Project 2: Defining and exploiting genetic dependencies in complex karyotype AML

项目 2：定义和利用复杂核型 AML 中的遗传依赖性

基本信息

批准号：
10474281
负责人：
SCOTT W. LOWE
金额：
$ 36.77万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-24 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474281
关键词：
17p Acute Myelocytic Leukemia Address Animal Model Antitumor Response Biological Cancer Model Cell Line Cessation of life Chemoresistance Chromatin Chromosome abnormality Chromosomes Clinical Clinical Trials Collaborations Complex Cytogenetic Analysis Data Deletion Mutation Dependence Development Diagnosis Disease Disease model Drug Targeting Enzymes Epigenetic Process Event FLT3 gene Face Frequencies Gene Expression Genetic Genetic Models Genetic Transcription Genetically Engineered Mouse Genome Genomics Genotype Human JAK2 gene Karyotype Karyotype determination procedure Ketoglutarate Dehydrogenase Complex Malignant Neoplasms Memorial Sloan-Kettering Cancer Center Metabolism Methods Modeling Molecular Mutation Mutation Analysis Oncogenes Oncogenic Oncoproteins Outcome Pathogenesis Patient-Focused Outcomes Patients Pharmacology Pre-Clinical Model Prognosis Proteins Recurrence Research Research Personnel Resistance Resolution Resources Safety Sampling Solid Specimen Study models System TP53 gene Testing Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Work actionable mutation acute myeloid leukemia cell antileukemic activity candidate validation chemotherapy chromosome 5q loss cohort cost diagnostic accuracy digital effective therapy exhaustion human disease human model improved inhibitor innovation insight leukemia mouse model mutant new therapeutic target next generation sequencing novel novel therapeutic intervention novel therapeutics patient derived xenograft model pre-clinical preclinical study programs self-renewal small molecule inhibitor therapeutic development therapeutic target therapeutically effective tool transcriptome transcriptome sequencing tumor tumorigenic whole genome

项目摘要

ABSTRACT Complex karyotype acute myeloid leukemia (CK AML) is defined by the presence of 3 or more detectable cytogenetic abnormalities and has one of the least favorable prognoses of any leukemia genotype. Genomic characterization indicates that this disease lacks conventional druggable oncoproteins, but instead is characterized by a set of recurrent segmental deletions and mutations in the TP53 tumor suppressor gene, the latter of which are absent from normal karyotype AML and confer resistance to standard chemotherapies. To better characterize the pathogenesis of CK AML and to develop new strategies to treat this disease, we will exhaustively analyze the genomes of a large cohort of CK AML samples using a new low-cost, high-resolution platform optimized in our group called “digital karyotyping”. These molecular features will be correlated with patient outcomes data, and used to generate murine and human models that accurately recapitulate CK AML- specific features. We will use these models to test a new therapeutic strategy for countering the pro-tumorigenic effects of p53 loss. This concept builds on preliminary data showing that p53 loss can perturb cellular metabolism in a manner that alters gene expression and drives aberrant self-renewal, and that reversing these effects with small molecule inhibitors can drive differentiation of p53-deficient AML. Specifically, we have found that p53 mutations reduce levels of the metabolite aKG, producing similar effects of oncogenic IDH1/2 mutant proteins that have proven to be drug targets in other sub-types of AML. In models studied to date, the tumor suppressive effects of p53 are recapitulated by inhibiting the TCA enzyme 2-oxoglutarate dehydrogenase (OGDH) and, as such, we consider OGDH a prime candidate for validation and development in CK AML. Successful completion of the proposed research will produce a detailed understanding of the genetic changes that accompany CK AML and allow for more faithful modeling of human disease. In addition, we hypothesize that oxoglutarate dehydrogenase (OGDH) a promising therapeutic target for the treatment of CK AML. Validating our novel drug target will pave the way for clinical trials in this indication. Given the paucity of effective therapeutic options for patients with CK AML, the proposed studies address an urgent, unmet clinical need.

抽象的复杂核型急性髓系白血病 (CK AML) 的定义是存在 3 个或更多可检测到的核型细胞遗传学异常，是所有白血病基因型中预后最差的一种。特征表明这种疾病缺乏传统的可药物癌蛋白，而是其特征是 TP53 抑癌基因中存在一组反复出现的片段缺失和突变，后者在正常核型 AML 中不存在，并赋予对标准化疗的耐药性。为了更好地描述 CK AML 的发病机制并开发治疗这种疾病的新策略，我们将使用一种新的低成本、高分辨率的方法详尽地分析大量 CK AML 样本的基因组我们小组优化的平台称为“数字核型分析”，这些分子特征将与相关。患者结果数据，并用于生成准确重现 CK AML- 的小鼠和人类模型我们将使用这些模型来测试对抗促肿瘤发生的新治疗策略。 p53 缺失的影响这一概念建立在初步数据的基础上，该数据表明 p53 缺失会扰乱细胞代谢。以改变基因表达并驱动异常自我更新的方式，并用以下方法逆转这些影响小分子抑制剂可以驱动 p53 缺陷的 AML 的分化，具体来说，我们发现 p53。突变降低了代谢物 aKG 的水平，产生与致癌 IDH1/2 突变蛋白类似的作用在迄今为止研究的模型中，已被证明是其他 AML 亚型的药物靶点。 p53 的作用可通过抑制 TCA 酶 2-酮戊二酸脱氢酶 (OGDH) 来重现，并且因此，我们认为 OGDH 是 CK AML 验证和开发的主要候选者。拟议研究的一部分将详细了解伴随 CK AML 的基因变化并允许对人类疾病进行更忠实的建模此外，我们还追求氧化戊二酸。脱氢酶 (OGDH) 是治疗 CK AML 的一个有前景的治疗靶点，验证我们的新药。鉴于缺乏有效的治疗选择，该目标将为该适应症的临床试验铺平道路。 CK AML 患者，拟议的研究解决了紧迫的、未满足的临床需求。