Elucidating and targeting the molecular foundations of IDH Mutant glioma

阐明和靶向 IDH 突变神经胶质瘤的分子基础

• 批准号: 10168250
• 负责人: Timothy An-thy Chan
• 金额: $ 7.49万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10168250
• 关键词: Elucidating; targeting; molecular; foundations; IDH

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is a primary malignancy of the central nervous system (CNS) that is nearly universally fatal. Our long-term goal is to understand the molecular mechanisms that underlie gliomagenesis and to use this information to develop better therapeutic modalities for GBM patients. Recent work has demonstrated that GBMs consist of several subgroups, each driven by different genetic alterations. The proneural subgroup of GBMs is a distinct class that includes tumors with isocitrate dehydrogenase (IDH) 1 and 2 mutation, PDGF pathway activation, and the glioma hypermethylator phenotype (G-CIMP). These alterations are potentially reversible and hold great promise as potential targets. However, the mechanisms of action underlying mutant IDH-mediated transformation remain unclear. Recently, our groups have shown that IDH mutation functions by remodeling the epigenome to establish G-CIMP and institute a block to differentiation. The central hypothesis of this application is that mutant IDH-induced epigenomic changes are critical events underlying the development of this subset of GBMs. The objective of this proposal is to understand the molecular foundations of mutant IDH-induced gliomagenesis and to evaluate the utility of targeting this alteration by pursuing 3 Specific Aims. In Aim 1, we will elucidate the chromatin state dynamics underlying mutant IDH1- associated epigenetic reprogramming. The working hypothesis here is that IDH mutation acts by remodeling the epigenome and blocking differentiation, an effect that may be reversible. We will systematically elucidate the details of IDH1 mutation-induced chromatin state changes globally and at the level of individual effector genes. We will interrogate the reversibility of mutant IDH-induced effects. In Aim 2, we will characterize oncogenic cooperativity between IDH1 mutation and IDH1 mutation-associated genetic alterations. Our data indicates that mutant IDH1 acts by promoting a dedifferentiated state, but does not transform cells alone. Our hypothesis here is that IDH1 mutation cooperates with other recurring genetic lesions to achieve transformation. We will define the tenants of this oncogenic context. We will investigate the ability of associated lesions to cooperate with mutant IDH1 in transformation using human astrocytes and the murine RCAS-TVA system. In Aim 3, we will optimize targeting of mutant IDH1-dependent biological alterations with epigenetic therapy. Since IDH-induced changes are in principle reversible, we hypothesize that the effects of mutant IDH1 can be reversed using targeted small molecules, which will then enable tissue-specific factors to drive differentiation. Inhibition of mutant IDH1 alone using a mutant IDH1 inhibitor (AGI-5198) blocks 2-HG production but affects tumor growth only modestly. In contrast, DNMT and H3K9 methylase inhibitors (DAC, BIX) directly reverse pathologic methylation and are very potent against IDH mutant cells. We will use these two approaches to optimize a therapeutic strategy. Using both in vitro and mouse models, we will use DNA/ histone methylation inhibitors, alone and in combination with AGI-5198, to reverse the effects of mutant IDH1.

描述（由申请方提供）：胶质母细胞瘤（GBM）是中枢神经系统（CNS）的原发性恶性肿瘤，几乎普遍具有致死性。我们的长期目标是了解胶质瘤形成的分子机制，并利用这些信息为GBM患者开发更好的治疗方法。最近的研究表明，GBM由几个亚组组成，每个亚组由不同的遗传改变驱动。GBM的前神经亚组是一个独特的类别，包括具有异柠檬酸脱氢酶（IDH）1和2突变、PDGF通路激活和胶质瘤高甲基化表型（G-CIMP）的肿瘤。这些改变可能是可逆的，并且作为潜在靶点具有很大的希望。然而，突变IDH介导的转化的作用机制仍不清楚。最近，我们的研究小组已经表明，IDH突变通过重塑表观基因组来建立G-CIMP并阻止分化。本申请的中心假设是突变IDH诱导的表观基因组变化是GBM这一子集发展的关键事件。本提案的目的是了解突变型IDH诱导的胶质瘤发生的分子基础，并通过追求3个特定目标来评估靶向这种改变的效用。在目标1中，我们将阐明突变IDH 1相关的表观遗传重编程背后的染色质状态动力学。这里的工作假设是IDH突变通过重塑表观基因组和阻断分化起作用，这种作用可能是可逆的。我们将系统地阐明IDH 1突变诱导的染色质状态变化的细节全球和在个别效应基因的水平。我们将询问突变IDH诱导效应的可逆性。在目标2中，我们将描述IDH 1突变和IDH 1突变相关遗传改变之间的致癌协同性。我们的数据表明，突变IDH 1通过促进去分化状态发挥作用，但不会单独转化细胞。我们的假设是IDH 1突变与其他复发性遗传病变合作实现转化。我们将定义这种致癌背景的租户。我们将使用人星形胶质细胞和鼠RCAS-TVA系统研究相关病变与突变IDH 1在转化中合作的能力。在目标3中，我们将优化靶向突变IDH 1依赖性生物学改变与表观遗传疗法。由于IDH诱导的变化原则上是可逆的，我们假设突变IDH 1的作用可以使用靶向小分子逆转，这将使组织特异性因子能够驱动分化。使用突变IDH 1抑制剂（AGI-5198）单独抑制突变IDH 1阻断2-HG产生，但仅适度影响肿瘤生长。相反，DNMT和H3 K9甲基化酶抑制剂（DAC，BIX）直接逆转病理性甲基化，并且对IDH突变细胞非常有效。我们将使用这两种方法来优化治疗策略。使用体外和小鼠模型，我们将使用DNA/组蛋白甲基化抑制剂，单独和与AGI-5198组合，以逆转突变IDH 1的影响。

项目成果

ChemoSensitivity Assay Guided Metronomic Chemotherapy Is Safe and Effective for Treating Advanced Pancreatic Cancer.

• DOI: 10.3390/cancers14122906
• 发表时间: 2022-06-13
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Isacoff, William H.;Cooper, Brandon;Bartlett, Andrew;McCarthy, Brian;Yu, Kenneth H.
• 通讯作者: Yu, Kenneth H.

In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors.

• DOI: 10.1016/j.cmet.2017.10.001
• 发表时间: 2017-12-05
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Salamanca-Cardona L;Shah H;Poot AJ;Correa FM;Di Gialleonardo V;Lui H;Miloushev VZ;Granlund KL;Tee SS;Cross JR;Thompson CB;Keshari KR
• 通讯作者: Keshari KR

Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling.

• DOI: 10.1038/s41467-018-03476-6
• 发表时间: 2018-03-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Danussi C;Bose P;Parthasarathy PT;Silberman PC;Van Arnam JS;Vitucci M;Tang OY;Heguy A;Wang Y;Chan TA;Riggins GJ;Sulman EP;Lang FF;Creighton CJ;Deneen B;Miller CR;Picketts DJ;Kannan K;Huse JT
• 通讯作者: Huse JT

Integrated genomic characterization of IDH1-mutant glioma malignant progression.

• DOI: 10.1038/ng.3457
• 发表时间: 2016-01
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Bai H;Harmancı AS;Erson-Omay EZ;Li J;Coşkun S;Simon M;Krischek B;Özduman K;Omay SB;Sorensen EA;Turcan Ş;Bakırcığlu M;Carrión-Grant G;Murray PB;Clark VE;Ercan-Sencicek AG;Knight J;Sencar L;Altınok S;Kaulen LD;Gülez B;Timmer M;Schramm J;Mishra-Gorur K;Henegariu O;Moliterno J;Louvi A;Chan TA;Tannheimer SL;Pamir MN;Vortmeyer AO;Bilguvar K;Yasuno K;Günel M
• 通讯作者: Günel M