Candidate: The applicant is currently an Assistant Professor of Surgery in the Division of Surgical Oncology at the University of Cincinnati. Prior to starting this first faculty position in 8/96, he was a resident in surgery at Cornell University Medical Center and then a surgical oncology fellow at the M.D. Anderson Cancer Center. Dr. Lowy has a steadfast commitment to academic surgical oncology, and he strives to excel as both a caregiver and as a researcher. To this end, he would like to continue his basic research training in a structured, mentored environment w i t h the goal of becoming an effective, independent investigator. Environment: The research outlined in this proposal will be sponsored by Dr. Joanna Groden, an Associate Professor in the Department of Molecular Genetics, Biochemistry and Microbiology as well as an Assistant Investigator in the Howard Hughes Medical Institute. Dr. Groden is an internationally recognized expert in cancer genetics and in the study of the adenomatous polyposis coli gene. Dr. Groden and Dr. Lowy have an outstanding working relationship that has already resulted in publication of peer-reviewed manuscripts. This will be a tremendous asset in fostering Dr. Lowy's progress toward becoming an independent scientist. The University of Cincinnati is a rich and collegial intellectual environment in which to work, collaborate and study. Numerous core facilities are available within the Medical School. Research: Pancreatic cancer remains a common disease that is lethal in nearly all cases. The Wnt signaling pathway is activated in numerous malignancies by mutation of the adenomatous polyposis coli (APC) or beta-catenin genes. While APC has not previously been considered an important tumor suppressor in the pancreas, our preliminary work suggests that Wnt signaling is frequently activated in these tumors. The objective of this application is to identify target genes of Wnt signaling in pancreatic cancer. The central hypothesis is that aberrant Wnt signaling is active in a subset of pancreatic cancers and contributes to pancreatic duct carcinogenesis by transcriptional regulation of specific target genes. The central hypothesis will be tested by pursuing three specific aims: 1) To identify the genetic alterations associated with Wnt p a thway activation in pancreatic cancer in order to determine their relationship to known clinical and pathologic prognostic factors; 2) To determine whether Wnt pathway induced transcription is associated with loss of growth control in pancreatic cancer cells; 3) To identify target genes of Wnt signaling in pancreatic cancer cells. Our long-range goal is to understand how these genes contribute to pancreatic carcinogenesis with the hope that they can be modulated for therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA089403-05
Application #
6843143
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
5
Fiscal Year
2005
Total Cost
$137,943
Indirect Cost
Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Logan-Collins, Jocelyn; Thomas, Ryan M; Yu, Peter et al. (2010) Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer Res 70:1130-40
Qian, Jiang; Sarnaik, Amod A; Bonney, Tera M et al. (2008) The APC tumor suppressor inhibits DNA replication by directly binding to DNA via its carboxyl terminus. Gastroenterology 135:152-62
Thomas, R M; Kim, J; Revelo-Penafiel, M P et al. (2008) The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia. Gut 57:1555-60
Wells, James M; Esni, Farzad; Boivin, Gregory P et al. (2007) Wnt/beta-catenin signaling is required for development of the exocrine pancreas. BMC Dev Biol 7:4
Lowy, Andrew M; Clements, Wilson M; Bishop, John et al. (2006) beta-Catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer. Cancer Res 66:4734-41
Clements, Wilson M; Wang, Jiang; Sarnaik, Amod et al. (2002) beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res 62:3503-6
Lowy, Andrew M; Knight, Joy; Groden, Joanna (2002) Restoration of E-cadherin/beta-catenin expression in pancreatic cancer cells inhibits growth by induction of apoptosis. Surgery 132:141-8