Evaluating the PKC Enzyme System in Human Colon Cancer

评估人类结肠癌中的 PKC 酶系统

• 批准号: 9111892
• 负责人: JENNIFER D. BLACK
• 金额: $ 16.37万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111892
• 关键词: Address; Animal Model; Antisense Oligonucleotides; Apoptotic; Cancer Etiology; Carcinoma; Cell Line; Cells; Cessation of life; Classification; Clinic; Clinical; Clinical Research; Collection; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; DNA; DNA Binding; Data; Defect; Development; Diagnosis; Disease; Disease Management; Ensure; Enzymes; Epithelial; Exposure to; Family; Family member; Growth; Health; Homeostasis; Human; Incidence; Individual; Intestines; Investments; Isoenzymes; Laboratories; Link; MSH2 gene; Maintenance; Mismatch Repair; Molecular; Mucous Membrane; Neoplasm Metastasis; Oncogenic; Outcome; PKC-betaII; PRKCA gene; Pathway interactions; Patient risk; Patients; Play; Pre-Clinical Model; Prognostic Marker; Property; Protein Kinase C; Protein-Serine-Threonine Kinases; Recurrence; Regulation; Relapse; Resources; Role; Sampling; Second Primary Neoplasms; Signal Pathway; Signal Transduction; Source; Staging; System; TGFBR2 gene; Testing; Therapeutic; Tissue Microarray; Toxic effect; Transforming Growth Factor beta; Translating; Treatment Protocols; Tumor Suppressor Proteins; United States; Up-Regulation; adenoma; base; bryostatin; cancer cell; candidate marker; chemotherapy; clinical efficacy; colon cancer cell line; colon cancer patients; colon tumorigenesis; drug discovery; high risk; human data; improved; in vitro Assay; inhibitor/antagonist; intestinal homeostasis; member; mutant; neoplastic; new therapeutic target; novel; novel marker; novel therapeutics; patient subsets; pre-clinical; prognostic; prognostic tool; prognostic value; receptor; repair enzyme; screening; targeted agent; targeted treatment; therapeutic target; treatment strategy; tumor; tumor progression

 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.

 描述（由适用提供）：结直肠癌（CRC）是美国最常见的恶性肿瘤之一，也是美国癌症死亡的第二大主要原因，估计发生了136,830例病例，2014年50,310例死亡。尽管筛查策略和治疗方案的进展进展，CRC患者的三分之一的CRC患者最终会死于转型疾病。 CRC管理的主要未满足需求包括（a）鉴定新型生物标志物，这些标志物将改善肿瘤的预后分类，从而确保较高的继电器风险患者接受适当的治疗，而低风险患者免于不必要地暴露于化学疗法相关的毒性，以及（b）疗法治疗的新靶标。蛋白激酶C（PKC）酶系统提供了候选生物标志物和CRC管理的治疗靶标的很大程度上尚未开发的来源。资源和研究工作的大量投资主要是在细胞系和动物模型中，导致了有关PKC家族成员在维持肠道上皮稳态中的作用的大量信息，并且PKC同工酶信号的缺陷与CRC的发展和进展密切相关。重要的是，PKC同工酶与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/-catenin增殖途径，转化的生长因子II型生长抑制途径，突变体Ras和P120 catenin信号传导以及DNA MISMISMATCHINS MISMATCHIND READION。但是，这些引人注目的发现，将这些信息转化为诊所几乎没有取得的进展。考虑到人类患者的数据稀少 许多人是PKC同工酶信号传导临床开发的最大障碍。我们假设对人类CRC中关键PKC同工酶的表达，靶标和调节的深入分析将有助于通过开发这些分子作为新的预后工具和/或治疗靶标的开发这些分子的机会来解决该疾病的主要挑战。为了检验这一假设，我们将在各个阶段（腺瘤，I期IV期癌，转移性病变和邻近的正常粘膜）上使用大约1200个注释良好的人结肠肿瘤样品，以及良好表征的人类CRC细胞系列，以解决两个特定的目标：在各个阶段的人类结肠肿瘤中的关键上游调节剂和下游架子的背景下，并确定CRC中PKC酶系统的预后价值，以及（2）检查CRC中PKC同学表达改变的机制。这些研究将确定PKC景观是否可以用作CRC的预后指标，揭示可能受益于PKC同工酶靶向疗法的患者子集，并指出如何可以恢复肿瘤抑制PKC的表达以治疗该疾病。预计这些研究的结果将对CRC管理PKC酶系统的临床发展产生重大影响。