Novel Approaches in Anaplastic Thyroid Cancer Therapy

Hsu, Kun-Tai; Yu, Xinhua; Audhya, Anjon; Jaume, Juan Carlos; Lloyd, Ricardo V.; Miyamoto, Shigeki; Prolla, Tomas A.; Chen, Herbert

doi:10.1634/theoncologist.2014-0182

Cited by 48 publications

(36 citation statements)

References 152 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite the generally good prognosis, DTC patients with aggressive phenotypes, like extrathyroidal invasion or metastases, reveal a much higher disease recurrence rate, which is still challenging for clinical management (13,14). Recently, the Notch1 pathway has garnered great interest as a potential target of treating aggressive thyroid cancers (15-18). However, unlike the consistent observation on the loss of Notch1 expression in anaplastic thyroid carcinoma (17,19,20), the expression pattern and biological function of Notch1 in DTC are controversial.…”

Section: Introductionmentioning

confidence: 99%

Notch1 Signaling Regulates the Aggressiveness of Differentiated Thyroid Cancer and Inhibits SERPINE1 Expression

Jaskula-Sztul

Georgen

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose Notch1, a trans-membrane receptor, has been recently shown to aid in the determination of thyroid cell fate associated with tumorigenesis. The present study aimed to investigate the clinical relevance of Notch1 and its role in the regulation of differentiated thyroid cancer (DTC) behavior. Experimental design We examined Notch1 expression level and its relationship with clinicopathologic features and outcomes of DTC. Notch1 intracellular domain (NICD) was further characterized both in vitro and in vivo by gain-of-function assays using an inducible system. Results Notch1 expression levels were down-regulated in primary DTC tissue samples compared with contralateral non-tumor and benign thyroid tissues. Decreased Notch1 expression in DTC was associated with advanced patient age (p=0.032) and the presence of extrathyroidal invasion (p=0.005). Patients with lower Notch1 expression had a significantly higher recurrence rate (p=0.038). Restoration of NICD in a stably doxycycline-inducible metastatic DTC cell line reduced cell growth and migration profoundly. Using an orthotopic thyroid cancer model, NICD induction significantly reduced the growth of the primary thyroid tumor and inhibited the development of lung metastasis. SERPINE1 was discovered by microarray as the most significant gene down-regulated by NICD. Further validation showed that induction of NICD reduced SERPINE1 expression in a dose-dependent manner while restoration of a relative higher level of SERPINE1was observed with NICD back to minimal level. Additionally, SERPINE1 knock-down inhibited DTC cell migration. Conclusions Notch1 regulates the aggressive phenotypes of DTC, which could be mediated by SERPINE1 inhibition. Notch1/SERPINE1 axis warrants further investigation as a novel therapeutic target for advanced DTC.

show abstract

Section: Introductionmentioning

confidence: 99%

Notch1 Signaling Regulates the Aggressiveness of Differentiated Thyroid Cancer and Inhibits SERPINE1 Expression

Jaskula-Sztul

Georgen

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…In recent years, molecular biological studies have revealed that the mutation of the genes BRAF and N-RAS is associated with anaplastic transformation (17,18), and conventional cancer chemotherapy has been shifting to molecular-targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Anaplastic Thyroid Carcinoma Treated with Lenvatinib

et al. 2017

View full text Add to dashboard Cite

Anaplastic thyroid carcinoma (ATC), which accounts for 1%-2% of all malignant tumors of the thyroid, is known to be highly resistant to any therapy and has a 1-year survival rate of 5%-20% [1][2][3]. ATC patients are limited in number, and most die within 6 months after diagnosis, making it difficult to establish a standard treatment protocol. Multimodal therapy including surgery, radiotherapy and chemotherapy has been introduced, but survival times remain poor [4][5][6].The use of molecular-targeted drugs as cancer therapy has been rapidly increasing over the past decade. Lenvatinib, a new molecular-targeted anticancer drug, is a multi-targeted receptor tyrosine kinase inhibitor that inhibits the activities of vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet-derived growth factor receptors, KIT, and RET [7,8]. Lenvatinib exerts its anticancer activity via the suppression of tumor angiogenesis, and it is generally indicated for unresectable radioiodine-refractory differentiated thyroid cancers [9]. However, the evidence of the clinical effect of this drug on ATC is very limited. We herein report a case of ATC with local recur- Kurume Medical Journal, 64, 00-00, 2017 Summary: Objective: We report a case of anaplastic thyroid carcinoma (ATC) with local recurrence and distant metastasis that responded very well to treatment with lenvatinib, a new molecular-targeted anticancer drug. Case Report: A 91-year-old Japanese woman presented with a 5-month history of a painless mass in her left anterior neck. She had a past history of total thyroidectomy and neck dissection for papillary carcinoma of the thyroid. Here she underwent neck dissection, and the histopathological diagnosis was lymph node metastasis of papillary carcinoma with anaplastic transformation. Five months later, a cervical lymph node swelled up again.Computed tomography demonstrated an enhanced mass in the neck and multiple nodules in both lungs. Recurrent ATC with multiple lung metastases was diagnosed, and molecular-targeted therapy with lenvatinib was initiated. The neck tumor reduced in 1 week, and the pulmonary nodules became completely hollow within 1 month. However, we had to discontinue lenvatinib because of severe side effects including high blood pressure, hypocalcemia, and hypoalbuminemia. Soon after discontinuation, the side effects subsided, but the tumor rapidly regrew. The patient died of lymphangiosis carcinomatosa 6 days after discontinuation. Conclusion: Although recent advances in molecular-targeted therapy have provided powerful cancer therapy tools, the negative side of this therapy must be addressed.

show abstract

“…Anaplastic thyroid carcinoma (ATC) is one of the most aggressive endocrine neoplasms, which has a high mortality rate despite the fact that ATC only accounts for 2% of all thyroid cancers (1). The median survival period of patients with ATC is less than half a year, and the 1-year survival rate is less than 20% after diagnosis (2)(3)(4). However, many patients spend money and ultimately succumb to ATC due to dismal prognosis, incurability, side effects, and complexity of treatment (5).…”

Section: Introductionmentioning

confidence: 99%

Effect of mesoporous silica nanoparticles co‑loading with 17‑AAG and Torin2 on anaplastic thyroid carcinoma by targeting VEGFR2

et al. 2020

View full text Add to dashboard Cite

Anaplastic thyroid carcinoma (ATC) is a highly aggressive tumor with a poor prognosis and a low median survival rate because of insufficient effective therapeutic modalities. Recently, mesoporous silica nanoparticles (MSNs) as a green non-toxic and safe nanomaterial have shown advantages to be a drug carrier and to modify the targeting group to the targeted therapy. To aim of the study was to explore the effects of MSNs co-loading with 17-allylamino-17-demethoxy-geldanamycin (17-AAG; HSP90 inhibitor) and 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl) phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2; mTOR inhibitor) by targeting vascular endothelial growth factor receptor 2 (VEGFR2) on the viability of human anaplastic thyroid carcinoma FRO cells. The cytotoxicity of 17-AAG and Torin2 were analyzed by MTT assay. The possible synergistic antitumor effects between 17-AAG and Torin2 were evaluated by CompuSyn software. Flow cytometry was performed to assess the VEGFR2 targeting of (17-AAG+Torin2)@ MSNs-anti-VEGFR2 ab and uptake by FRO cells. An ATC xenograft mouse model was established to assess the antitumor effect of (17-AAG+Torin2)@MSNs-anti-VEGFR2 ab in vivo. The results revealed that the combination of 17-AAG and Torin2 inhibited the growth of FRO cells more effectively compared with single use of these agents. Additionally, the synergistic antitumor effect appeared when concentration ratio of the two drugs was 1:1 along with total drug concentration greater than 0.52 µM. Furthermore, in an ATC animal model, it was revealed that the (17-AAG+Torin2)@MSNs-anti-VEGFR2 ab therapy modality could most effectively prolong the median survival time [39.5 days vs. 33.0 days (non-targeted) or 27.5 days (control)]. Compared to (17-AAG+Torin2)@MSNs, the (17-AAG+Torin2)@MSNs-anti-VEGFR2 ab could not only inhibit ATC cell growth but also prolong the median survival time of tumor-bearing mice in vivo and vitro more effectively, which may provide a new promising therapy for ATC.

show abstract

Novel Approaches in Anaplastic Thyroid Cancer Therapy

Cited by 48 publications

References 152 publications

Notch1 Signaling Regulates the Aggressiveness of Differentiated Thyroid Cancer and Inhibits SERPINE1 Expression

Notch1 Signaling Regulates the Aggressiveness of Differentiated Thyroid Cancer and Inhibits SERPINE1 Expression

Anaplastic Thyroid Carcinoma Treated with Lenvatinib

Effect of mesoporous silica nanoparticles co‑loading with 17‑AAG and Torin2 on anaplastic thyroid carcinoma by targeting VEGFR2

Contact Info

Product

Resources

About