SPRY2 predicts survival post-chemotherapy in advanced ovarian cancer.

SPRY2 预测晚期卵巢癌化疗后的生存率。

• 批准号: 7707876
• 负责人: RAYMOND P PEREZ
• 金额: $ 17.4万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707876
• 关键词: Address; Biological Assay; Biological Markers; Biology; Breast; Cancer Etiology; Cancer Patient; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Cox Models; Data; Diagnosis; Disease; Disease-Free Survival; ERBB2 gene; Environment; Equilibrium; Family; Gynecologic; Gynecologic Oncology Group; Human; Immunohistochemistry; Investigational Therapies; Lung; Malignant Neoplasms; Malignant neoplasm of ovary; Mitogen-Activated Protein Kinases; Molecular Biology; Outcome; Ovarian Carcinoma; Patients; Performance Status; Pharmaceutical Preparations; Phase III Clinical Trials; Prognostic Factor; Prostate; Protein Family; Protein Tyrosine Kinase; Proteins; Public Health; Quality of life; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Refractory Disease; Relapse; Signal Transduction; Specimen; Staging; Statistical Methods; Testing; Therapeutic; Translating; Tumor Debulking; Tumor Suppressor Proteins; Validation; Woman; Women Physicians; base; cancer cell; chemotherapy; improved; inhibitor/antagonist; malignant phenotype; member; novel; outcome forecast; prognostic; public health relevance; receptor; response; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Ovarian cancer remains a common and lethal disease. Most women diagnosed with ovarian cancer are destined to die from advanced, refractory disease, even though most also respond well to initial therapy. At least 80% of human cancers depend on aberrant signaling from receptor tyrosine kinases (RTK) to the mitogen-activated protein kinase (MAPK) ERK. These signals drive proliferation, survival, and expression of the malignant phenotype in cancer cells and also critically maintain tumor micro- environments. Moreover, aberrant RTK-ERK signaling via Her2/neu (ERBB2) is an adverse prognostic factor in ovarian cancer. Sprouty 2 (SPRY2) protein is a tumor suppressor and endogenous inhibitor of RTK-ERK signaling. Many of its actions depend on a dynamic equilibrium with Cbl, an E3-ligase that targets SPRY2 as well as EGF-family receptors for proteosomal degradation. SPRY2 is inactivated in 25-40% of breast, prostate, hepatocellular, lung, and melanocytic cancers. In preliminary studies, we did not detect SPRY2, by immunohistochemistry, in a similar fraction of ovarian cancer patients. Patients without detectible SPRY2 had uniformly good outcomes (all with disease-free intervals > 60 mos). The central hypothesis of this application is that Spry2 predicts post-chemotherapy outcomes in advanced ovarian cancer. Two Specific Aims are proposed as initial tests of this hypothesis: (1) to determine whether the presence or level of SPRY2 predicts survival in women with advanced ovarian cancer; and, (2) to determine whether SPRY2 provides additional predictive information in context with Her2 status. We will address these Aims in 299 archival tumor specimens, originally obtained from women with advanced-stage (III-IV) ovarian carcinoma, treated on five national phase III trials (GOG 114, 132, 152, 158, and 162) In aim 1, SPRY2 and Cbl protein levels, assayed by quantitative automated immunohistochemistry, are entered into Cox models as potential predictors of survival and disease-free interval. Multivariate Cox models will include known clinical prognostic factors (grade, stage, extent of debulking, drug treatment, and performance status). In Aim 2, the ability of SPRY2 to predict clinical outcomes in context with Her2 status (amplified versus not, by FISH) will be determined using similar statistical methods. These initial studies of SPRY2, a novel candidate biomarker, will hopefully provide a basis to better predict outcomes following chemotherapy i ovarian cancer. PUBLIC HEALTH RELEVANCE: has become apparent that many cancers depend on signaling from specific proteins, called receptor tyrosine kinases (RTK) to a protein called ERK, including ovarian cancer. Ovarian cancer is a major public health problem. It is the fifth most common cause of cancer-related death in women, responsible for more deaths than all other gynecologic malignancies combined. Therapies help women, but many still relapse and succumb to their disease, We presently lack the means to predict which patient's tumors will respond to therapy and which will not. We have found that SPRY2, a key regulator of RTK to ERK signaling, is absent in about 1/3 of a small set of ovarian cancers we have investigated. We propose to test whether levels of SPRY2 predict survival of women with advanced ovarian cancer who have been treated with standard chemotherapy regimens. Information gained from these studies will help us better understand the biology of RTK function in tumors, and may be used by subsequent women and physicians to make therapeutic choices. Patients could also choose to avoid the adverse quality of life impact of ineffective therapies. By refining prediction of outcomes post-chemotherapy, the proposed studies could therefore potentially translate into significant improvements in public health.

描述（由申请人提供）：卵巢癌仍然是一种常见和致命的疾病。大多数被诊断患有卵巢癌的妇女注定会死于晚期难治性疾病，尽管大多数人对最初的治疗反应良好。至少80%的人类癌症依赖于从受体酪氨酸激酶（RTK）到丝裂原活化蛋白激酶（MAPK） ERK的异常信号。这些信号驱动癌细胞的增殖、存活和恶性表型的表达，也至关重要地维持肿瘤微环境。此外，通过Her2/neu （ERBB2）传递的异常RTK-ERK信号是卵巢癌的不良预后因素。Sprouty 2 （SPRY2）蛋白是一种肿瘤抑制因子和RTK-ERK信号的内源性抑制剂。它的许多作用依赖于与Cbl的动态平衡，Cbl是一种靶向SPRY2和egf家族受体的e3连接酶，用于蛋白体降解。SPRY2在25-40%的乳腺癌、前列腺癌、肝细胞癌、肺癌和黑色素细胞癌中失活。在初步研究中，我们没有通过免疫组织化学在类似比例的卵巢癌患者中检测到SPRY2。未检测到SPRY2的患者均有良好的预后（所有患者的无病间隔均为60 ~ 60个月）。该应用的中心假设是Spry2预测晚期卵巢癌化疗后的预后。提出了两个具体目的作为该假设的初步检验：(1)确定SPRY2的存在或水平是否预测晚期卵巢癌妇女的生存；(2)确定SPRY2是否在Her2状态上下文中提供了额外的预测信息。我们将在299份档案肿瘤标本中解决这些目标，这些标本最初来自晚期（III- iv）卵巢癌妇女，接受了5项国家III期试验（GOG 114、132、152、158和162）的治疗。在目标1中，通过定量自动免疫组织化学检测的SPRY2和Cbl蛋白水平被输入Cox模型，作为生存和无病期的潜在预测因子。多变量Cox模型将包括已知的临床预后因素（分级、分期、减积程度、药物治疗和表现状态）。在Aim 2中，将使用类似的统计方法确定SPRY2在Her2状态（通过FISH扩增或未扩增）背景下预测临床结果的能力。SPRY2是一种新的候选生物标志物，这些初步研究有望为更好地预测卵巢癌化疗后的预后提供基础。公共卫生相关性：很明显，许多癌症依赖于从称为受体酪氨酸激酶（RTK）的特定蛋白质到称为ERK的蛋白质的信号，包括卵巢癌。卵巢癌是一个重大的公共卫生问题。它是妇女癌症相关死亡的第五大常见原因，造成的死亡人数超过所有其他妇科恶性肿瘤的总和。治疗帮助了女性，但许多人仍然复发并死于疾病。我们目前缺乏预测哪些患者的肿瘤对治疗有反应，哪些没有反应的手段。我们发现RTK到ERK信号的关键调节因子SPRY2在我们所研究的一小部分卵巢癌中缺失约1/3。我们建议测试SPRY2水平是否能预测接受标准化疗方案治疗的晚期卵巢癌患者的生存。从这些研究中获得的信息将帮助我们更好地了解肿瘤中RTK功能的生物学，并可能被随后的妇女和医生用于做出治疗选择。患者也可以选择避免无效治疗对生活质量的不良影响。通过改进化疗后结果的预测，拟议的研究可能因此潜在地转化为公共卫生的重大改善。