Evaluating the PKC Enzyme System in Human Colon Cancer

 描述（由申请人提供）：结直肠癌（CRC）是美国最常诊断的恶性肿瘤之一，也是癌症死亡的第二大原因，2014年估计发病率为136，830例，死亡50，310例。尽管筛查策略和治疗方案取得了进展，但约三分之一的CRC患者最终将死于转移性疾病。CRC管理中主要未满足的需求包括（a）鉴定新的生物标志物，其将改善肿瘤的预后分类，从而确保具有高复发风险的患者接受适当的治疗，同时使低风险患者免于不必要地暴露于化疗相关毒性，以及（B）开发用于治疗转移性疾病的新靶点。蛋白激酶C（PKC）酶系统为CRC管理提供了大量未开发的候选生物标志物和治疗靶点。大量的资源投入和研究工作，主要是在细胞系和动物模型中，已经产生了大量关于PKC家族成员在维持肠上皮稳态中的作用的信息，并且PKC同工酶信号传导的缺陷与CRC的发展和进展密切相关。重要的是，在PKC同工酶和驱动结肠肿瘤发生的信号传导途径之间存在串扰，包括Wnt/Apc/β-连环蛋白增殖途径、转化生长因子β受体II型生长抑制途径、突变型Ras和p120连环蛋白信号传导以及DNA错配修复酶系统。然而，尽管有这些令人信服的发现，但将这些信息转化为临床的进展甚微。考虑到人类患者的数据缺乏 被许多人认为是PKC同工酶信号传导临床开发的最大障碍。我们假设，深入分析人类CRC中关键PKC同工酶的表达、靶点和调控，将有助于通过揭示这些分子作为新的预后工具和/或治疗靶点的发展机会，解决疾病管理中的主要挑战。为了验证这一假设，我们将使用一个大的面板约1200良好注释的人类结肠肿瘤样品在不同阶段（腺瘤、I-IV期癌、转移性病变和邻近正常粘膜）以及充分表征的人CRC细胞系的集合，以解决两个特定目的：（1）PKC同工酶谱（PKC、PKC、PKC、PKC和PKC）在不同阶段的人结肠肿瘤中的关键上游调节因子和下游靶点的表达，并确定CRC中PKC酶系统的预后价值，（2）探讨CRC中PKC同工酶表达改变的机制。这些研究将确定PKC景观是否可以作为CRC的预后指标，揭示可能受益于PKC同工酶靶向治疗的患者亚群，并表明如何恢复肿瘤抑制剂PKC的表达以管理疾病。预计这些研究的结果将对用于CRC管理的PKC酶系统的临床开发产生重大影响。

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and the second leading cause of cancer death in the United States, with an estimated incidence of 136,830 cases and 50,310 deaths in 2014. Despite advances in screening strategies and treatment regimens, approximately one third of CRC patients will ultimately die from metastatic disease. Major unmet needs in the management of CRC include (a) the identification of novel biomarkers that will improve the prognostic classification of tumors and thus ensure that patients with high risk of relapse receive appropriate treatment, while low risk patients are spared from needless exposure to chemotherapy-associated toxicities, and (b) the development of novel targets for therapy of metastatic disease. The protein kinase C (PKC) enzyme system provides a largely untapped source of candidate biomarkers and therapeutic targets for CRC management. Considerable investment of resources and research effort, predominantly in cell lines and animal models, has resulted in a wealth of information on the role of PKC family members in maintenance of intestinal epithelial homeostasis, and defects in PKC isozyme signaling have been strongly linked to CRC development and progression. Importantly, there is crosstalk between PKC isozymes and signaling pathways that drive colon tumorigenesis, including the Wnt/Apc/-catenin proliferative pathway, the transforming growth factor beta receptor type II growth suppressive pathway, mutant Ras and p120 catenin signaling, and the DNA mismatch repair enzyme system. However, despite these compelling findings, little progress has been made in translating this information into the clinic. The paucity of data from human patients is considered by many to be the greatest impediment to clinical exploitation of PKC isozyme signaling. We hypothesize that an in-depth analysis of the expression, targets, and regulation of key PKC isozymes in human CRC will help to address major challenges in management of the disease by unveiling opportunities for the development of these molecules as novel prognostic tools and/or therapeutic targets. To test this hypothesis, we will use a large panel of approximately 1200 well annotated human colon tumor samples at various stages (adenomas, stage I-IV carcinomas, metastatic lesions, and adjacent normal mucosa) as well as a collection of well characterized human CRC cell lines to address two Specific Aims: (1) To profile PKC isozyme (, , , , and ) expression in the context of key upstream regulators and downstream trgets in human colon neoplasms at various stages, and determine the prognostic value of the PKC enzyme system in CRC, and (2) To examine the mechanism(s) underlying altered expression of PKC isozymes in CRC. These studies will determine if the PKC landscape can serve as a prognostic indicator for CRC, reveal patient subsets that may benefit from PKC isozyme-targeted therapies, and indicate how expression of tumor suppressor PKCs may be restored for management of the disease. Findings from these studies are anticipated to have significant impact on clinical development of the PKC enzyme system for CRC management.