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Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer.

ABSTRACT: Differentiated thyroid cancer (DTC) patients are usually known for their excellent prognoses. However, some patients with DTC develop refractory disease and require novel therapies with different therapeutic mechanisms. Targeting Wee1 with adavosertib has emerged as a novel strategy for cancer therapy. We determined the effects of adavosertib in four DTC cell lines. Adavosertib induces cell growth inhibition in a dose-dependent fashion. Cell cycle analyses revealed that cells were accumulated in the G2/M phase and apoptosis was induced by adavosertib in the four DTC tumor cell lines. The sensitivity of adavosertib correlated with baseline Wee1 expression. In vivo studies showed that adavosertib significantly inhibited the xenograft growth of papillary and follicular thyroid cancer tumor models. Adavosertib therapy, combined with dabrafenib and trametinib, had strong synergism in vitro, and revealed robust tumor growth suppression in vivo in a xenograft model of papillary thyroid cancer harboring mutant BRAFV600E, without appreciable toxicity. Furthermore, combination of adavosertib with lenvatinib was more effective than either agent alone in a xenograft model of follicular thyroid cancer. These results show that adavosertib has the potential in treating DTC.

SUBMITTER: Lu YL

PROVIDER: S-EPMC8306685 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer.

Lu Yu-Ling YL Wu Ming-Hsien MH Lee Yi-Yin YY Chou Ting-Chao TC Wong Richard J RJ Lin Shu-Fu SF

Cancers 20210712 14

Differentiated thyroid cancer (DTC) patients are usually known for their excellent prognoses. However, some patients with DTC develop refractory disease and require novel therapies with different therapeutic mechanisms. Targeting Wee1 with adavosertib has emerged as a novel strategy for cancer therapy. We determined the effects of adavosertib in four DTC cell lines. Adavosertib induces cell growth inhibition in a dose-dependent fashion. Cell cycle analyses revealed that cells were accumulated in ...[more]

PMID: 34298699

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Project description:Differentiated thyroid cancer (DTC) is a common type of cancer among women with an increasing worldwide incidence rate. However, there are no specific and sensitive molecular biomarkers for DTC diagnosis or prognosis. Angiopoietin-like protein 1 (ANGPTL1) may be a novel tumor suppressor in lung, breast, colorectal and hepatocellular carcinoma. However, little is known about the influence of ANGPTL1 on the malignant properties of thyroid cancer cells or DTC recurrence in patients. Thus, the present study aimed to investigate the effects of ANGPTL1 on thyroid cancer malignancy or recurrence. The present study examined the mRNA levels of ANGPTL1 in thyroid cancer and paracancerous tissues using RNA sequencing data from The Cancer Genome Atlas. The present study also determined the effects of ANGPTL1 on thyroid cancer cell proliferation using the Cell Counting Kit-8 assay. Associations were identified among ANGPTL1 expression levels and thyroid cancer proliferation, migration and metastasis using The Cancer Genome Atlas data set and by Gene Set Enrichment Analysis. The expression of ANGPTL1 in patients with DTC and without recurrence was compared in order to assess its potential as a prognostic biomarker for DTC. In addition, ANGPTL1 concentrations in the serum of patients with DTC and individuals with benign thyroid nodules were compared to evaluate the sensitivity and specificity of ANGPTL1 as a predictive biomarker for DTC. The results of the present study demonstrated that ANGPTL1 expression levels were lower in thyroid cancer compared with those in adjacent normal thyroid tissues. ANGPTL1 expression was observed to decrease with thyroid cancer progression. In addition, ANGPTL1 was demonstrated to inhibit thyroid cancer cell proliferation, migration and invasion and ANGPTL1 expression levels were reduced in patients with DTC with recurrence compared with those in patients with non-recurrent DTC. Additionally, serum concentrations of ANGPTL1 in patients with DTC were decreased compared with those in individuals with benign thyroid nodules. In conclusion, ANGPTL1 may be a novel predictive biomarker for DTC diagnosis and recurrence in patients with DTC.

Project description:Background: Multiple targeted therapeutics are available for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), but it remains unclear which treatment is optimal to achieve long-term survival. Methods: A systematic search of the PubMed, Embase, and ClinicalTrials.gov databases was conducted to identify eligible randomized controlled trials (RCTs) comparing the efficacy and safety of targeted treatments for patients with RAIR-DTC from inception to April, 2022. Data were extracted by following the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. We calculated the odds ratio (OR) or hazard ratio (HR), its corresponding 95% credible intervals (CrI), and the surface under the cumulative ranking curve (SUCRA) to indicate ranking probability using Bayesian network meta-analyses. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events. Results: A total of 12 eligible RCTs involved 1,959 patients and 13 treatments: apatinib, cabozantinib, anlotinib, nintedanib, lenvatinib, lenvatinib with low dose (LD), sorafenib, sorafenib plus everolimus, donafenib (200 mg), donafenib (300 mg), pazopanib (continuous), pazopanib (intermittent), and vandetanib. Pooled analyses indicated that targeted therapeutics significantly prolonged PFS and OS in patients with RAIR-DTC (0.31, 0.21-0.41; 0.69, 0.53-0.85, respectively) compared with placebo. Network meta-analyses indicated that lenvatinib showed the most favorable PFS, with significant differences versus sorafenib (0.33, 0.23-0.48), vandetanib (0.31, 0.20-0.49), nintedanib (0.30, 0.15-0.60), and placebo (0.19, 0.15-0.25), while apatinib was most likely to be ranked first for prolonging OS with a SUCRA of 0.90. Lenvatinib showed the highest ORR (66%, 61%-70%), followed by anlotinib (59%, 48%-70%) and apatinib (54%, 40%-69%). Lenvatinib caused the most adverse events of grade 3 or higher, followed by lenvatinib (LD) and apatinib. Different toxicity profiles of individual treatment were also revealed. Conclusion: This network meta-analysis suggests that lenvatinib and apatinib were associated with the best progression-free survival and overall survival benefits, respectively, for patients with RAIR-DTC, compared with other targeted therapeutics. Patients who received lenvatinib or apatinib also had more grade 3 or higher adverse events. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=302249], identifier [CRD42022302249].

Project description:BackgroundThyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer.MethodsThe specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.ResultsThe revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research.ConclusionsWe have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Dataset Information

Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer.

Publications

Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer.

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