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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：
Biplab Dasgupta
金额：
$ 43.24万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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

来源：
https://reporter.nih.gov/project-details/10301007
关键词：
1p36 Ablation Address Algorithms Alleles Analytical Chemistry Atlases Biological Markers Biology Blood - brain barrier anatomy Brain Mass Brain Neoplasms CDKN2A gene CRISPR/Cas technology Cancer Etiology Cell Line Cell Survival Cells Chromosome 10 Chromosomes Classification Clinical Trials Collaborations Combined Modality Therapy Culture Media Custom Data Data Analyses Data Set Databases Deletion Mutation Diet Diet Research Diet therapy Dietary Component Dose Down-Regulation Environmental Risk Factor Enzyme Inhibitor Drugs Enzymes Epidermal Growth Factor Receptor Etiology Event FRAP1 gene Fatty Acids Feasibility Studies Gene Deletion Genes Genetic Glioblastoma Glioma Goals Growth Human Hypersensitivity Lesion Lipids Malignant Neoplasms Malignant neoplasm of prostate Maximum Tolerated Dose Melanoma Cell Membrane Fluidity Messenger RNA Methods Methylation Molecular Monounsaturated Fatty Acids Mus Mutation Oleates Oleic Acids Oral PI3K/AKT PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacology Plant Oils Point Mutation Proteins Proto-Oncogene Proteins c-akt RNA Polymerase II Reducing diet Refractory Regimen Research Residual state Resistance Resistance development Signal Transduction Specificity Stearoyl-CoA Desaturase Stress Subgroup TP53 gene Testing The Cancer Genome Atlas Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation Validation acquired drug resistance biological adaptation to stress cancer cell cell growth chromosome 1p loss classification trees dietary driver mutation drug sensitivity efficacy evaluation endoplasmic reticulum stress enolase experience experimental study in vivo inhibitor inhibitor therapy insight loss of function mTOR Inhibitor melanoma metabolomics mouse model novel novel therapeutics overexpression pharmacokinetics and pharmacodynamics pre-clinical preclinical study regression trees statistics stem cells targeted cancer therapy treatment response tumor tumor growth validation studies

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。