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.

项目概要/摘要 BRAFV600E 突变在甲状腺未分化癌（ATC，50-75% 阳性）中很常见，这种突变对甲状腺癌是难治性的。 治疗标准高，死亡率高。 BRAF抑制剂单一疗法对患者无效 带有 BRAFV600E 突变型 ATC。虽然，使用 BRAF 抑制剂和促细胞分裂原激活剂的联合治疗 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 常见的原因是 BRAF 和 MEK 作用于相同的下游靶标并且基本上是相同的途径。一个 对 BRAF 抑制或 BRAF 和 MEK 联合抑制的抗性特征是对 诱导铁死亡（一种依赖于铁的程序性细胞死亡的独特机制）的药物。而且， 研究表明，治疗耐药（包括 BRAF 抑制剂耐药）的癌细胞（持久性细胞） 与依赖 GPX4（铁死亡的看门人和抑制因子）的间充质状态相关 并表现出对铁死亡诱导的敏感性增加。我们未发表的初步数据表明铁死亡 BRAFV600E 突变体中的诱导作用比野生型 ATC 细胞更明显，并且 BRAF 组合 抑制和铁死亡诱导在导致 BRAFV600E 突变 ATC 细胞中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，以改善 ATC 患者的结果。本申请的总体目标是确定安全性和临床前治疗 BRAF 抑制剂和铁死亡诱导联合治疗对 BRAFV600E 突变型 ATC 的疗效。中央 该提案中的假设是 BRAF 抑制剂和铁死亡诱导的联合治疗将具有 BRAFV600E 突变体 ATC 的协同/累加抗癌活性。该项目的理由是 确定 BRAF 抑制诱导铁死亡的安全性和临床前治疗效果 可能为将这种新颖的组合治疗策略转化为临床提供强有力的科学基础。 中心假设将通过追求两个具体目标来检验：1）评估安全性和抗癌性 BRAFV600E突变体ATC中靶向铁死亡与BRAF抑制相结合的体外和体内活性 体内； 2) 评估铁死亡诱导和 BRAF 抑制相结合的功效 BRAF 和 MEK 联合抑制。本申请提出的研究具有创新性， 申请人的意见，因为它与当前仅针对 BRAF 的策略存在重大背离，或者 BRAFV600E 突变 ATC 中的单一信号通路与 BRAF 联合治疗的概念 抑制剂和铁死亡诱导将导致更强大和协同/相加的抗癌活性。这 拟议的研究意义重大，因为预计它将为未来提供强有力的科学依据 研究可为 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，这些知识有可能为人们提供新的机会 开发针对 BRAFV600E 突变 ATC 的新治疗策略。