying a therapeutic drug based on genomic analysis is an acceptable treatment strategy for ATC while halting the disease progression.
| S-EPMC10442759 | biostudies-literature
Project description:BackgroundAnaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors for which no effective therapies are currently available. Oncolytic Newcastle disease virus (NDV) has shown the potential to induce oncolytic cell death in a variety of cancer cells of diverse origins. However, whether oncolytic NDV displays antitumor effects in ATC remains to be investigated. We have previously shown that the oncolytic NDV strain FMW (NDV/FMW) induces oncolytic cell death in several cancer types. In the present study, we investigated the oncolytic effects of NDV/FMW in ATC.MethodsIn this study, a recombinant NDV expressing green fluorescent protein (GFP) was generated using an NDV reverse genetics system. The resulting virus was named after rFMW/GFP and the GFP expression in infected cells was demonstrated by direct fluorescence and immunoblotting. Viral replication was evaluated by end-point dilution assay in DF-1 cell lines. Oncolytic effects were examined by biochemical and morphological experiments in cultural ATC cells and in mouse models.ResultsrFMW/GFP replicated robustly in ATC cells as did its parent virus (NDV/FMW) while the expression of GFP protein was detected in lungs and spleen of mice intravenously injected with rFMW/GFP. We further showed that rFMW/GFP infection substantially increased early and late apoptosis in the ATC cell lines, THJ-16 T and THJ-29 T and increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage in ATC cells as assessed by immunoblotting. In addition, rFMW/GFP induced lyses of spheroids derived from ATC cells in three-dimensional (3D) cultures. We further demonstrated that rFMW/GFP infection resulted in the activation of p38 MAPK signaling, but not Erk1/2 or JNK, in THJ-16 T and THJ-29 T cells. Notably, inhibition of p38 MAPK activity by SB203580 decreased rFMW/GFP-induced cleavage of caspase-3 and PARP in THJ-16 T and THJ-29 T cells. Finally, both rFMW/GFP and its parent virus inhibited tumor growth in mice bearing THJ-16 T derived tumors.ConclusionTaken together, these data indicate that both the recombinant reporter virus rFMW/GFP and its parent virus NDV/FMW, display oncolytic activities in ATC cells in vitro and in vivo and suggest that oncolytic NDV may have potential as a novel therapeutic strategy for ATC.
| S-EPMC6052588 | biostudies-literature
Project description:Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.
| S-EPMC6982268 | biostudies-literature
Project description:E7080, known as lenvatinib, is an oral multitargeted tyrosine kinase inhibitor that has been shown to improve the survival rate of patients with radioiodine-refractory thyroid cancer. However, a majority of patients do not continue lenvatinib intake due to disease progression or significant toxicity. To improve treatment success rates, we propose the combination of lenvatinib with mitogen-activated protein kinase (MEK) inhibitors. To test this hypothesis, we tested the effects of lenvatinib with the MEK inhibitor U0126 in vitro using two human anaplastic thyroid cancer (ATC) cell lines, 8505C and TCO1, and with another MEK inhibitor, selumetinib (AZD6244), in an ATC mouse model. We found that the combination of lenvatinib with MEK inhibitors enhanced the antitumor effects of monotherapy with either agent in vitro and in vivo, and these effects may be through the AKT (Protein Kinase B) and extracellular signal-regulated kinase (ERK) signaling pathways. Furthermore, the combination does not have significant adverse effects in the ATC mouse models in terms of body weight, blood biochemical parameters, and histopathology. In conclusion, the combination of lenvatinib with an MEK inhibitor is a potentially viable therapeutic approach for ATC treatment.
| S-EPMC7922355 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects in ATC cells and xenografts that were associated with potentiated mitotic catastrophe. We hypothesized that combined effects may reflect enhanced paclitaxel-induced cytotoxicity mediated by cell cycle regulatory kinase inhibition by pazopanib. Indeed, pazopanib potently inhibited aurora A, with pazopanib/paclitaxel synergy recapitulated by aurora A short hairpin RNA knockdown or by specific aurora A pharmacological inhibition. Pazopanib/paclitaxel synergy was reversed by aurora A knockdown. Moreover, aurora A (but not B or C) message and protein levels were significantly increased in patient ATCs, and durable benefit resulted from pilot clinical translation of pazopanib/paclitaxel therapy in a patient with metastatic ATC. Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC.
| S-EPMC3905331 | biostudies-literature
Project description:Background: Survival rates for anaplastic thyroid cancer (ATC) have not improved in the past four decades; however, preliminary clinical data indicate that lenvatinib may provide efficacy benefits for patients with ATC. This real-world study aimed to define the potential role of lenvatinib in ATC by examining the impact of treatment administered alongside existing therapies. Methods: This was a retrospective, single-center analysis of Korean patients with confirmed ATC who received lenvatinib between October 2015 and February 2018. Eighteen patients were included (mean ± standard deviation age, 64.9 ± 11.1 years; 61.1% female). Six [33.3%] had resectable disease that progressed after a combination of surgery, radiotherapy, and chemotherapy, and 12 [66.7%] had unresectable disease that progressed after radiation treatment and chemotherapy. Study endpoints were overall survival (OS) and change in volume of the largest tumor assessed via imaging. Results: Median OS for the 18 lenvatinib-treated patients was 230 days (range 64-839 days). Survival rates at 6 months and 1 year were 61.1 and 22.2%, respectively. Three patients (16.7%) survived beyond 1 year; 15 patients died, of whom four (26.7%) had local disease and 11 (73.3%) had distant metastasis. Two patients (11.1%) had tumor volume increases of 9-10%. The other 16 patients (88.9%) had tumor volume reductions of 2-69%. Six patients (33.3%) had tumor volume reductions ≥50%. Conclusions: In patients with ATC who had progressed on prior therapy, addition of lenvatinib could improve survival duration and reduce tumor volume. Further studies of lenvatinib in ATC are warranted.
| S-EPMC7492269 | biostudies-literature
Project description:Background Lenvatinib has shown promising efficacy in targeted therapies that have been tested to treat anaplastic thyroid carcinoma (ATC) in both preclinical and clinical studies. The aim of this study was to evaluate the efficacy and safety of lenvatinib in the treatment of patients with ATC. Methods PubMed, the Cochrane Library, Embase, and ClinicalTrials.gov were searched for potential eligible studies from inception to February 1, 2022. The outcomes included partial response (PR), stable disease (SD), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS). Effect sizes for all pooled results were presented with 95% CIs with upper and lower limit. Results Ten studies met the inclusion criteria. The aggregated results showed that the pooled PR, SD, and DCR were 15.0%, 42.0%, and 63.0%, respectively. The pooled mPFS and mOS were 3.16 (2.18–5.60) months and 3.16 (2.17–5.64) months, respectively. Furthermore, PFS rate at 3 months (PFSR-3m), PFSR-6m, PFSR-9m, PFSR-12m, and PFSR-15m were 52.0%, 22.5%, 13.9%, 8.4%, and 2.5%, respectively. Meanwhile, the 3-month OS rate (OSR-3m), OSR-6m, OSR-9m, OSR-12m, and OSR-15m were 64.0%, 39.3%, 29.7%, 18.9%, and 14.2%, respectively. The most common adverse events (AEs) of lenvatinib were hypertension (56.6%), proteinuria (32.6%), and fatigue (32%). Conclusions This meta-analysis showed that lenvatinib has meaningful antitumor activity, but limited clinical efficacy in ATC. Systematic Review Registration PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022308624].
| S-EPMC9279913 | biostudies-literature