HMGP - Dennis Ahnen, M.D.

Dr. Dennis Ahnen is a Professor of Medicine and has been on the faculty of the University of Colorado School of Medicine since 1982. His research interest is in understanding the process of colorectal cancer and its prevention and his laboratory conducts both basic and clinical investigations. At the basic level Dr. Ahnen's laboratory is examining the biologic and the biochemical mechanisms of chemopreventive effects of the non-steroidal anti-inflammatory drugs (NSAIDs). Dr. Ahnen's laboratory was one of the first to demonstrate that NSAIDs induce apoptotic cell death as well as cause cell cycle arrest and his laboratory showed that this effect could be induced by metabolites of NSAIDs that did not inhibit cyclooxygenases suggesting that there were other biochemical targets for these drugs, one of which is a subclass of cGMP phosphodiesterases. Current studies are designed to identify the multiple biochemical targets of the NSAIDs on cell lines and in vivo. Pam Rice PhD is an Instructor in the Department of Medicine faculty and a co-investigator in the laboratory. Dr. Rice is examining the effect of NSAIDs on the ras signaling pathway in colon cancer cell lines.

The second basic science area of interest in Dr. Ahnen's laboratory is to define the clinical meaning of the molecular genetics of colonic adenomas and carcinomas. The hypothesis for this work is that colonic carcinogenesis is fundamentally driven by mutations in a finite set of genes, that the environmental risk factors associated with colon cancer interact with genetic predisposition genes (polymorphisms) to induce a specific sets of somatic mutations and that the understanding of the genetic profile of colonic adenomas and carcinomas should provide independent information about the clinical and biologic behavior of the tumor. We have examined the genetic profile of over 1000 colonic adenomas and carcinomas and have found that Ki-ras and p53 mutation status is independently related to prognosis and likelihood of benefit of adjuvant therapy but the presence of Microsatellite Instability is not an independent prognostic factor. In adenomas we have found that loss of the second allele of the APC gene appears to occur at the adenoma-carcinoma interface rather than earlier in the process and that Ki-ras mutations are more likely to occur in adenomas of subjects with a low dietary folate intake and Ki-ras mutations are closely associated with villous histology of colonic adenomas. The laboratory has a bank of adenoma and carcinoma tissues that are useful for fellows who are interested in studying the molecular epidemiology of colonic carcinogenesis.

Dr. Ahnen's laboratory also is active in clinical and behavioral studies of colon cancer prevention. The laboratory is conducting clinical trials of screening colonoscopy, stool DNA testing, chemoprevention with non-steroidal anti-inflammatory drugs folate, selenium and DFMO and conducts behavioral trial designed to improve colorectal cancer screening rates. These clinical trials provide populations for fellows not only to learn the basic tenants of epidemiology and clinical trial design/conduct but also provide a source of material for biomarker studies. Dr. Ahnen is also the Director of 2 Cancer Registries that identify families with clustering of colorectal cancer. These families are valuable resources for studies to identify cancer predisposition genes and for prevention trials. The extensive experience and broad expertise found in Dr. Ahnen's laboratory group can provide a strong environment for research training of graduate students.

Piazza GA, Rahm AK, Finn T, Fryor B, Li H, Stoumen AL, Pamukcu R, Ahnen DJ. Apoptosis primarily accounts for the growth inhibitory properties of sulindac metabolitos and involves a mechanism that is independent of cyclooxygenose inhibition, cell cycle arrest, and p53 induction. Cancer Res. 57:2452-9, 1997

Piazza GA, Alberts DS, Hixson LJ, Paranka NS, Li H, Finn T, Borert C, Guillen JM, Brendel K, Gross PH, Sperl G, Ritchie J Burt R, Ellsworth L, Ahnen DJ, Pamuckcu R. Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res. 57:2909-16, 1997

Ahnen DJ, Feigle P, Quan G, Fenoglio-Preiser C, Lovato LC, Bunn PA, Stemmerman G, Qells JD, Macdonald JS, Meyskens FL. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: A Southwest Oncology Group study. Cancer Res 58:1149-58, 1998

Karagas MR,Tosteson E, Greenberg R, Rothstein R, Roebuck B, Herrin M, Ahnen DJ: Dairy Products and Cell Proliferation, Cancer Epidemiol Biomarkers Prev 7:757-66, 1998.

Brensinger JD, Laken SJ, Luce MC, Powell SM, Vance GH, Ahnen DJ, Petersen GM, Hamilton SR, Giardiello FM: Variable pheonotype of familial adenomatous polyposis in pedigrees with 3 mutation in the APC gene. Gut 43:548-552, 1998.

Hoffenberg, EJ, Sauaia A, Maltzman T, Knoll K, Ahnen DJ: Symptomeatic Colonic Polyps in Childhood: Not so Benign, Journal of Pediatric Gastroenterology and Nutrition 28:175-181, 1999.

Marcus A, Ahnen DJ: Cutter G, Colange n, Russell BA, Sedlacek S, Woos M, Manchester D, Fox L, MaCaskill-Stevens, Fairclough, D, Hines S, Wenzel L, Osborn K. Promoting Cancer Screening Among the First Degree relatives of Breast and Colorectal Cancer Patients; The Design of Two Nationwide Randomized Trials. Preventive Medicine 28:229-242,1999.

Martinez ME, Maltzman T, Marshall JR, Einspahr J, Reid ME, Sampliner R, Ahnen DJ, Hamilton SR., Alberts DS: Risk Factors for Ki-ras Protooncogene Mutation in Sporadic Colorectal Adenomas. Cancer Research 59:5181-5, 1999.

Lieberman DA, Weiss D, Bond J, Ahnen D, Garewal H, Chejfec G and the VA Cooperative Study #380 Group. Screening asymptomatic subjects with colonoscopy: prevalence and location of advanced colonic neoplasia. N Engl J Med. 343:162-8, 2000.

Iwamoto M, Ahnen DJ, Franklin WA, Maltzman. Expression of ß-catenin and full length APC in normal and neoplastic colonic tissues. Carcinogenesis 21:1935-40, 2000Rice PL, Goldberg RJ, Ray EC, Driggers LD, Ahnen DJ. Inhibition of ERK1/2 Phosphorylation and Induction of Apoptosis by Sulindac Metabolites. Cancer Res. 61:1541-7, 2001

Spechler SJ, Lee E, Ahnen D, Goyal RK, Hirano I, Ramirez F, Toufman JP, Sampliner R Schnell T, Sontag S, Vlahcevic ZR, Young R, Williford W. Long-term outcome of mecial and surgical treatments for gastroesophageal refluz disease. J Am Med Assoc 2001:285:2331-8, 2001

Maltzman T, Knoll K, Martinez ME, , Byers T, Stevens BR,. Marshall JR, Reid MR, Einspahr J, Hart N, Bhattacharyya, A.B., Bogert C, Sampliner R, Alberts DS, Ahnen DJ., Ki-ras protooncogene mutations in sporadic colorectal adenomas: relationship to histologic and clinical characteristics. Gastroenterology 121:302-9,2001.

Lieberman DA, Weiss DG, Harford, WV, Ahnen DJ et al. One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med 345:555-60,2001

Brock J, Sauaia A, Ahnen DJ, Marine W, Schluter W, Stevens BR, Scinto JD, Karp H: ImprovingProcess of Care and Outcomes for Elderly Patients Hospitalized with Peptic Ulcer Disease in the Era of Guidelines: NSAIDs Are More Important than Helicobacter pylori. In press J Am Med Assoc.Disease. J Am Med Assoc. 286:1985-93, 2001.

Nelson, DB, McQuaid DR, Bond JH, Lieberman DA, Weiss DG, Johnston T, Harford WV, Ahnen DJ, Provenzale D, Sontag SG, Schnell RG, Campbell DR, Durbin TE, Lee JG, Triadafilopoulos G, Ramirez FC, Collins JR, Fennerty G, Garewal G, Sampliner R, Morales TG, Fass R, Smith RE, Maheshwari Y: Procedural success and complications of large-scale screening colonoscopy. Gastrointest Endosc 55:307-14, 2002.

Rice PL, Washington M, Schleman S, Beard KS, Driggers LJ, and Ahnen DJ: Sulindac Sulfide Inhibits EGF-Induced Phosphorylation of ERK1/2 and Bad in Human Colon Cancer Cells. Cancer Research 63: 616-20, 2003.

Lynch KL, Ahnen DJ, Byers T, Wiess DG, Lieberman DA, and Veterans Affairs Cooperative Study Group #380. First degree relatives of patients with advanced colorectal cancer. Clin Gastroenterol Hepatol 1:96-102, 2003.

Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen DJ, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA., Pearson L, Saibil F and Von Stolk RU: Randomized Trial of Aspirin to Prevent Colorectal Adenomas. N Eng J 2003: 348:891-9.

Rice, PL, Kelloff, J, Sullivan, H., Driggers, LJ, Beard, KS, Kwada, S, and Ahnen, DJ. Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in colon cancer cells. Mol Cancer Therapeutics 885-92, 2003

Lieberman DA, Prindiville S, Weiss DG, Willett W, for the VA Cooperative Study Group 380 (Ahnen DJ et al). Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA. 290:2959-67, 2003

Rice PL, Beard KS, Driggers LJ, Ahnen DJ. Inhibition of extracellular-signal regulated kinases ½ is required for apoptosis of human colon cancer cells in vitro by sulindac metabolites. Cancer Research 64, 2004

Iwamoto M, Hoffenberg EJ., Carethers JM, Doctolero R, Tajima A, Sugano K,. Franklin WA, Ahnen DJ. Nuclear accumulation of ß-catenin occurs commonly in the epithelial cells of juvenile polyps. In press Ped Research

Wold KS, Byers T, Crane LA, Ahnen DJ. What do cancer survivors believe causes cancer? In press Cancer Causes and Control.

Rice PL, Beard KS, Driggers LJ, and Ahnen DJ. Inhibition of Extracellular-signal Regulated Kinases ½ Is Required for Apoptosis of Human Colon Cancer Cells in Vitro by Sulindac Metabolites. Cancer Research. November 15, 2004.