Efficacy of a Selective MEK (Trametinib) and BRAFV600E (Dabrafenib) Inhibitors Associated With Radioactive Iodine (RAI) for the Treatment of Refractory Metastatic Differentiated Thyroid Cancer With RAS or BRAFV600E Mutation

This is a multicentric prospective non-randomized phase II trial, with two independent arms: one for patients with RAS mutation and one for patients with BRAFV600E mutation.

开始日期2017-12-27

申办/合作机构

Institut Gustave Roussy EURL

NCT01723202 / Active, not recruiting临床2期IIT

A Randomized Phase 2 Study of Single Agent Dabrafenib (BRAFi) vs. Combination Regimen Dabrafenib (BRAFi) and Trametinib (MEKi) in Patients With BRAF Mutated Thyroid Carcinoma

This randomized phase II trial studies how well dabrafenib works with or without trametinib in treating patients with recurrent thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether dabrafenib is more effective when given with or without trametinib in treating thyroid cancer

开始日期2012-11-07

申办/合作机构

Ohio State University Comprehensive Cancer Center

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100 项与 BRAF突变甲状腺癌相关的临床结果

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100 项与 BRAF突变甲状腺癌相关的转化医学

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0 项与 BRAF突变甲状腺癌相关的专利（医药）

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项与 BRAF突变甲状腺癌相关的文献（医药）

2024-12-31·Cancer Biology & Therapy

The effects of Aurora Kinase inhibition on thyroid cancer growth and sensitivity to MAPK-directed therapies

Article

作者: Rose, Madison M ; Nassar, Veronica L ; Lund, Jane ; Hicks, Hannah M ; Schweppe, Rebecca E

Thyroid cancer is one of the deadliest endocrine cancers, and its incidence has been increasing. While mutations in BRAF are common in thyroid cancer, advanced PTC patients currently lack therapeutic options targeting the MAPK pathway, and despite the approved combination of BRAF and MEK1/2 inhibition for BRAF-mutant ATC, resistance often occurs. Here, we assess growth and signaling responses to combined BRAF and MEK1/2 inhibition in a panel of BRAF-mutant thyroid cancer cell lines. We first showed that combined BRAF and MEK1/2 inhibition synergistically inhibits cell growth in four out of six of the -BRAF-mutant thyroid cancer cell lines tested. Western blotting showed that the MAPK pathway was robustly inhibited in all cell lines. Therefore, to identify potential mechanisms of resistance, we performed RNA-sequencing in cells sensitive or resistant to MEK1/2 inhibition. In response to MEK1/2 inhibition, we identified a downregulation of Aurora Kinase B (AURKB) in sensitive but not resistant cells. We further demonstrated that combined MEK1/2 and AURKB inhibition slowed cell growth, which was phenocopied by inhibiting AURKB and ERK1/2. Finally, we show that combined AURKB and ERK1/2 inhibition induces apoptosis in BRAF-mutant thyroid cancer cell lines, together suggesting a potential combination therapy for BRAF-mutant thyroid cancer patients.

2024-07-01·Journal for ImmunoTherapy of Cancer

Exploring markers of immunoresponsiveness in papillary thyroid carcinoma and future treatment strategies

Article

作者: Gernon, Thomas ; Do, Dana ; Reyes, Amanda ; Li, Haiqing ; Bell, Diana ; Maghami, Ellie ; Villaflor, Vicky ; Sampath, Sagus ; Kang, Robert ; Yin, Holly ; Massarelli, Erminia ; Mohanty, Atish ; Afkhami, Michelle ; Pillai, Raju ; Kulkarni, Prakash ; Chang, Sue ; Amini, Arya ; Salgia, Ravi ; Pharaon, Rebecca ; Nam, Arin

BackgroundThe study summarizes the potential use of immunotherapy forBRAF-mutated papillary thyroid cancer (PTC) by analyzing the immune profile of City of Hope PTC patient samples and comparing them to the thyroid dataset available in the TCGA database.Materials and methodsPTC cases with available formalin-fixed paraffin-embedded archived tumor tissue were identified. RNA was extracted from the tumor tissue and analyzed by NanoString to evaluate their immune gene expression profile. Immunohistochemistry was used to determine the expression of immune suppressive genes and lymphocytic infiltration into the tumor tissue. Thyroid cancer cell lines (MDA-T32, MDA-T68, MDA-T85, and MDA-T120) were used to determine the correlation between the BRAF inhibition and CD274 expression.ResultsThe study found that PTC cases withBRAFmutations had higher expression of immune checkpoint markers CD274 and CTLA4, as well as higher tumor-infiltrating lymphocytes, particularly CD4+T cells. Additionally, the study identified immunosuppressive markers expressed by tumor cells like CD73, CD276, and CD200 that could be targeted for immunotherapy. Further experiments using PTC cell lines lead to the conclusion that CD274 expression correlates withBRAFactivity and that inhibitors ofBRAFcould potentially be used in combination with immunotherapy to treat PTC.ConclusionsThese findings suggest that PTC cases withBRAFmutations or high expression may be correlated with an immune hot signature and could benefit from immunotherapeutic strategies.

2024-05-01·Clinical and Translational Medicine

Targeting miR‐31 represses tumourigenesis and dedifferentiation of BRAF^V600E‐associated thyroid carcinoma

Article

作者: Zhang, Peitao ; Zhao, Li ; Yuan, Shukai ; Yu, Zhengquan ; Du, Yaying ; Li, Xingrui ; Sun, Wei ; Cao, Xiaolong ; Zhang, Yu ; Jia, Qiang ; Guan, Lizhao ; Zheng, Xiangqian ; Meng, Zhaowei

AbstractBackgroundBRAFV600E is the most common genetic mutation in differentiated thyroid cancer (DTC) occurring in 60% of patients and drives malignant tumour cell phenotypes including proliferation, metastasis and immune‐escape. BRAFV600E‐mutated papillary thyroid cancer (PTC) also displays greatly reduced expression of thyroid differentiation markers, thus tendency to radioactive iodine (RAI) refractory and poor prognosis. Therefore, understanding the molecular mechanisms and main oncogenic events underlying BRAFV600E will guide future therapy development.MethodsBioinformatics and clinical specimen analyses, genetic manipulation of BRAFV600E‐induced PTC model, functional and mechanism exploration guided with transcriptomic screening, as well as systematic rescue experiments were applied to investigate miR‐31 function within BRAFV600E‐induced thyroid cancer development. Besides, nanoparticles carrying miR‐31 antagomirs were testified to alleviate 131I iodide therapy on PTC models.ResultsWe identify miR‐31 as a significantly increased onco‐miR in BRAFV600E‐associated PTC that promotes tumour progression, metastasis and RAI refractoriness via sustained Wnt/β‐catenin signalling. Mechanistically, highly activated BRAF/MAPK pathway induces miR‐31 expression via c‐Jun‐mediated transcriptional regulation across in vitro and transgenic mouse models. MiR‐31 in turn facilitates β‐catenin stabilisation via directly repressing tumour suppressors CEBPA and DACH1, which direct the expression of multiple essential Wnt/β‐catenin pathway inhibitors. Genetic functional assays showed that thyroid‐specific knockout of miR‐31 inhibited BRAFV600E‐induced PTC progression, and strikingly, enhanced expression of sodium‐iodide symporter and other thyroid differentiation markers, thus promoted 131I uptake. Nanoparticle‐mediated application of anti‐miR‐31 antagomirs markedly elevated radio‐sensitivity of BRAFV600E‐induced PTC tumours to 131I therapy, and efficiently suppressed tumour progression in the pre‐clinical mouse model.ConclusionsOur findings elucidate a novel BRAF/MAPK‐miR‐31‐Wnt/β‐catenin regulatory mechanism underlying clinically BRAFV600E‐associated DTC tumourigenesis and dedifferentiation, also highlight a potential adjuvant therapeutic strategy for advanced DTC.