FGFR2 MUTATIONS IN INTERMEDIATE RISK ENDOMETRIAL CANCERS

中危子宫内膜癌中的 FGFR2 突变

基本信息

批准号：
7644524
负责人：
Paul Joseph Goodfellow
金额：
$ 11.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-25 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7644524
关键词：
Address Adjuvant Adjuvant Therapy Biological Response Modifier Therapy Body of uterus Cancer Patient Cell Death Cell Line Cisplatin Clinical Clinical Data Clinical Management Clinical Trials Cytotoxic agent DNA Data Diagnosis Diagnostic Neoplasm Staging Disease Doxorubicin Endometrial Endometrial Carcinoma Event FGFR2 gene Fibroblast Growth Factor Receptor 2 Fibroblast Growth Factor Receptors Frequencies Funding Genetic Models Gynecologic Gynecologic Oncology Group Hormonal Hysterectomy Incidence Link Malignant Neoplasms Mediating Mismatch Repair Modality Molecular Molecular Abnormality Mutation Mutation Analysis Mutation Detection Mutation Spectra Oncogenes Operative Surgical Procedures Outcome Paclitaxel Pathway interactions Patients Play Population Proteins Protocols documentation Radiation Receptor Protein-Tyrosine Kinases Receptor Tyrosine Kinase Gene Recurrence Recurrent disease Risk Role Screening procedure Specimen Staging Survival Rate Testing Therapeutic Time Tumor stage United States Uterine Cancer Woman Work base chemotherapy clinically significant effective therapy high risk inhibitor/antagonist mortality novel outcome forecast public health relevance small hairpin RNA success therapeutic target tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in the United States. Approximately 39,800 new cases of cancer of the uterine corpus will be diagnosed and 7,400 women will die of this disease in 2007. The incidence in the United States is among the highest in the world. Fortunately, most women present with early stage disease and surgery alone (hysterectomy) is curative. The overall five-year survival rate for endometrial cancer patients is estimated at 80-85%. Despite the high cure rate, endometrial cancer remains a clinically challenging disease. Adjuvant therapies (radiation, hormonal, chemotherapy, or combinations) for women with advanced stage, progressive or recurrent disease are not very effective at this time. The median survival after recurrence is ten months and the five-year survival for patients who have recurred is <15%. Effective treatments for advanced and recurrent endometrial carcinoma remain to be defined. New biologic or targeted therapies based on an understanding of the underlying causes of disease hold promise for better outcomes for women with endometrial cancer. We recently determined activating mutations in the FGFR2 oncogene are present in approximately 15% of endometrioid endometrial cancers. Anti-FGFR therapeutics are already in clinical trails for other malignancies and may prove useful in the treatment of endometrial cancers. We propose to analyze endometrial cancers from the Gynecologic Oncology Group Protocol 210 to better understand the clinical significance of FGFR2 mutations and the relationship between activation of FGFR2 and loss of DNA mismatch repair, a key early event in the initiation of ~30% of endometrioid endometrial cancers. Two specific aims are proposed: Specific Aim 1: Determine the role FGFR2 mutations play in intermediate and high risk endometrial cancers. We will assess the rate and spectrum of mutations by direct sequencing and test targeted mutation detection in ~550 endometrioid cancer specimens from GOG-210. We will determine the relationship between FGFR2 mutation and clinicopathologic variables including disease-free and overall survival. Specific Aim 2: Determine the relationship between loss of DNA mismatch repair and FGFR2 mutation. Our preliminary studies suggest FGFR2 mutation may be more common in tumors lacking DNA mismatch repair. Understanding what pathways are dysregulated in cancers will be critical to developing biologic therapies. Understanding of the clinical significance of FGFR2 mutations in endometrial cancer is a critical first step towards determining whether FGFR inhibitors could be useful in treating patients with endometrial cancer. PUBLIC HEALTH RELEVANCE: Our collaborative group recently determined activating mutations in the fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinase gene are frequent in uterine endometrial cancers. The FGFR2 gene product is a potential therapeutic target, with several biologics with activity against FGFR2 already in clinical trials. In this proposal we will evaluate endometrial cancers from the NCI-funded Gynecologic Oncology Group Protocol 210 "A molecular staging study of endometrial carcinoma" for mutations in FGFR2. We will determine the frequency and spectrum of mutations and the relationship between mutations and outcome. Furthermore, we will determine how FGFR2 mutations are related to important clinical variables and other molecular abnormalities in endometrial cancers. These studies are an important first step in considering anti-FGFR2 treatments for endometrial cancer.

描述（由申请人提供）：子宫内膜癌是美国最常见的妇科恶性肿瘤。 2007年，大约有39,800例新的子宫体癌病例被诊断出来，7,400名妇女将死于这种疾病。美国是世界上发病率最高的国家之一。幸运的是，大多数女性都患有早期疾病，仅手术（子宫切除术）即可治愈。子宫内膜癌患者的总体五年生存率估计为 80-85%。尽管治愈率很高，但子宫内膜癌仍然是一种临床上具有挑战性的疾病。对于晚期、进展性或复发性疾病的女性来说，辅助疗法（放射、激素、化疗或联合疗法）目前并不是很有效。复发后的中位生存期为十个月，复发患者的五年生存率<15%。晚期和复发性子宫内膜癌的有效治疗仍有待确定。基于对疾病根本原因的了解的新生物或靶向疗法有望为患有子宫内膜癌的女性带来更好的结果。我们最近确定 FGFR2 癌基因的激活突变存在于大约 15% 的子宫内膜样子宫内膜癌中。抗 FGFR 疗法已经进入其他恶性肿瘤的临床试验，并可能被证明可用于治疗子宫内膜癌。我们建议分析妇科肿瘤组方案 210 中的子宫内膜癌，以更好地了解 FGFR2 突变的临床意义以及 FGFR2 激活与 DNA 错配修复缺失之间的关系，DNA 错配修复缺失是约 30% 子宫内膜样子宫内膜开始形成的关键早期事件癌症。提出了两个具体目标：具体目标 1：确定 FGFR2 突变在中危和高危子宫内膜癌中的作用。我们将通过直接测序来评估突变率和谱，并在约 550 个来自 GOG-210 的子宫内膜样癌样本中测试靶向突变检测。我们将确定 FGFR2 突变与临床病理变量（包括无病生存期和总生存期）之间的关系。具体目标 2：确定 DNA 错配修复缺失与 FGFR2 突变之间的关系。我们的初步研究表明，FGFR2 突变在缺乏 DNA 错配修复的肿瘤中可能更常见。了解癌症中哪些途径失调对于开发生物疗法至关重要。了解 FGFR2 突变在子宫内膜癌中的临床意义是确定 FGFR 抑制剂是否可用于治疗子宫内膜癌患者的关键的第一步。公共健康相关性：我们的合作小组最近确定，成纤维细胞生长因子受体 2 (FGFR2) 受体酪氨酸激酶基因的激活突变在子宫内膜癌中很常见。 FGFR2 基因产物是一个潜在的治疗靶点，几种具有抗 FGFR2 活性的生物制剂已进入临床试验。在本提案中，我们将根据 NCI 资助的妇科肿瘤学组方案 210“子宫内膜癌分子分期研究”评估子宫内膜癌的 FGFR2 突变。我们将确定突变的频率和谱以及突变与结果之间的关系。此外，我们将确定 FGFR2 突变如何与子宫内膜癌的重要临床变量和其他分子异常相关。这些研究是考虑抗 FGFR2 治疗子宫内膜癌的重要第一步。