Bystander gene deletions in cancer: mechanisms of therapeutic opportunities and challenges

癌症中的旁观者基因缺失:治疗机会和挑战的机制

基本信息

  • 批准号:
    10301007
  • 负责人:
  • 金额:
    $ 43.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT: A status-quo in targeted cancer therapy is that out of the thousands of somatic alterations found in cancer, alterations only in driver genes like oncogenes and tumor suppressors determine therapeutic strategy. For example, cancers with deletion/mutation of the driver tumor suppressor gene PTEN and consequently elevated AKT and mTOR signaling are considered rational candidates for PI3K/AKT/mTOR inhibitor therapy. Accordingly, PI3K/mTOR inhibitors are approved or in clinical trials for various cancers with PTEN/PI3K alterations. However, in glioblastoma (GBM) where PTEN loss of function occurs in over 60% of patients, PI3K/AKT/mTOR inhibitors have been largely ineffective. It is often overlooked that when tumor suppressor genes undergo deletion, nearby genes also undergo inadvertent co-deletion. These bystander genes are not necessarily tumor suppressor genes. In fact, many of them are important for cell growth and survival. In some cases, such bystander deletion events create a unique drug sensitivity specifically in cancer cells. For example, deletion of one of the two alleles of POLR2 (a subunit of RNA polymerase II co- deleted as a bystander to P53 deletion) reduces the amount of POLR2 protein and creates high sensitivity of these cells to low dose POLR2 inhibitors. There are several other such bystander deletion events in cancer that causes vulnerability specifically to cancer cells (e.g., PSMC2 deletion due to chromosome 7q22 loss, Enolase 1 deletion due to loss of 1p36 tumor suppressor locus, MAGOHB deletion as part of chromosome 1p loss, and MTAP co-deletion with the tumor suppressor CDKN2A). Searching the TCGA database we have identified that a crucial lipogenic gene is hemizygously deleted as bystander to the tumor suppressor PTEN (on chromosome 10) in glioblastoma, melanoma and prostate cancer. The fatty acid synthesized by the lipogenic enzyme is also present in our diet. Therefore, when we reduced this fatty acid from diet, inhibition of residual activity of the lipogenic gene with specific inhibitors killed glioblastoma and melanoma cells. This subset (subset 1) ultimately acquired drug resistance through a stress response pathway, and were eliminated by a specific pre-clinical grade inhibitor of the stress pathway. During our analysis, we also surprisingly discovered that this lipogenic gene in completely suppressed in a second GBM subset (subset 2) due to a combination of deletion and methylation. Subset 2 lost a gene that is important for growth and proliferation, and yet thrived, through yet unknown alternative mechanisms. Due to loss of the target lipogenic gene, subset 2 lines were completely resistant to the lipogenic enzyme inhibitor. Investigating the mechanism of survival of subset 2 GBM is outside the scope of this application. In this proposal we will use a repertoire of primary GBM lines and test if deletion and methylation status of the lipogenic gene can be used as biomarkers for inhibitor therapy in combination with a custom medicinal diet. Secondly, we will perform molecular, pharmacokinetic/pharmacodynamic and preclinical studies to address the mechanism of acquired resistance of subset 1 GBM. These tests will be performed in a well-established preclinical mouse model of intracranial glioma.
摘要:靶向癌症治疗的现状是,在癌症中发现的数千种体细胞改变中, 仅癌基因和肿瘤抑制基因等驱动基因的改变决定了治疗策略。例如, 驱动肿瘤抑制基因 PTEN 缺失/突变导致 AKT 和 mTOR 升高的癌症 信号传导被认为是 PI3K/AKT/mTOR 抑制剂治疗的合理候选者。因此,PI3K/mTOR 抑制剂已被批准或正在进行临床试验,用于治疗具有 PTEN/PI3K 改变的各种癌症。然而,在胶质母细胞瘤中 (GBM),超过 60% 的患者发生 PTEN 功能丧失,PI3K/AKT/mTOR 抑制剂已在很大程度上 无效。人们经常忽视的是,当抑癌基因被删除时,附近的基因也会被删除。 无意的共同删除。这些旁观者基因不一定是抑癌基因。事实上,他们中的许多人都是 对于细胞生长和存活很重要。在某些情况下,此类旁观者删除事件会产生独特的药物敏感性 特别是在癌细胞中。例如,POLR2(RNA 聚合酶 II 的一个亚基)的两个等位基因之一的缺失 作为 P53 缺失的旁观者被删除)减少了 POLR2 蛋白的量,并使这些细胞对 低剂量 POLR2 抑制剂。癌症中还有其他几个导致脆弱性的旁观者删除事件 特别针对癌细胞(例如,由于染色体 7q22 丢失而导致 PSMC2 缺失,由于 1p36 丢失而导致烯醇化酶 1 缺失) 抑癌基因座、作为染色体 1p 丢失一部分的 MAGOHB 缺失以及与肿瘤共缺失的 MTAP 抑制器 CDKN2A)。搜索 TCGA 数据库,我们发现一个关键的脂肪生成基因是半合子的 在胶质母细胞瘤、黑色素瘤和前列腺癌中作为肿瘤抑制基因 PTEN(位于 10 号染色体)的旁观者被删除。 由脂肪生成酶合成的脂肪酸也存在于我们的饮食中。因此,当我们减少这种脂肪酸时 通过饮食,用特定抑制剂抑制脂肪生成基因的残余活性,杀死胶质母细胞瘤和黑色素瘤 细胞。该子集(子集 1)最终通过应激反应途径获得耐药性,并通过以下方法消除: 应激途径的特定临床前级抑制剂。在我们的分析过程中,我们还惊奇地发现, 由于缺失和删除的组合,脂肪生成基因在第二个 GBM 子集(子集 2)中完全被抑制 甲基化。亚群 2 失去了一个对生长和增殖很重要的基因,但仍然蓬勃发展,通过未知的方式 替代机制。由于目标脂肪生成基因的丢失,子集 2 品系对脂肪生成完全具有抗性。 酶抑制剂。研究子集 2 GBM 的生存机制不属于本申请的范围。 在本提案中,我们将使用原代 GBM 系的库,并测试脂肪生成细胞系的缺失和甲基化状态是否 基因可以用作抑制剂治疗与定制药物饮食相结合的生物标志物。其次,我们将 进行分子、药代动力学/药效学和临床前研究,以解决获得性耐药的机制 子集 1 GBM 的抵抗力。这些测试将在完善的临床前颅内小鼠模型中进行 神经胶质瘤。

项目成果

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Biplab Dasgupta其他文献

Biplab Dasgupta的其他文献

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{{ truncateString('Biplab Dasgupta', 18)}}的其他基金

ATIC is a novel molecular target in diffuse intrinsic pontine glioma
ATIC是弥漫性内源性脑桥胶质瘤的新型分子靶点
  • 批准号:
    10712984
  • 财政年份:
    2023
  • 资助金额:
    $ 43.24万
  • 项目类别:
Bystander gene deletions in cancer: mechanisms of therapeutic opportunities and challenges
癌症中的旁观者基因缺失:治疗机会和挑战的机制
  • 批准号:
    10062522
  • 财政年份:
    2019
  • 资助金额:
    $ 43.24万
  • 项目类别:
Bystander gene deletions in cancer: mechanisms of therapeutic opportunities and challenges
癌症中的旁观者基因缺失:治疗机会和挑战的机制
  • 批准号:
    10518398
  • 财政年份:
    2019
  • 资助金额:
    $ 43.24万
  • 项目类别:
Biguanide Sensitivity of Glioma Stem Cells
胶质瘤干细胞的双胍敏感性
  • 批准号:
    10057268
  • 财政年份:
    2016
  • 资助金额:
    $ 43.24万
  • 项目类别:
Mechanisms of Biguanide Sensitivity in GBM
GBM 中双胍敏感性的机制
  • 批准号:
    10439389
  • 财政年份:
    2016
  • 资助金额:
    $ 43.24万
  • 项目类别:
Mechanisms of Biguanide Sensitivity in GBM
GBM 中双胍敏感性的机制
  • 批准号:
    10590644
  • 财政年份:
    2016
  • 资助金额:
    $ 43.24万
  • 项目类别:
Regulation of Forebrain Neurogenesis by the Energy Sensor AMP Kinase
能量传感器 AMP 激酶对前脑神经发生的调节
  • 批准号:
    8685351
  • 财政年份:
    2012
  • 资助金额:
    $ 43.24万
  • 项目类别:
Regulation of Forebrain Neurogenesis by the Energy Sensor AMP Kinase
能量传感器 AMP 激酶对前脑神经发生的调节
  • 批准号:
    8468224
  • 财政年份:
    2012
  • 资助金额:
    $ 43.24万
  • 项目类别:
Regulation of Forebrain Neurogenesis by the Energy Sensor AMP Kinase
能量传感器 AMP 激酶对前脑神经发生的调节
  • 批准号:
    9130292
  • 财政年份:
    2012
  • 资助金额:
    $ 43.24万
  • 项目类别:
Regulation of Forebrain Neurogenesis by the Energy Sensor AMP Kinase
能量传感器 AMP 激酶对前脑神经发生的调节
  • 批准号:
    8868186
  • 财政年份:
    2012
  • 资助金额:
    $ 43.24万
  • 项目类别:

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