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Project 3: Molecular Markers for CRC Recurrence

The identification of colorectal cancer (CRC) patients who will benefit from adjuvant chemotherapy after surgical resection poses a major unmet need in providing them safe and effective care. The current practice results in under-treatment of high-risk stage II patients and overtreatment of low-risk stage III patients. The core obstacle is the lack of a definitive diagnostic biomarker(s) to identify cancers with a high probability of metastasis and correspondingly poor clinical outcome. Translation of microarray-based profiles into clinical diagnostics as biomarkers is complicated by the fact that the technology required to reproduce them requires fresh tissue samples. Conventional assessment of solid tumors typically involves immunohistochemistry (IHC) to detect protein expression in formalin-fixed, paraffin-embedded (FFPE) tissue sections. Thus, there is a gap between an emerging body of genomic information and diagnostic application. We propose to fill this gap by combining emerging genomic and proteomic technologies to identify new molecular markers of CRC recurrence, which then can be analyzed by current methods in surgical pathology.

We hypothesize that molecular encoding of a recurrence-prone phenotype in CRC is reflected by both transcriptomic and proteomic features. We will combine high-dimensional network analysis and new, targeted analysis platforms for specific transcripts and proteins to develop and test new biomarkers in archival FFPE specimens. We will test this hypothesis and develop these approaches according to the following specific aims:

Aim 1: Develop our 34-gene nucleic acid-based colon cancer prognostic classifier for use in FFPE CRC tissue samples and refine.

Aim 2: Identify candidate protein biomarkers by targeted proteomics analysis.

Aim 3: Test the protein-based and nucleic acid-based signature biomarkers in an independent set of archived colon cancer tissue samples annotated with patient treatment course and outcomes.