Evaluating the PKC Enzyme System in Human Colon Cancer

 描述(申请人提供)：结直肠癌(CRC)是美国最常见的恶性肿瘤之一，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，但大约三分之一的结直肠癌患者最终将死于转移性疾病。结直肠癌治疗中尚未满足的主要需求包括：(A)确定新的生物标志物，以改善肿瘤的预后分类，从而确保高复发风险的患者得到适当的治疗，同时低风险患者避免不必要的化疗相关毒性，以及(B)为转移疾病的治疗开发新的靶点。蛋白激酶C(PKC)酶系统为结直肠癌治疗提供了大量未开发的候选生物标记物和治疗靶点。大量的资源和研究投入，主要是在细胞系和动物模型上，已经导致了关于PKC家族成员在维持肠上皮内稳态中的作用的丰富信息，并且PKC同工酶信号转导的缺陷与结直肠癌的发生和发展密切相关。重要的是，PKC同工酶和驱动结肠肿瘤发生的信号通路之间存在串扰，包括Wnt/Apc/-catenin增殖通路，转化生长因子β受体II型生长抑制通路，突变的RAS和p120 Catenin信号，以及dna错配修复酶系统。然而，尽管有这些令人信服的发现，但在将这些信息转化为临床方面进展甚微。考虑到人类患者数据的匮乏 被许多人认为是PKC同工酶信号临床开发的最大障碍。我们假设，深入分析关键的PKC同工酶在人类结直肠癌中的表达、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，来应对疾病管理中的主要挑战。为了验证这一假设，我们将使用一大组不同阶段(腺瘤、I-IV期癌症、转移灶和邻近正常粘膜)的约1200个注释良好的人类结肠癌样本以及一组特征良好的人类结直肠癌细胞系来解决两个特定目标：(1)在不同阶段的人类结肠癌中关键的上游调节因子和下游调控因子的背景下，分析PKC同工酶(，，，和)的表达，并确定PKC酶系统在结直肠癌中的预后价值。(2)探讨大肠癌中PKC同工酶表达改变的机制(S)。这些研究将确定PKC环境是否可以作为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，并指出如何恢复肿瘤抑制因子PKCs的表达以用于疾病管理。这些研究的结果预计将对用于结直肠癌治疗的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.