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:癌症靶向治疗的现状是,在癌症中发现的数千种体细胞改变中, 仅在驱动基因如癌基因和肿瘤抑制基因中的改变决定治疗策略。比如说, 具有驱动肿瘤抑制基因PTEN的缺失/突变并因此升高的AKT和mTOR的癌症 认为PI 3 K/AKT/mTOR抑制剂疗法的合理候选物。PI3K/mTOR 抑制剂已被批准或用于具有PTEN/PI 3 K改变的各种癌症的临床试验中。然而,在胶质母细胞瘤中, (GBM)在超过60%的患者中发生PTEN功能丧失的情况下,PI 3 K/AKT/mTOR抑制剂已经在很大程度上被用于 无效。人们常常忽视的是,当肿瘤抑制基因发生缺失时,附近的基因也发生缺失。 无意的共缺失。这些旁观者基因不一定是肿瘤抑制基因。事实上,他们中的许多人都是 对细胞生长和存活很重要。在某些情况下,这种旁观者缺失事件会产生独特的药物敏感性, 尤其是癌细胞。例如,缺失POLR 2的两个等位基因之一(RNA聚合酶II的亚基共 作为P53缺失的旁观者缺失)减少了POLR 2蛋白的量,并使这些细胞对 低剂量POLR 2抑制剂。在癌症中还有其他几个这样的旁观者缺失事件导致脆弱性 特异性针对癌细胞(例如,染色体7 q22缺失导致PSMC 2缺失,1 p36缺失导致烯醇化酶1缺失 肿瘤抑制基因座,MAGOHB缺失作为染色体1 p缺失的一部分,MTAP与肿瘤共缺失 抑制基因CDKN 2A)。检索TCGA数据库,我们已经确定了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因子PTEN(在10号染色体上)的旁观者而缺失。 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 从饮食中,用特异性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。 细胞这一亚群(亚群1)最终通过应激反应途径获得耐药性,并通过 应激途径的特异性临床前级抑制剂。在我们分析的过程中,我们还惊奇地发现, 在第二GBM亚组(亚组2)中,由于缺失和缺失的组合,脂肪生成基因被完全抑制。 甲基化亚群2失去了一个对生长和增殖很重要的基因,但通过未知的途径, 替代机制。由于靶脂肪生成基因的丢失,亚组2系对脂肪生成基因完全抗性。 酶抑制剂研究亚组2 GBM的存活机制不在本申请的范围内。 在这个建议中,我们将使用一个原始GBM系的库,并测试脂肪生成基因的缺失和甲基化状态是否与GBM系的基因组序列一致。 基因可用作与定制药物饮食组合的抑制剂疗法的生物标志物。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 子集1 GBM的耐药性。这些试验将在完善的颅内肿瘤临床前小鼠模型中进行。 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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