Anaplastic thyroid cancer (ATC) is an almost invariable lethal cancer in humans.
Most patients present with a rapid progressive mass in the neck with progressive complaints like dyspnoea, dysphagia or pain. The risk of suffocation is the main reason for rapid surgical intervention, but we know from literature that an oncological resection with clear margins is seldomly achieved. Some patients deteriorate that fast after surgery that radiation therapy and/or chemotherapy is not feasible anymore. Patients with BRAF-mutated ATC already have shown to benefit from targeted BRAF/MEK inhibition. This study aims to increase the number of patients that undergo a successful R0 tumor resection after neo-adjuvant BRAF/MEK inhibitor treatment.

开始日期2023-01-01

申办/合作机构

Academisch Ziekenhuis Leiden

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NCT04675710 / Recruiting临床2期IIT

Pembrolizumab in Combination With Dabrafenib and Trametinib as a Neoadjuvant Strategy Prior to Surgery in BRAF-Mutated Anaplastic Thyroid Cancer

This phase II trial studies the effect of pembrolizumab, dabrafenib, and trametinib before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer. BRAF V600E is a specific mutation (change) in the BRAF gene, which makes a protein that is involved in sending signals in cells and in cell growth. It may increase the growth and spread of tumor cells. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pembrolizumab, dabrafenib, and trametinib may help to control BRAF V600E-mutated anaplastic thyroid cancer when given before surgery.

开始日期2021-06-24

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT03975231 / Recruiting临床1期IIT

A Phase I Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic Thyroid Cancer

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

开始日期2020-09-14

申办/合作机构

City of Hope National Medical Center

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100 项与 BRAF突变的甲状腺未分化癌相关的临床结果

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100 项与 BRAF突变的甲状腺未分化癌相关的转化医学

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0 项与 BRAF突变的甲状腺未分化癌相关的专利（医药）

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项与 BRAF突变的甲状腺未分化癌相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors

Article

作者: Yuan, Mengmeng ; Hou, Peng ; Sui, Fang ; Chen, Pu ; Liu, Juan ; Yao, Yao ; Zhang, Shaoqiang ; Ji, Meiju ; Wang, Guanjie

AbstractBRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.

2022-09-01·Cellular and Molecular Life Sciences

Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer

Article

作者: Morante, Marta ; Riesco-Eizaguirre, Garcilaso ; Zaballos, Miguel A ; Acuña-Ruiz, Adrián ; Crespo, Piero ; Santisteban, Pilar

AbstractBackgroundRAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo.MethodsWe used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efficacy in an orthotopic mouse model of ATC.ResultsDEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasis-related processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions.ConclusionsOur findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.

2022-08-01·Pharmacology & Therapeutics

“RB-reactivator screening” as a novel cell-based assay for discoveries of molecular targeting agents including the first-in-class MEK inhibitor trametinib (trade name: Mekinist)

Review

作者: Sakai, Toshiyuki

The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.