The AACR Career Development Award for Colorectal Cancer Research is open to junior faculty who are in the first four years of a faculty appointment. Eligible research projects are restricted to translational or clinical research that focuses on novel therapeutic approaches for colorectal cancer.
Richard B. Halberg, PhD
Assistant Professor of Medicine
University of Wisconsin
Molecular Differences Predicting Tumor Progression in Colorectal Cancer
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States, accounting for 50,000 deaths annually. The current gold standard for CRC screening is colonoscopy, which identifies polyps as well as cancers. Screening recommendations are based on patient factors, such as age and family history of cancer. In addition, screening is guided by information obtained during the initial colonoscopy. Despite accumulated demographic data, these recommendations may lead to more frequent colonoscopies than might be necessary. Alternatively, the interval between colonoscopies might not be frequent enough, leading to development of cancers when polyps were recently seen. Currently, we are unable to provide more individualized prognostic information to patients based on existing tests.
Advances in gene sequencing and high-throughput bioinformatic technologies have made it possible to perform systematic analyses of genetic alterations in CRC. A more subtle understanding of the genomic "landscape" of cancer reveals a small number of commonly mutated genes interspersed with a much larger number of additional mutations that occur at lower frequencies. A thorough understanding of the role of these less frequent mutations in tumor growth and progression will lead to more accurate stratification of patients into groups at low and high risk for progression. Improvements in the risk stratification system will ultimately translate into individualized screening regimens and improved survival in patients at risk for developing CRC.
A number of groups are trying to gain insight by analyzing samples from human CRC. Hundreds of candidate genes and genetic profiles, which have been shown to correlate with prognosis, have been identified, but none have been validated in large prospective trials. The major weakness in this approach stems from the genetic heterogeneity of human tumors and the lack of insight into the relevance of these genetic events for the critical steps of tumorigenesis. In addition, polyp studies have proven to be difficult in humans since the entire lesion is removed at the time of colonoscopy, making it difficult to identify potentially high-risk tumors.
Animal models afford us the opportunity to study progression while controlling for the genetic variability of an outbred population. In addition, each genetic event can be interrogated separately, providing an understanding of the relevance of each genetic mutation. The animal models in existence have their own shortcomings, as most do not culminate in CRC. However, we have developed a model of CRC that closely resembles human cancer in its earliest stages. Using this model, we will identify genetic events that are coupled to progression in vivo using a combination of state-of-the-art imaging technologies to meticulously document the natural history of the tumor, and DNA microarrays to detect molecular changes. Having biomarkers that predict the likelihood that a tumor will remain a polyp or progress to cancers will allow clinicians to stratify patients based on risk of progression and prevent disease.
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