Month: March 2022

Focus on Gastroenterology

UConn Health Is on the Frontier of Colon Cancer Research

The Colon Cancer Prevention Program (CCPP) was created in 2006 by Dr. Joel Levine and Dr. Daniel Rosenberg. It was among the first clinical–translational programs directed to the study of the risks for colon cancer, the earliest changes in colon cell biology, and the implications for risk reduction and long-term prevention. With Dr. Rosenberg as Scientific Director and Dr. Levine as Clinical Director, the CCPP was the first to develop an endoscopic methodology to detect the earliest colon surface changes, Aberrant Crypt Foci (ACF). Dr. Tom Devers in the Division of Gastroenterology began translational collaborations with the Rosenberg Laboratory starting in 2010, and Dr. John Birk and Dr. Haleh Vaziri have continued these collaborations. In particular, we all deeply miss the humanity and scholarship of the late Dr. Devers.

The Rosenberg Laboratory in the Center for Molecular Oncology is a leader in novel investigations related to improving early detection of cancer, developing population-based studies of colon cancer risk, including inflammatory bowel diseases, and developing effective chemoprevention strategies for the treatment of high-risk individuals. Dr. Rosenberg’s research extends across a wide range of research topics in colon cancer biology, applying a variety of mouse genetic cancer models to further our understanding of carcinogenic mechanisms, eicosanoid biology, and the application of new chemoprevention approaches. His ongoing studies sponsored by the NCI and American Institute of Cancer Research, in collaboration with GI and Dr. George Weinstock at The Jackson Laboratory, have so far shown the salutary influences of dietary walnuts with effects on urolithin production, inflammation and colon microbiome diversity. Dr. Masako Nakanishi’s research in the Rosenberg Lab focuses on examining the role of bioactive lipid signaling in colon carcinogenesis as well as therapeutic interventions and nutritional modulation of cancer risk.

The CCPP model has been to engage patients, over time, with a focus on individual risk profile, detailed interpretation of their colonoscopy findings and a related long-term prevention plan. CCPP has studied the consequences of low Vitamin D levels on the higher risks for colon polyps. Vitamin D supplementation is now a common recommendation for risk reduction of various malignancies and inflammatory diseases. The CCPP also advises patients on dietary changes, over time, that seek to prevent the shifts in colon bacteria populations that favor colon polyps and cancer. To enhance early detection of colonoscopic interval polyps, the CCPP introduced the first US quantitative fecal immuno-hemoglobin test (FIT). This is consistent with our longitudinal risk modulation clinical–laboratory approach. Currently, in collaboration with Dr. Joseph Anderson and colleagues at Dartmouth Medical Center and East Carolina Medical University, we are examining a vast data set of FIT in 3000 at-risk patients over a decade. Consistent with our goal of translational clinical and basic science, the Srivastava Lab is studying gene expression and the biologic context of when a polyp becomes FIT +.

Other complementary approaches to the study of colon cancer are taking place at UConn Health and UConn Storrs. Dr. Christopher Heinen’s laboratory in the Center for Molecular Oncology studies a condition called Lynch syndrome, which is the most common hereditary form of colorectal cancer. This disease is caused by inherited mutations in genes of the DNA mismatch repair (MMR) pathway. The MMR pathway normally corrects mistakes made by the cell when attempting to copy its DNA during division. The Heinen lab is running multiple NIH-funded studies to understand how defects in the MMR pathway could cause a cell to become cancerous. They use various cutting-edge approaches including CRISPR gene editing to re-create patient mutations as well as human colonic organoids, which are like tiny little human colons in a plastic dish, to study how loss of the MMR pathway affects colon biology.

Dr. Charles Giardina’s lab in the Department of Molecular and Cell Biology is looking at colon cancer in young patients, which is disturbingly on the rise. These cancers are often discovered at an advanced stage, suggesting that they progress rapidly. We are pursuing studies to understand the role of fibroblasts obtained on colonoscopy here at UConn Health in early onset colorectal cancer to determine their contribution to cancer progression in young patients. Knowledge from these studies may help identify high-risk individuals and suggest approaches to prevent early onset colorectal cancers. In another more basic cancer cell biology project, we are studying how colon cancer cells successfully navigate mitotic checkpoints. Unlike normal cells, cancer cells have aberrant chromosomes and actively suppress mitotic checkpoints to divide. Understanding how cancer cells overcome mitotic checkpoints could suggest new approaches for colon cancer treatment.

None of this would have been possible without our patients and the remarkable staff that has been so devoted to explanation, education, science and the human connection here in the Division of Gastroenterology, the CCPP, and the Center for Molecular Oncology/Neag Comprehensive Cancer Center.