The candidate, James Robinson Ph.D. proposes a comprehensive five year research and training program within the Huntsman Cancer Institute part of the University of Utah. Familial Adenomatous Polyposis (FAP) is an inherited syndrome characterized by the development of hundreds of pre- cancerous polyps in the large intestine, some of which progress to cancers. Prophylactic colectomy is usually performed as a preventative measure. FAP is caused by germline mutations in the Adenomatous Polyposis Coli (APC) gene. APC mutations are also found in sporadic colorectal adenomas and 85% of colon cancers carry APC mutations. Consequently, FAP is an excellent model for the study of colon cancer because each adenoma represents an early step in tumorigenesis. Until recently it was widely accepted that APC mutations were alone sufficient for nuclear accumulation of ?-Catenin in intestinal epithelial cells and the onset of intestinal polyposis, but preliminary data suggests that additional growth signals or mutations are required. The candidate's hypothesis is that aberrant stromal cell signaling following loss or haploinsufficiency of APC drives tumorigenesis in adjacent predisposed epithelial cells. This project will expand the understanding of how stromal APC loss contributes to the development of neoplastic intestinal epithelium. The candidate's long-term research goals are to facilitate the development of new measures to prevent colonic adenoma formation by understanding the earliest cellular perturbations that follow APC mutation. If he can demonstrate that growth of early adenomas is driven by stromal signaling and identify which components of this signaling are potential therapeutic targets, completion of this project may radically improve measures to prevent and treat FAP and sporadic colon cancer. An accompanying research training program under the direction of Dr David Jones is a core component of the mentored (K99) period of the award, providing the candidate with a strong foundation in basic science, cancer research and the biology of colorectal cancer. This carefully developed research and training program will lead to: 1) important advances in the study of colorectal cancer, 2) the development of mouse models in which to test novel therapeutic agents, 3) the generation of data that will provide the basis for a highly competitive submission for R01 funding at the conclusion of the independent award (R00) period; and 4) transition of the candidate into an independent researcher.

Public Health Relevance

Familial Adenomatous Polyposis (FAP) is an inherited colon cancer syndrome characterized by the development of hundreds of pre-cancerous polyps in the large intestine, a proportion of which progress to carcinoma. The objective of this proposal is to determine what drives the initial growth of FAP polyps. The candidate has an outstanding research and training program and has generated substantial preliminary data to support this application. Both his mentor and institute are strongly supportive of this application. This K99/R00 Award would support his transition into an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
4R00CA175690-03
Application #
8965544
Study Section
Special Emphasis Panel (NSS)
Program Officer
Jhappan, Chamelli
Project Start
2015-01-27
Project End
2017-11-30
Budget Start
2015-01-27
Budget End
2015-11-30
Support Year
3
Fiscal Year
2015
Total Cost
$248,953
Indirect Cost
$85,705
Name
University of Minnesota Twin Cities
Department
Type
Organized Research Units
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Shin, Clifford H; Grossmann, Allie H; Holmen, Sheri L et al. (2015) The BRAF kinase domain promotes the development of gliomas in vivo. Genes Cancer 6:9-18