Gastrointestinal (GI) malignancies account for nearly half of worldwide cancer deaths. A small population of cells, termed tumor-initiating cells or cancer stem-like cells (CSCs), are important for tumor maintenance, progression and post-treatment recurrence. It is speculated that this specialized population of cells mediates the treatment resistance that is a hallmark of GI malignancy. Reg4 expression is an early event in carcinogenesis in colon, gastric and pancreatic carcinomas and is independently associated with poor clinical outcomes from colorectal, gastric and pancreatic cancers. This proposal follows our recent discovery of the Reg4 receptor, and our preliminary data that suggests that it may play an important role in the proliferation and survival of the CSC. Since these pathways are not addressed by existing therapeutics, targeting Reg4-CD44ICD signaling in the stem cell could dramatically change the current treatment paradigm and enhance responsiveness to chemotherapeutic agents. This proposal has three Aims; one focused on identification of the CD44 isoforms that can serve as the Reg4 receptor, an experimental Aim focused on examining the role of CD44ICD in the CSC, and a clinical Aim focused on determining the relationship between CD44ICD signaling and clinicopathologic features in colorectal cancer.
Gastrointestinal (GI) malignancies account for nearly half of worldwide cancer deaths. This is a disease that heavily impacts VA patent demographic populations, with a large number of patents between 50-80. Previous studies have shown that despite colon cancer screening, only 39% of colon cancers are being diagnosed in early stage. In patients for whom early detection and complete resection are not possible, chemotherapeutics are largely palliative, as treatment only has a modest impact on survival time and is associated with significant costs for care. This application looks at a new potential target for colon cancer therapy that could result in substantially improved treatment response rates.
