Abstract

IGFIR and IGFII are antiapoptotic, growth-stimulatory receptor-ligand pair that play an important role in human tumorigenesis. The hypothesis of this proposal is that at least a subset of gastrointestinal tumorigenesis relies on IGFIR signal transduction to prevent apoptosis, and that inhibition of IGFIR signaling will cause cancer cells to undergo apoptosis. In addition, the P.I. hypothesizes that IGFII-catabolizing protein, the IGFII receptor (IGFIIR), is a growth-suppressive component of the IGFIR signaling pathway whose inactivation advances tumor growth. Finally the P.I. states that primary tumors will exhibit reciprocal alterations in p53 and IGFIR or its pathway components, and that these alterations have an effect on the biologic aggressiveness of gastrointestinal tumors.
The specific aims of the proposal are: To test agents that effectively and specifically block signaling through the IGFIR with the final goal to augment apoptosis induced by chemotherapeutic regimens. To determine the involvement of IGFIIR in the IGFIR growth axis both in vitro and in primary gastrointestinal tumors in vivo To correlate IGFIR and IGFIIR expression and function with p53 status and clinical outcome in primary human gastrointestinal tumors in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078843-03
Application #
6174084
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Lively, Tracy (LUGO)
Project Start
1998-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$247,290
Indirect Cost

  Institution

Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201

  Publications

Mori, Yuriko; Sato, Fumiaki; Selaru, Florin M et al. (2002) Instabilotyping reveals unique mutational spectra in microsatellite-unstable gastric cancers. Cancer Res 62:3641-5
Xu, Yan; Selaru, Florin M; Yin, Jing et al. (2002) Artificial neural networks and gene filtering distinguish between global gene expression profiles of Barrett's esophagus and esophageal cancer. Cancer Res 62:3493-7
Toretsky, J A; Zitomersky, N L; Eskenazi, A E et al. (2001) Glypican-3 expression in Wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol 23:496-9
Brabender, J; Usadel, H; Danenberg, K D et al. (2001) Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival. Oncogene 20:3528-32
Takashima, H; Matsumoto, Y; Matsubara, N et al. (2001) Effect of naturally occurring E2F-4 alterations on transcriptional activation and proliferation in transfected cells. Lab Invest 81:1565-73
Trojan, J; Plotz, G; Brieger, A et al. (2001) Activation of a cryptic splice site of PTEN and loss of heterozygosity in benign skin lesions in Cowden disease. J Invest Dermatol 117:1650-3
Meltzer, S J (2001) Tumor genomics vs. tumor genetics: a paradigm shift? Gastroenterology 121:726-9
Fleisher, A S; Esteller, M; Tamura, G et al. (2001) Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia. Oncogene 20:329-35
Umansky, M; Yasui, W; Hallak, A et al. (2001) Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus. Oncogene 20:7987-91
Fleisher, A S; Esteller, M; Harpaz, N et al. (2000) Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res 60:4864-8

Showing the most recent 10 out of 18 publications