): Dr. William Grady completed an Internal Medicine residency at the University of Washington and is now completing a Gastroenterology fellowship at Case Western Reserve University. He has also commenced a research postdoctoral fellowship with Dr. Sanford Markowitz aimed at studying the role of TGF-beta receptor mutations in causing human g a strointestinal cancers. Dr. Markowitz's laboratory will provide a stimulating environment that will allow Dr. Grady to advance toward his long-term goal of becoming an independent investigator studying the molecular defects that give rise to human gastrointestinal cancers. The broad long-range objectives of this proposal are to define the role of TGF-beta receptor mutations in the genesis of gastrointestinal cancers. TGF-beta inhibits the growth of and induces apoptosis in human colonic epithelial cells. Previous studies in Dr. Markowitz's lab have demonstrated that TGF-beta receptor subunit type II (RII) mutations are found in 80%-95% of colon and gastric cancers that have the replicative error phenotype (RER) and that TGF-beta RII acts as a tumor suppressor gene in RER colon cancer.
The aims of this proposal are: 1) to determine the timing of RII mutations in the sequence of RER colon adenoma to colon carcinoma progression; 2) to determine the clinical subset of human gastric cancers which arise via RII mutations and the RER cancer pathway; 3) to determine the contributions of TGF-beta resistance, TGF-beta receptor type II (RII) and type I (RI) mutations, and defects in post-TGF-beta receptor signaling in the genesis of NonRER human colon cancers; 4) to use TGF-beta RII viral vectors to determine the anti-tumor activity of restored wild-type RII in suppressing colon cancer cell line growth, both in culture and in nude mice xenografts, and to determine the role of induction of apoptosis as part of the mechanism by which TGF-beta RII exerts its anti-tumor activity; and 5) to determine in the azoxymethane model of mouse colon carcinogenesis the promotion of colon adenoma and/or carcinoma formation resulting from introduction of a heterozygous RII gene knockout, and to confirm the role of RII inactivation in augmenting formation of these tumors by establishing the presence in them of mutational inactivation of the remaining wild-type RII allele.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Subcommittee G - Education (NCI)
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Gorelic, Lester S
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Biswas, Swati; Chytil, Anna; Washington, Kay et al. (2004) Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. Cancer Res 64:4687-92
DeFrancisco, John; Grady, William M (2003) Diagnosis and management of hereditary non-polyposis colon cancer. Gastrointest Endosc 58:390-408
Grady, W M; Rajput, A; Lutterbaugh, J D et al. (2001) Detection of aberrantly methylated hMLH1 promoter DNA in the serum of patients with microsatellite unstable colon cancer. Cancer Res 61:900-2
Grady, W M; Willis, J; Guilford, P J et al. (2000) Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet 26:16-7
Grady, W M; Myeroff, L L; Swinler, S E et al. (1999) Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 59:320-4