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：
10518398
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/10518398
关键词：
1p36 Ablation Acids Address Algorithms Alleles Analytical Chemistry Atlases Biological Availability Biological Markers Biology 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 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 Medicine Melanoma Cell Membrane Fluidity Messenger RNA Methods Methylation Molecular Monounsaturated Fatty Acids Mus Mutation Oleates Oleic Acids Oncogenes Oral PI3K/AKT PIK3CG gene PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacology Plant Oils Point Mutation Proliferating 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 blood-brain barrier crossing 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：靶向癌症治疗中的一种现状是，在癌症中发现的数千种体细胞改变中，仅在癌症基因和肿瘤抑制剂等驱动基因中的改变决定了治疗策略。例如，具有驱动肿瘤抑制基因PTEN的缺失/突变的癌症，因此升高了Akt和MTOR 信号传导被认为是PI3K/AKT/MTOR抑制剂治疗的有理候选者。因此，pi3k/mtor 抑制剂已批准或在临床试验中针对PTEN/PI3K改变的各种癌症。但是，在胶质母细胞瘤中（GBM）如果超过60％的患者发生PTEN功能丧失，则PI3K/AKT/MTOR抑制剂已在很大程度上是无效。经常忽略的是，当肿瘤抑制基因经历缺失时，附近的基因也会经历无意的共同删除。这些旁观者基因不一定是肿瘤抑制基因。实际上，其中许多是对于细胞生长和生存至关重要。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，删除POLR2的两个等位基因之一（RNA聚合酶II的亚基被删除为旁观者p53删除）减少了polr2蛋白的量，并产生这些细胞对低剂量POLR2抑制剂。癌症中还有其他几种旁观者删除事件会导致脆弱性特别针对癌细胞（例如，由于7q22染色体损失，烯醇酶1删除造成的pSMC2缺失，损失1p36 肿瘤抑制基因座，MagOHB缺失是染色体1p损失的一部分，并与肿瘤共同删除抑制器CDKN2A）。搜索TCGA数据库，我们已经确定了关键的脂肪生成基因是半齐的被删除为胶质母细胞瘤，黑色素瘤和前列腺癌的肿瘤抑制剂PTEN（染色体10）的旁观者。我们的饮食中也存在由脂肪生成酶合成的脂肪酸。因此，当我们减少这种脂肪酸时从饮食中，用特异性抑制剂抑制脂肪生成基因的残留活性杀死胶质母细胞瘤和黑色素瘤细胞。该子集（子集1）最终通过应力反应途径获得了耐药性，并被应力途径的特定临床前级抑制剂。在分析过程中，我们还出人意料地发现由于缺失和甲基化。子集2失去了一个对生长和增殖很重要的基因替代机制。由于靶脂基因的丧失，子集2线完全抵抗脂肪生成酶抑制剂。研究子集2 GBM生存的机制不在该应用程序的范围之内。在此提案中，我们将使用主要GBM线的曲目，并测试脂肪生成的缺失和甲基化状态基因可以用作抑制剂疗法的生物标志物与自定义药用饮食结合使用。其次，我们会的进行分子，药代动力学/药效和临床前研究，以解决获得的机制子集1 GBM的电阻。这些测试将在颅内良好的临床前小鼠模型中进行神经胶质瘤。