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.
Colorectal (CRC) cancer is a leading cause of cancer death in the United States. Major unmet needs for CRC management include the identification of prognostic markers that accurately predict recurrence and the development of novel therapeutic strategies for metastatic disease. Preclinical data point to a key role of the protein kinase C (PKC) enzyme system in the development of CRC; however, its clinical exploitation is significantly hindered by a lack of human data. The proposed studies will help fill this gap by profiling PKC isozyme expression in a large panel of patient samples, correlating PKC signaling with clinical outcome, and examining the regulation of PKC isozyme levels in human colon cancer cells. These studies will establish if PKC profiling can serve as a prognostic indicator for CRC, identify patient subsets that may benefit from therapies that target PKC isozymes, and determine how expression of tumor suppressor PKCs may be restored for management of the disease.
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