Abstract P120: Novel in vitro targeted combination therapies for anaplastic thyroid cancer

Author(s):  
Muthusamy Kunnimalaiyaan ◽  
Parag Parekh ◽  
Jalyn Golden ◽  
Ying Anderson ◽  
Stephen Lai ◽  
...  
Head & Neck ◽  
2020 ◽  
Vol 42 (12) ◽  
pp. 3678-3684
Author(s):  
Soo Young Kim ◽  
Seok‐Mo Kim ◽  
Hojin Chang ◽  
Hang‐Seok Chang ◽  
Cheong Soo Park ◽  
...  

Nutrients ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 125 ◽  
Author(s):  
Hye-Ji Shin ◽  
Kyung-A Hwang ◽  
Kyung-Chul Choi

Thyroid cancers developed from the tissues of the thyroid gland are classified into papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic thyroid cancer (ATC). Although thyroid cancers have been generally known as mild forms of cancer, undifferentiated MTC and ATC have a more unfavorable prognosis than differentiated PTC and FTC because they are more aggressive and early metastatic. A variety of therapies such as surgery, radiotherapy, and chemotherapy have been currently used to treat thyroid cancer, but they still have limitations including drug resistance or unfavorable side effects. Phytochemicals are plant-derived chemicals having various physiological activities that are expected to be effective in cancer treatment. In this review, anticancer efficacy of phytochemicals, such as resveratrol, genistein, curcumin, and other substances in each type of thyroid cancer was introduced with their chemopreventive mechanisms. English articles related with thyroid cancer and anti-thyroid cancer of phytochemicals were searched from PubMed and Google Scholar. This article mainly focused on in vitro or animal studies on phytochemicals with anti-thyroid cancer activity. These various phytochemicals have been shown to induce apoptosis in all types of thyroid cancer cells, inhibit cell proliferation and invasion, and to be helpful in enhancing the effect of radioiodine therapy that is a typical therapy to thyroid cancer. These results suggest that thyroid cancer can be more effectively treated by the combinations of phytochemicals and the existing therapies or substances.


2020 ◽  
Author(s):  
Guohong Zhao ◽  
Jianqin Kang ◽  
Guanghui Xun ◽  
Jing Wei ◽  
Xiaoguang Wang ◽  
...  

Abstract Background Thyroid cancer(TC)is the most common type of endocrine malignant tumor and the incidence is increasing by years. Conventional surgery, radiotherapy and chemotherapy are difficult to improve significantly effects due to the aggression and metastasis of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) which are the most malignant type of thyroid cancer. Glucose-regulated protein (GRP78) as the key molecule is related to tumor growth, apoptosis and metastasis. However, the mechanisms responsible for the effects of TC on GRP78 still need to be discussed. Therefore, the purpose of this study was to explore the presence of GRP78 and the potential mechanism of TC. Results GRP78 expression is increased in thyroid carcinoma tissues in comparison with the adjacent normal tissues. Besides, down-regulation of GRP78 significantly inhibited the metastatic and proliferative potential of ATC cells in vitro studies. In addition, tunicomycin (TM)-induced ER stress could up-regulate the expression of GRP78, PERK and XBP1 as well as reverse metastatic ability of GRP78 in TC cells. Bioinformatics and statistical analysis of gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for RNA-seq data from si-GRP78 and si-control showed GRP78 may regulate the ability of metastasis through the ECM remodeling in ATC cells, as well as the expression of ECM components such as COL1A1 and MMP13 were illustrated to be highly relevant to ATC. The analysis of GEPIA database confirmed that high genomic amplification of MMP13 and COL1A1 in TC tissues and were correlated with TNM stage. A further western blot analysis showed MMP13 may be the target of GRP78 in ATC cells and ER stress could activate the expression of MMP13 which was suppressed by depletion of GRP78. Conclusions GRP78 is an important regulator of metastasis under the ER stress. In addition, GRP78’s functions might be mediated by ECM remodeling in ATC cells, which implicates GRP78 as a therapeutic target in thyroid cancer.


2021 ◽  
Author(s):  
Yu-Ling Lu ◽  
Yu-Tung Huang ◽  
Ming-Hsien Wu ◽  
Ting-Chao Chou ◽  
Richard J Wong ◽  
...  

Wee1 is a kinase that regulates the G2/M progression by inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.


2019 ◽  
Vol 26 (1) ◽  
pp. 153-164 ◽  
Author(s):  
Xianhui Ruan ◽  
Xianle Shi ◽  
Qiman Dong ◽  
Yang Yu ◽  
Xiukun Hou ◽  
...  

There is no effective treatment for patients with poorly differentiated papillary thyroid cancer or anaplastic thyroid cancer (ATC). Anlotinib, a multi-kinase inhibitor, has already shown antitumor effects in various types of carcinoma in a phase I clinical trial. In this study, we aimed to better understand the effect and efficacy of anlotinib against thyroid carcinoma cells in vitro and in vivo. We found that anlotinib inhibits the cell viability of papillary thyroid cancer and ATC cell lines, likely due to abnormal spindle assembly, G2/M arrest, and activation of TP53 upon anlotinib treatment. Moreover, anlotinib suppresses the migration of thyroid cancer cells in vitro and the growth of xenograft thyroid tumors in mice. Our data demonstrate that anlotinib has significant anticancer activity in thyroid cancer, and potentially offers an effective therapeutic strategy for patients of advanced thyroid cancer type.


2009 ◽  
Vol 16 (1) ◽  
pp. 17-44 ◽  
Author(s):  
Robert C Smallridge ◽  
Laura A Marlow ◽  
John A Copland

Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of ∼ 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.


2021 ◽  
Vol 22 (15) ◽  
pp. 8083
Author(s):  
Lorenzo Allegri ◽  
Francesca Capriglione ◽  
Valentina Maggisano ◽  
Giuseppe Damante ◽  
Federica Baldan

ATC is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. In patients without known genetic aberrations, the current treatment is still represented by palliative surgery and systemic mono- or combined chemotherapy, which is often not fully effective for the appearance of drug resistance. Comprehension of the mechanisms involved in the development of the resistance is therefore an urgent issue to suggest novel therapeutic approaches for this very aggressive malignancy. In this study, we created a model of anaplastic thyroid cancer (ATC) cells resistant to paclitaxel and investigated the characteristics of these cells by analyzing the profile of gene expression and comparing it with that of paclitaxel-sensitive original ATC cell lines. In addition, we evaluated the effects of Dihydrotanshinone I (DHT) on the viability and invasiveness of paclitaxel-resistant cells. ATC paclitaxel-resistant cells highlighted an overexpression of ABCB1 and a hyper-activation of the NF-κB compared to sensitive cells. DHT treatment resulted in a reduction of viability and clonogenic ability of resistant cells. Moreover, DHT induces a decrement of NF-κB activity in SW1736-PTX and 8505C-PTX cells. In conclusion, to the best of our knowledge, the results of the present study are the first to demonstrate the antitumor effects of DHT on ATC cells resistant to Paclitaxel in vitro.


2020 ◽  
Author(s):  
Guohong Zhao ◽  
Jianqin Kang ◽  
Guanghui Xun ◽  
Jing Wei ◽  
Xiaoguang Wang ◽  
...  

Abstract Background: Thyroid cancer (TC) is the most common type of endocrine malignancy tumor and the incidence of it is increasing over years. Conventional surgery, radiotherapy and chemotherapy are difficult to improve the significant effects of it due to aggression and metastasis of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), which are regarded as the most malignant type of TC. Glucose-regulated protein (GRP78) is the key molecule of tumor growth, apoptosis and metastasis. However, the underlying mechanisms of GRP78 on TC still require discussion. This study aimed to explore the role of GRP78 and its potential mechanism in TC.Results: GRP78 expression was increased in TC tissues when compared with adjacent normal tissues. Besides, down-regulation of GRP78 significantly inhibited the metastatic and proliferative ability of ATC cells in in vitro studies. In addition, tunicamycin-induced ER stress up-regulated the expression of GRP78, PERK and XBP1 as well as reversed the metastatic ability of GRP78 in ATC cells. Bioinformatics and statistical analysis of gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for RNA-sequencing data from si-GRP78 and si-control showed that GRP78 might regulate the ability of metastasis through extracellular matrix (ECM) remodeling in ATC cells, as well as the expression of ECM components such as COL1A1 and MMP13 were shown to be highly relevant to ATC. The analysis of GEPIA database confirmed high genomic amplification of MMP13 and COL1A1 in TC tissues and showed correlation with TNM stage. Further western blotting analysis showed that MMP13 might be the target of GRP78 in ATC cells and ER stress could activate the expression of MMP13 that was suppressed by the GRP78 depletion.Conclusions: GRP78 acts as an important regulator of metastasis under ER stress. In addition, the function of GRP7 might be mediated by ECM remodeling in ATC cells, implicating it as a therapeutic target in TC.


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