Targeting Ferroptosis in BRAF (V600E) Mutant Anaplastic Thyroid Cancer

项目摘要/摘要 BRAFV600E突变在间变性甲状腺癌(ATC，50%-75%)中很常见，这种癌对 标准的治疗方法，死亡率很高。单用BRAF抑制剂治疗对患者无效 与BRAFV600E-突变体ATC。然而，使用BRAF抑制剂和丝裂原激活的联合治疗 蛋白激酶(MEK)抑制剂比BRAF抑制剂单一治疗更有效，获得性耐药是 常见是因为BRAF和MEK作用于相同的下游靶点和基本相同的途径。一个 对BRAF抑制或BRAF和MEK联合抑制的抗性特征是对 引起铁性下垂的药物(一种依赖于铁的程序性细胞死亡的独特机制)。此外， 已有研究表明，耐药(包括BRAF抑制剂耐药)癌细胞(持久细胞) 与依赖于Gpx4(铁性下垂的把关和抑制因子)的间质状态相关 并表现出对铁性下垂诱导的敏感度增加。我们未公布的初步数据显示，上睑下垂 在BRAFV600E突变体中诱导比野生型ATC细胞和组合BRAF更明显 抑制和诱导铁下垂在引起BRAFV600E突变的ATC细胞死亡方面具有协同作用。 长期目标是开发新的以科学为基础的ATC治疗策略，以改善 病人的结果。该应用的总体目标是确定安全性和临床前治疗。 BRAF抑制剂联合铁下垂诱导治疗BRAFV600E突变ATC的疗效中环 这项建议中的假设是，BRAF抑制剂和铁下垂诱导的联合治疗将有 BRAFV600E突变体ATC的协同/相加抗癌活性这个项目的基本原理是 BRAF抑制诱导铁性下垂的安全性和临床前疗效的测定 为将这一新的联合治疗策略推向临床提供了有力的科学依据。 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 靶向性铁下垂联合BRAF抑制BRAFV600E突变ATC的体外和体内活性 活体；以及2)评估联合应用铁性下垂诱导和抑制BRAF的效果 联合抑制BRAF和MEK。本申请中提出的研究是创新的，在 申请人的意见，因为这与目前只针对英国皇家空军或 BRAFV600E突变体ATC中的单一信号通路与BRAF联合治疗的概念 抑制剂和铁下垂的诱导将导致更强大的和协同/相加的抗癌活性。这个 拟议的研究具有重要意义，因为它有望为未来提供强有力的科学依据 可能为BRAFV600E突变ATCs提供一种新的基于机制的治疗方案的研究 导致持久的反应。归根结底，这种知识有可能为 BRAFV600E突变ATC治疗新策略的研究进展

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 Our unpublished preliminary data show that ferroptosis induction is more pronounced in BRAFV600E-mutant than wild type ATC cells and that combination BRAF inhibition and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.