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

• 批准号: 10006204
• 负责人: RUSSELL R BROADDUS
• 金额: $ 30.28万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006204
• 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; Estrogen receptor positive; Europe; Event; Exons; Gene Expression; Genes; Genetic; Goals; Growth; Gynecologic; Hormonal; Hot Spot; Hysterectomy; 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; tumor-immune system interactions; tumorigenesis; young woman

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.

摘要 子宫内膜样型子宫内膜癌（EEC）约占所有子宫内膜癌的75 癌症是美国女性第四大常见癌症。许多早期和低血糖患者 分级EEC将通过单独手术治愈，但对于出现更高分级、晚期EEC的女性， 需要更积极的治疗方法来控制疾病。从TCGA数据（并从我们的 我们自己的患者）我们已经确定了四种具有不同临床病理学特征的EEC转录组亚型 特征和突变谱。第二组由年轻、肥胖的患者组成， 减少生存。尽管第二类肿瘤的总体突变率最低，但CTNNB 1外显子3 突变非常普遍。这些突变与Wnt/β-catenin信号通路的激活有关。 通路我们假设CTNNB 1外显子3的突变重新编程了分子景观， 临床攻击性EEC。对这些突变的了解将更好地为针对这些突变的特定策略提供信息。 Wnt通路包括细胞周期蛋白D和CDK 4。为检验这一假设，提出了以下具体目标。 具体目标1.检验CTNNB 1外显子3突变改变细胞表观遗传程序的假设， 抑制激素基因表达程序并激活间充质/神经元， 免疫抑制基因表达程序。1.1.通过以下方法对7种热点突变体进行功能表征： 建立表达每种突变体的等基因稳定系。1.2.描述监管网络的特点， 通过转录组和稳定系的miRNA谱分析突变CTNNB 1，并确定靶基因，初步 关注ESR 1、PGR、N-钙粘蛋白、PDGFA、WNT 5A、WNT 5 B、IL-10和TGFB 2。1.3.确定 N-钙粘蛋白、WNT 5A和WNT 5 B通过siRNA获得功能或丧失功能的可能驱动作用 （单独或组合）和检查相关的体外细胞终点。具体目标2。建立 临床前和临床模型，以检验CTNNB 1的激活突变是重要驱动因素的假设 肿瘤的发生。2.1.评价CTNNB 1突变的体内效应。2.2.利用3D体外系统， 测试靶向Wnt/β-catenin信号传导的替代疗法。2.3.确定CTNNB 1突变是否促进 子宫切除标本中免疫抑制微环境的形成。具体目标3。 进行ribociclib（诺华CDK 4/6抑制剂）、来曲唑和 依维莫司治疗晚期/复发性EEC。我们以前已经证明来曲唑+依维莫司在治疗抑郁症中是有效的。 这些患者的子集。细胞周期蛋白D1是CTNNB 1突变子宫内膜中最高诱导蛋白之一 癌，并与CDK 4/6相互作用以促进细胞周期进展。我们假设， 具有CTNNB 1突变的癌将具有更高的细胞周期蛋白D1表达，因此更敏感。 这种组合的治疗。该试验将富集CTNNB 1突变肿瘤患者。