| Version 2.5.2.0 |
|
|
Abstract
Grant Number: 1R03MH082387-01 Project Title: The Role of Wnts in Stem Cell
PI Information: Name Title COOMBS, GARY (Contact) gary.coombs@hci.utah.edu FITZPATRICK, FRANK A. frank.fitzpatrick@hci.utah.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): The connection between Wnt/a-catenin or "canonical" Wnt signaling and cancer is well appreciated. Some cancers, such as colon cancer, have mutations in components of the signaling pathway (i.e. adenomatous polyposis coli protein, "APC", axin, and a-catenin). Others have upregulated signaling due to methylation of promoters driving expression of secreted signaling inhibitors such as sFRP or DKK1. Still others have upregulated expression of Wnts or their receptors. In breast cancer and some leukemias, cancer stem cell maintenance has been shown to depend on Wnt signaling. Both a-catenin dependent and independent signaling pathways are implicated in stem cell maintenance. It is unclear in most cases exactly how Wnt signaling is upregulated in cancer stem cells. However, in the more overtly Wnt dependent cancers, it is clear that intervention at multiple points in the signaling pathway(s) is required for effective treatment of a broad range of cancers. We have developed and validated a cell based screen for inhibitors of Wnt signaling which can identify inhibitors throughout the entire pathway including secretion from Wnt expressing cells. We have also characterized a series of secondary assays which can place the function of each inhibitor within one of six defined portions or compartments of the signaling pathway. Through high throughput screening, we hope to identify inhibitors in each compartment and characterize them in a broad range of cancer cell based assays. We propose to identify inhibitors of Wnt signaling effectors throughout the signaling cascade, from Wnt secretion to transcription of target genes, and identify their targets and epistatic locations. Much accumulated evidence implicates both a-catenin dependent and independent Wnt signaling in overtly Wnt dependent cancers and cancer stem cell self renewal. With these compounds we propose to identify targets with the highest therapeutic indices and efficacy for treatment of Wnt dependent cancers.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
Wnt gene /protein, antineoplastic, drug discovery /isolation, neoplastic cell, posttranslational modification, stem cell
biological signal transduction, cadherin, chemical registry /resource, radiation resistance, receptor binding
NIH Roadmap Initiative tag, cell line, high throughput technology, western blotting
Institution: UNIVERSITY OF UTAH 75 South 2000 East SALT LAKE CITY, UT 84112 Fiscal Year: 2007 Department: ONCOLOGICAL SCIENCES Project Start: 27-AUG-2007 Project End: 31-JUL-2008 ICD: NATIONAL INSTITUTE OF MENTAL HEALTH IRG: ZMH1