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Project description:Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC
2022-09-19 | GSE137697 | GEO
Project description:Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC
2022-09-19 | GSE137696 | GEO
Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma
| PRJNA566339 | ENA
Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [RNA-seq]
| PRJNA566341 | ENA
Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [ChIP-seq]
| PRJNA566340 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-07-07 | GSE126729 | GEO
Project description:Anaplastic thyroid carcinoma (ATC) is a rare and undifferentiated form of thyroid cancer. Its prognosis is poor: the median overall survival (OS) of patients varies from 4 to 10 months after diagnosis. However, a doubling of the OS time may be possible owing to a more systematic use of molecular tests for targeted therapies and integration of fast-track dedicated care pathways for these patients in tertiary centers. The diagnostic confirmation, if needed, requires an urgent biopsy reread by an expert pathologist with additional immunohistochemical and molecular analyses. Therapeutic management, defined in multidisciplinary meetings, respecting the patient's choice, must start within days following diagnosis. For localized disease diagnosed after primary surgical treatment, adjuvant chemo-radiotherapy is recommended. In the event of locally advanced or metastatic disease, the prognosis is very poor. Treatment should then involve chemotherapy or targeted therapy and decompressive cervical radiotherapy. Here we will review current knowledge on ATC and provide perspectives to improve the management of this deadly disease.
| S-EPMC8869821 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-08-13 | E-GEOD-72031 | biostudies-arrayexpress
Project description:Ubiquitin-specific protease 22 (USP22) aberrance has been implicated in several malignancies; however, whether USP22 plays a role in anaplastic thyroid carcinoma (ATC) remains unclear. Here, we report that USP22 expression is highly elevated in ATC tissues, which positively correlated with tumor size, extracapsular invasion, clinical stages, and poor prognosis of ATC patients. In vitro assays showed that USP22 depletion suppressed ATC cell survival and proliferation by decreasing Rb phosphorylation and cyclin D2, inactivating Akt, and simultaneously upregulating Rb; USP22 silencing restrained cell migration and invasion by inhibiting epithelial-mesenchymal transition; USP22 knockdown promoted mitochondrion- mediated and caspase-dependent apoptosis by upregulating Bax and Bid and promoting caspase-3 activation. Consistent with in vitro findings, downregulation of USP22 in ATC cells impeded tumor growth and lung metastasis in vivo. These results raise the applicability for USP22 as a useful predictor of ATC prognosis and a potential therapeutic target for ATC.
| S-EPMC5058749 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and it is less than 2% of thyroid carcinomas (TCs). The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated external beam radiation therapy (EBRT), and chemotherapy, in particular with cisplatin or doxorubicin, achieving about 10 months of median survival. Since ATC is a rare and aggressive tumor, it is still challenging to predict the patient clinical therapy responsiveness. Several genetic mutations have been described in ATC, involved in different molecular pathways linked to tumor progression, and novel therapies acting on these molecular pathways have been investigated, to improve the quality of life in these patients. Here we review the new targeted therapy of ATC. We report interesting results obtained with molecules targeting different pathways: angiogenesis (vandetanib, combretastatin, sorafenib, lenvatinib, sunitinib, CLM94, CLM3, etc.); EGFR (gefitinib, docetaxel); BRAF (dabrafenib/trametinib, vemurafenib); PPARγ agonists (rosiglitazone, pioglitazone, efatutazone); PD-1 and PD-L1 (pembrolizumab); TERT. To escape resistance to monotherapies, the evaluation of combination strategies with radiotherapy, chemotherapy, or targeted drugs is ongoing. The results of clinical trials with dabrafenib and trametinib led to the approval from FDA of this combination for patients with BRAF V600E mutated ATC with locally advanced, unresectable, or metastatic ATC. The anti-PD-L1 antibody immunotherapy, alone or combined with a BRAF inhibitor, has been shown also promising in the treatment of ATC. Furthermore, to increase the therapeutic success and not to use ineffective or even harmful treatments, a real tailored therapy should be pursued, and this can be achieved thanks to the new available genomic analysis methods and to the possibility to test in vitro novel treatments directly in primary cells from each ATC patient. Exploring new treatment strategies is mandatory to improve the survival of these patients, guaranteeing a good quality of life.
| S-EPMC6995904 | biostudies-literature