Targeting Ferroptosis in BRAF (V600E) Mutant Anaplastic Thyroid Cancer

靶向 BRAF (V600E) 突变型甲状腺未分化癌中的铁死亡

• 批准号: 10721967
• 负责人: Electron Kebebew
• 金额: $ 22.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721967
• 关键词: Advanced Malignant Neoplasm; Apoptosis; BRAF gene; Cancer cell line; Cell Death; Cells; Cessation of life; Clinic; Combined Modality Therapy; Data; Development; Diagnosis; Future; Gatekeeping; Goals; Growth; Human; In Vitro; Incidence; Iron; Knowledge; Lipids; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Malignant Neoplasms; Malignant neoplasm of thyroid; Mesenchymal; Mission; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Mutate; Mutation; Oncoproteins; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peroxidases; Persons; Public Health; Refractory; Research; Resistance; Safety; Science; Signal Induction; Signal Pathway; Testing; Therapeutic; Time; Toxic effect; Translations; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; acquired treatment resistance; anaplastic thyroid cancer; anticancer activity; cancer cell; cancer therapy; cell type; combinatorial; disability; efficacy evaluation; evidence base; improved; in vivo; inhibitor; innovation; melanoma; mortality; mutant; novel; novel therapeutic intervention; pre-clinical; preclinical safety; response; standard care; therapeutic effectiveness; translational framework; treatment strategy

PROJECT SUMMARY/ABSTRACT BRAFV600E mutations are common in anaplastic thyroid cancer (ATC, 50-75% positive), which is refractory to standard treatment and has high mortality rates. Monotherapy with BRAF inhibitors is ineffective in patients with BRAFV600E-mutant ATC. Although, combination therapy using a BRAF inhibitor, and a mitogen-activated protein kinase (MEK) inhibitor is more effective than BRAF inhibitor monotherapy, acquired resistance is common because BRAF and MEK act on the same downstream target and largely the same pathway. A feature of resistance to BRAF inhibition or combined BRAF and MEK inhibition is increased sensitivity to agents that induce ferroptosis (a distinct mechanism of programmed cell death dependent on iron). Moreover, it has been shown that treatment-resistant (including BRAF inhibitor-resistant) cancer cells (persister cells) are associated with a mesenchymal state that is dependent on GPX4 (a gatekeeper and suppressor of ferroptosis) and show increased sensitivity to ferroptosis induction. Our unpublished preliminary data show that ferroptosis induction is more pronounced in BRAFV600E-mutant than wild type ATC cells and that combination BRAF inhibition and ferroptosis induction has synergistic activity in causing cell death in BRAFV600E-mutant ATC cells. The long-term goal is the development of novel science-based treatment strategies for ATC that improve patient outcomes. The overall objective in this application is to determine the safety and preclinical therapeutic efficacy of combined BRAF inhibitor and ferroptosis induction treatment in BRAFV600E-mutant ATC. The central hypothesis in this proposal is that combination therapy with BRAF inhibitor and ferroptosis induction will have synergistic/additive anti-cancer activity in BRAFV600E-mutant ATC. The rationale for this project is that determination of the safety and preclinical therapeutic efficacy of ferroptosis induction with BRAF inhibition is likely to offer a strong scientific basis for translation of this novel combinatorial treatment strategy to the clinic. The central hypothesis will be tested by pursuing two specific aims: 1) Evaluate the safety and anticancer activity of targeting ferroptosis in combination with BRAF inhibition in BRAFV600E-mutant ATC in vitro and in vivo; and 2) Evaluate the efficacy of combined ferroptosis induction and BRAF inhibition compared to combination BRAF and MEK inhibition. The research proposed in this application is innovative, in the applicant’s opinion, as it represents a significant departure from the current strategy of targeting BRAF only or a single signaling pathway in BRAFV600E-mutant ATC to the concept that combined treatment with a BRAF inhibitor and ferroptosis induction will result in more robust and synergistic/additive anticancer activity. The proposed research is significant because it is expected to provide a strong scientific justification for future studies that could provide a new mechanism-based treatment regimen for BRAFV600E-mutant ATCs that could result in durable response. Ultimately, such knowledge has the potential of offering new opportunities for the development of novel therapeutic strategy for BRAFV600E-mutant ATC.

项目总结/摘要 BRAFV600E突变在甲状腺未分化癌（ATC，50 - 75%阳性）中很常见， 标准治疗，死亡率高。BRAF抑制剂单药治疗对患者无效 BRAFV600E突变型ATC。虽然，使用BRAF抑制剂和促分裂原活化的促细胞增殖剂的联合疗法是有效的。 蛋白激酶（MEK）抑制剂比BRAF抑制剂单药治疗更有效，获得性耐药是 这是因为BRAF和MEK作用于相同的下游靶点，并且在很大程度上是相同的途径。一 对BRAF抑制或组合的BRAF和MEK抑制的抗性的特征是对以下的敏感性增加： 诱导铁凋亡（一种依赖于铁的程序性细胞死亡的独特机制）的药物。此外，委员会认为， 已经表明，治疗抗性（包括BRAF受体抗性）癌细胞（持续细胞）是 与依赖GPX 4（铁凋亡的看门人和抑制剂）的间充质状态相关 并显示出对铁凋亡诱导的敏感性增加。我们未发表的初步数据显示， 在BRAFV600 E突变体中诱导比野生型ATC细胞更明显，且组合BRAF 抑制和铁凋亡诱导在引起BRAFV600E突变ATC细胞中的细胞死亡方面具有协同活性。 长期目标是开发新的基于科学的ATC治疗策略， 患者结局。本申请的总体目标是确定安全性和临床前治疗 BRAF抑制剂和铁凋亡诱导联合治疗在BRAFV600E突变型ATC中的功效。中央 该建议中假设是，BRAF抑制剂和铁凋亡诱导的联合治疗将具有 在BRAFV600E-突变ATC中的协同/加和抗癌活性。该项目的基本原理是， 确定BRAF抑制诱导铁凋亡的安全性和临床前治疗效果， 可能为将这种新型组合治疗策略转化为临床提供强有力的科学依据。 将通过追求两个特定目标来检验中心假设：1）评价安全性和抗癌性 在体外和体内BRAFV600E突变ATC中靶向铁凋亡与BRAF抑制的组合的活性 和2）评价组合的铁凋亡诱导和BRAF抑制与对照组相比的功效。 BRAF和MEK抑制的组合。本申请中提出的研究是创新的， 申请人的意见，因为它代表了对当前仅针对BRAF的策略的重大偏离，或 BRAFV600E突变型ATC中的单一信号通路与BRAF联合治疗的概念 抑制剂和铁凋亡诱导将导致更强和协同/加和的抗癌活性。的 拟议的研究是重要的，因为它有望为未来的研究提供强有力的科学依据。 这些研究可以为BRAFV600E突变型ATC提供一种新的基于机制的治疗方案， 产生持久的反应。最终，这种知识有可能为发展中国家提供新的机会。 BRAFV600E突变型ATC的新治疗策略的开发。