Research / Clinical
Summary
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Diseases/Research Topics
Cancer, Colon Cancer
Dr. Carethers’ laboratory studies the development of colorectal neoplasms. A key area of focus is the clinical consequences of developing tumors with inactivation of the DNA mismatch repair system. The lab has investigated the effect of chemotherapeutic agents on cells with and without an intact mismatch repair system. There appears to be selectivity among agents, as well as cytotoxicity when the mismatch repair system is intact. There is discrimination for the utility of 5-fluorouracil depending on the genetic make-up of a patient’s colorectal cancer.
The lab further investigated this biochemically, with evidence of mismatch repair protein binding to the chemically-modified nucleotides. The lab is also investigating whether certain genes that are targeted for inactivation in mismatch repair deficient tumors can predict survival. The lab is also examining if ethnic groups have differing pathogenesis of colorectal cancer, which has involved the prospective collection of over five hundred colon cancers, and a second study of 1000 rectal tumors from patients.
A second area of focus for the laboratory is the effects of the TGFβ superfamily signaling pathways on colorectal cancer. Notably, the lab is investigating activin signaling (biallelically mutated in over 80% of microsatellite unstable colorectal cancers), BMP signaling (mutated in the germline of some juvenile polyposis patients), and TGFβ (involved in 75% of colorectal and pancreatic cancers). The Carethers lab has developed models for which to study and dissect out the signaling pathways, and the pathway’s interaction with other key pathways involved in colorectal tumorigenesis.
A final area of focus is on the pathogenesis of hamartomatous polyposis syndromes. Dr. Carethers has demonstrated that some families with clinical juvenile polyposis syndrome have germline mutations in the PTEN phosphatase protein. This finding is in addition to the finding by others of germline mutations in SMAD4, involved in intracellular signaling after TGFβ stimulation. Thus, investigations also include whether the two pathways interconnect at the molecular level. His investigations are also being extended to sporadic colorectal cancers.
Additionally, Dr. Carethers is investigating mechanisms of tumor suppressor gene inactivation in hamartomatous polyps, and mechanisms at the molecular level for the increased rate of cancer transformation in polyps from individuals with these syndromes. They are extending these investigations to sporadic colorectal cancers as well.
Dr. Carethers is collaborating with a number of Cancer Center members on a variety of projects: Drs. Ajit Varki, Michael Bouvet, Web Cavenee, Cheryl Rock, Richard Kolodner, Barbara Jung, and Lisa Madlensky.
Keywords: colon cancer, translational, polyposis syndromes, DNA mismatch repair, microsatellite instability, genetics, colonoscopy, genetic counseling, colon cancer screening, colon cancer biology, transforming growth factor beta.
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