Metabolic modulation of alkylating agent efficacy in MEK inhibitor resistant thyroid cancers.

MEK 抑制剂耐药性甲状腺癌中烷化剂功效的代谢调节。

基本信息

  • 批准号:
    10512889
  • 负责人:
  • 金额:
    $ 22.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Anaplastic thyroid cancer (ATC) is a lethal entity characterized by frequent mutations in the BRAF oncogene. Until recently there were no treatment options to substantially prolong survival in ATC patients. Unlike BRAFV600E- driven melanomas, thyroid cancers with BRAFV600E mutations are only modestly responsive to targeted kinase inhibitor monotherapy, which emphasizes the significant context dependent differences in the molecular mechanisms that compensate for oncogenic signaling blockade. The recent approval of dual BRAF + MEK inhibition is a critical addition to the arsenal against advanced ATC, with results showing improved tumor control. Despite the initial success of targeted therapies, acquisition of resistance and relapse occur frequently and severely limit complete responses and cures. Such therapy-induced adaptive mechanisms include the rewiring of metabolic pathways that protect from BRAF pathway inhibition, however, it is not known if metabolic alterations occur in ATCs during the evolution of acquired resistance and if they have any potential clinical utility. In preliminary experiments we found that MEK inhibitors induce lipolysis and lipid droplet (LD) loss in ATC cells. LD are dynamic organelles participating in crucial cellular functions including metabolism, protein trafficking, membrane synthesis and signaling. We generated in vitro models of acquired resistance to MEK inhibitors with re-established LD abundance and analyzed their gene expression patterns to identify candidate vulnerabilities that can be pharmacologically targeted with clinically approved therapies. We found that expression of the DNA repair enzyme MGMT was downregulated in LDhigh but not LDlow MEK inhibitor resistant (MEKiR) clones. Here we propose to rigorously evaluate the hypothesis that LD abundance and MGMT expression can serve as biomarkers indicating alkylating agent sensitivity in preclinical models of MEKi resistant thyroid cancers. In aim 1 we will identify metabolic determinants of MGMT expression in MEKiR by uncovering nutritional requirements and epigenetic marks that control MGMT expression and sensitivity to alkylating agents. We will engineer isogenic cell lines with perturbed expression of the rate limiting triglyceride lipase ATGL/PNPLA2 to ask if LD accumulation is necessary or sufficient for MGMT silencing, and will assess if protein- protein interactions regulate ATGL activity in MEKiR. In aim 2 we will quantify the efficacy of alkylating agents in xenotransplanted MEKiR model tumors. Further, we will generate novel in vivo preclinical models of MEKi resistance by intermittent trametinib treatment of tumors in mice, and will validate LD abundance as a biomarker for alkylating agent efficacy by determining tumoral LD turnover, MGMT expression and response to alkylating agent therapy in these tumors.
项目摘要 间变性甲状腺癌(ATC)是一种致命的实体,其特征是BRAF癌基因的频繁突变。 直到最近,还没有治疗方案可以显著延长ATC患者的生存期。与BRAFV 600 E不同- 由于BRAFV 600 E突变导致的黑色素瘤,具有BRAFV 600 E突变的甲状腺癌仅对靶向激酶 抑制剂单药治疗,强调在分子水平上的显著背景依赖性差异, 补偿致癌信号阻断的机制。最近批准的双重BRAF + MEK 抑制是对抗晚期ATC的关键补充,结果显示改善的肿瘤控制。 尽管靶向治疗取得了初步成功,但耐药性的获得和复发频繁发生, 严重限制了完全缓解和治愈。这种治疗诱导的适应性机制包括 然而,目前尚不清楚代谢途径是否可以防止BRAF途径抑制, 在获得性耐药性的演变过程中,如果它们具有任何潜在的临床用途,则在ATC中发生改变。 在初步实验中,我们发现MEK抑制剂诱导ATC细胞中的脂解和脂滴(LD)损失。 LD是参与重要细胞功能的动态细胞器,包括代谢,蛋白质运输, 膜合成和信号传导。我们在体外建立了对MEK抑制剂获得性耐药的模型, 重新建立LD丰度,并分析其基因表达模式,以确定候选漏洞 可以通过临床批准的疗法来靶向治疗。我们发现DNA的表达 修复酶MGMT在LD高而不是LD低MEK抑制剂抗性(MEKiR)克隆中下调。 在这里,我们建议严格评估的假设,LD丰度和MGMT的表达可以服务于 作为指示MEKi抗性甲状腺临床前模型中烷化剂敏感性的生物标志物 癌的在目标1中,我们将通过揭示MEKiR中MGMT表达的代谢决定因素, 营养需求和控制MGMT表达和对烷化剂敏感性的表观遗传标记。 我们将工程化的同基因细胞系与扰动表达的限速甘油三酯脂肪酶 ATGL/PNPLA 2询问LD积累对于MGMT沉默是否是必要的或足够的,并将评估蛋白质- 蛋白质相互作用调节MEKiR中的ATGL活性。在目标2中,我们将量化烷化剂在以下方面的功效: 异种移植的MEKiR模型肿瘤。此外,我们将产生新的MEKi体内临床前模型, 通过间歇性曲美替尼治疗小鼠肿瘤的耐药性,并将验证LD丰度作为生物标志物 通过测定肿瘤LD转换、MGMT表达和对烷化剂的反应, 药物治疗这些肿瘤。

项目成果

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Ioanna Papandreou其他文献

Ioanna Papandreou的其他文献

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{{ truncateString('Ioanna Papandreou', 18)}}的其他基金

Metabolic modulation of alkylating agent efficacy in MEK inhibitor resistant thyroid cancers.
MEK 抑制剂耐药性甲状腺癌中烷化剂功效的代谢调节。
  • 批准号:
    10675021
  • 财政年份:
    2022
  • 资助金额:
    $ 22.09万
  • 项目类别:
HILPDA and lipid metabolism in colorectal cancer
HILPDA 与结直肠癌中的脂质代谢
  • 批准号:
    9000676
  • 财政年份:
    2015
  • 资助金额:
    $ 22.09万
  • 项目类别:

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