P2: CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma

P2：CTNNB1 突变和 Wnt 通路激活定义临床侵袭性子宫内膜样子宫内膜癌

基本信息

批准号：
9763470
负责人：
RUSSELL R BROADDUS
金额：
$ 29.02万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9763470
关键词：
3-Dimensional Antiestrogen Therapy Biological Markers Biological Models CDK4 gene CTNNB1 gene Cancer cell line Carcinoma Cell Cycle Progression Cells Cessation of life Characteristics Clinical Clinical Management Clinical Trials Design Cyclin D1 Data Development Dimensions ESR1 gene Endometrial Carcinoma Endometrioid Carcinoma Epigenetic Process Europe Event Exons Gene Expression Genes Genetic Goals Growth Gynecologic Gynecology Hormonal Hot Spot Hysterectomy Immunosuppressive Agents In Vitro Individual Inflammatory Infiltrate Interleukin-10 Journal of the National Cancer Institute Knowledge Letrozole Lymphocytic Infiltrate Malignant Female Reproductive System Neoplasm Malignant Neoplasms Mesenchymal MicroRNAs Modeling Molecular Molecular Genetics Mutate Mutation Mutation Spectra N-Cadherin Neoplasm Metastasis Neurons North America Obesity Operative Surgical Procedures PDGFA gene Pathway interactions Patients Phase Process Proteins Publishing Recurrence SDZ RAD Sampling Signal Pathway Signal Transduction Small Interfering RNA Specimen System TGFB2 gene Testing The Cancer Genome Atlas Therapeutic Therapeutic Trials Translating United States Uterine Cancer WNT5A gene Woman arm beta catenin cohort disorder control gain of function in vivo inhibitor/antagonist loss of function mTOR inhibition malignant breast neoplasm migration mutant overexpression patient subsets pre-clinical prevent programs response targeted treatment therapeutic target three-dimensional modeling transcriptome treatment group tumor tumorigenesis young woman

项目摘要

Abstract Endometrioid-type endometrial carcinoma (EEC) accounts for approximately 75% of all endometrial carcinomas, the fourth most common cancer in women in the US. Many patients with early stage and low grade EEC will be cured by surgery alone but for women who present with higher grade, advanced stage EEC, more aggressive therapeutics are needed to control the disease. From TCGA data (and validated from our own patients) we have identified four transcriptome subtypes of EEC with distinct clinicopathologic characteristics and mutation spectra. Cluster II consists of younger, obese patients with low grade EEC yet diminished survival. Although the Cluster II tumors had the lowest overall mutation rate, CTNNB1 exon 3 mutations were very common. These mutations were associated with activation of the Wnt/β-catenin signaling pathway. We hypothesize that mutations in exon 3 of CTNNB1 reprogram the molecular landscape leading to clinically aggressive EEC. Understanding of these mutations will better inform specific strategies targeting the Wnt pathway including cyclin D and CDK4. The following specific aims are proposed to test this hypothesis. Specific Aim 1. Test the hypothesis that exon 3 mutations of CTNNB1 alter cellular epigenetic programs, thus suppressing the hormonal gene expression program and activating a mesenchymal/neuronal and immunosuppressive gene expression programs. 1.1. Functionally characterize the 7 hot spot mutants by establishing isogenic stable lines expressing each of the mutants. 1.2. Characterize the regulatory network of mutant CTNNB1 by transcriptome and miRNA profiling of the stable lines and identify the target genes, initially focusing on ESR1, PGR, N-cadherin, PDGFA, WNT5A, WNT5B, IL-10, and TGFB2. 1.3. Determine the possible driver effect of N-cadherin, WNT5A, and WNT5B by gain of function or loss of function via siRNA (individually or in combinations) and examining relevant in vitro cellular endpoints. Specific Aim 2. Establish preclinical and clinical models to test the hypothesis that activating mutations of CTNNB1 are important drivers of tumorigenesis. 2.1. Evaluate the effects of CTNNB1 mutation in vivo. 2.2. Utilize a 3D in vitro system to test alternative therapeutics targeting Wnt/β-catenin signaling. 2.3. Determine if CTNNB1 mutation promotes the formation of an immunosuppressive microenvironment in hysterectomy specimens. Specific Aim 3. Conduct a phase II, single arm therapeutic trial of ribociclib (Novartis CDK4/6 inhibitor), letrozole, and everolimus for advanced/recurrent EEC. We have previously shown that letrozole+everolimus is effective in a subset of these patients. Cyclin D1 is one of the highest induced proteins in CTNNB1-mutated endometrial carcinomas, and it interacts with CDK4/6 to promote cell cycle progression. We hypothesize that patients with carcinomas with CTNNB1 mutation will have higher expression of Cyclin D1 and therefore be more responsive to treatment with this combination. The trial will be enriched for patients with tumors with CTNNB1 mutations.

抽象的子宫内膜样癌（EEC）约占所有子宫内膜癌的 75% 癌症，美国女性第四大常见癌症，许多患者处于早期和低水平。级别 EEC 仅通过手术即可治愈，但对于出现较高级别、晚期 EEC 的女性，根据 TCGA 数据（并经过我们的验证），需要更积极的治疗方法。我们自己的患者）我们已经确定了四种具有不同临床病理特征的 EEC 转录组亚型特征和突变谱。簇 II 由具有低级别 EEC 的年轻、肥胖患者组成。尽管 Cluster II 肿瘤的总体突变率最低，但 CTNNB1 外显子 3 的突变率较低。这些突变非常常见，这些突变与 Wnt/β-catenin 信号传导的激活有关。我们对 CTNNB1 外显子 3 进行突变，重新编程分子主导景观了解这些突变将更好地指导针对临床侵袭性 EEC 的具体策略。 Wnt 通路包括细胞周期蛋白 D 和 CDK4。提出以下具体目标来检验这一假设。具体目标 1. 检验 CTNNB1 外显子 3 突变改变细胞表观遗传程序的假设，从而抑制激素基因表达程序并激活间充质/神经元和 1.1 免疫抑制基因表达程序的功能特征建立表达每个突变体的等基因稳定系。通过对稳定株系的转录组和 miRNA 分析来识别突变体 CTNNB1 并识别靶基因，重点关注 ESR1、PGR、N-钙粘蛋白、PDGFA、WNT5A、WNT5B、IL-10 和 TGFB2 1.3。通过 siRNA 获得功能或丧失功能，驱动 N-钙粘蛋白、WNT5A 和 WNT5B 可能产生的影响（单独或组合）并检查相关的体外细胞终点 2. 建立具体目标。临床前和临床模型来检验 CTNNB1 激活突变是重要驱动因素的假设 2.1.利用3D体外系统评估CTNNB1突变的影响。测试针对 Wnt/β-连环蛋白信号传导的替代疗法 2.3. 确定 CTNNB1 突变是否促进。子宫切除标本中免疫抑制微环境的形成。进行 ribociclib（诺华 CDK4/6 抑制剂）、来曲唑和依维莫司治疗晚期/复发性 EEC 我们之前已经证明来曲唑+依维莫司对治疗晚期/复发性 EEC 有效。这些患者的子集 Cyclin D1 是 CTNNB1 突变子宫内膜中诱导程度最高的蛋白之一。癌症，并且它与 CDK4/6 相互作用以促进细胞周期进展。具有 CTNNB1 突变的癌症将具有更高的 Cyclin D1 表达，因此更具反应性该试验将针对患有 CTNNB1 突变的肿瘤患者进行丰富。