SPRY2 predicts survival post-chemotherapy in advanced ovarian cancer.

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女性注定会死于晚期难治性疾病，即使大多数人对初始治疗反应良好。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的异常信号传导。这些信号驱动癌细胞中恶性表型的增殖、存活和表达，并且还关键地维持肿瘤微环境。此外，通过Her 2/neu（ERBB 2）的异常RTK-ERK信号传导是卵巢癌的不良预后因素。Sprouty 2（SPRY 2）蛋白是一种肿瘤抑制因子和RTK-ERK信号传导的内源性抑制剂。它的许多作用依赖于与Cbl的动态平衡，Cbl是一种靶向SPRY 2以及EGF家族受体的E3连接酶，用于蛋白质体降解。SPRY 2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，我们没有检测SPRY 2，免疫组化，在卵巢癌患者的相似部分。未检测到SPRY 2的患者具有一致的良好结局（所有患者的无病间期> 60个月）。本申请的中心假设是Spry 2预测晚期卵巢癌的化疗后结局。提出两个具体目标作为该假设的初始检验：（1）确定SPRY 2的存在或水平是否预测晚期卵巢癌妇女的生存率;以及（2）确定SPRY 2是否在Her 2状态的背景下提供额外的预测信息。我们将在299个存档肿瘤标本中解决这些目标，这些标本最初来自五个国家III期试验中治疗的晚期（III-IV）卵巢癌妇女（GOG 114、132、152、158和162）在目的1中，通过定量自动免疫组织化学测定SPRY 2和Cbl蛋白水平，进入考克斯模型作为生存期和无病期的潜在预测因子。多变量考克斯模型将包括已知的临床预后因素（分级、分期、减积程度、药物治疗和体能状态）。在目标2中，将使用类似的统计方法确定SPRY 2在Her 2状态（扩增与未扩增，通过FISH）的背景下预测临床结果的能力。SPRY 2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结果提供基础。公共卫生相关性：已经很明显，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的蛋白质的信号传导，包括卵巢癌。卵巢癌是一个重大的公共卫生问题。它是女性癌症相关死亡的第五大常见原因，比所有其他妇科恶性肿瘤的死亡人数总和还要多。治疗可以帮助妇女，但许多人仍然复发并屈服于他们的疾病，我们目前缺乏预测哪些患者的肿瘤会对治疗产生反应，哪些不会。我们发现SPRY 2是RTK到ERK信号传导的关键调节因子，在我们研究的一小组卵巢癌中约有1/3缺失。我们建议测试SPRY 2水平是否可以预测接受标准化疗方案治疗的晚期卵巢癌患者的生存率。从这些研究中获得的信息将帮助我们更好地了解RTK在肿瘤中的生物学功能，并可供后续的女性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转化为公共卫生的显着改善。

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.