A significant challenge facing the cancer research community is the identification of proteins that present therapeutic opportunities for the specific elimination of cancer cells. This application presents a rational approach to the discovery of novel anti-cancer targets that is based upon the genetic principle of synthetic lethality. The goal is to identify mutations which are tolerated on their own but which are incompatible with alterations in oncogenes and tumor suppressors that are commonly if not universally altered in cancer cells. Such a search is, at a minimum, technically daunting in mammals. However, the availability of facile genetic tools and fully sequenced genomes make model organisms an attractive alterative. It is well established that Drosophila is a convenient model in which to examine oncogene and tumor suppressor pathways. We have recently demonstrated that RNA interference can be used to ablate gene expression in cultured Drosophila cells. In this exploratory application, we propose to take advantage of the Drosophila unigene set to create an array of cell strains in which each gene in the set is disrupted individually. The viability of cells containing each disruption will be evaluated in the absence and in the presence of either activated ras or Rb-loss. Cell strains that show apoptosis only in the presence of the cancer mutation will identify synthetically lethal interactions. The development of this technology will allow not only allow a search for anti-cancer targets but will also undoubtedly find application to a broad range of biological problems.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA091069-01
Application #
6331975
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Arya, Suresh
Project Start
2001-03-01
Project End
2003-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
1
Fiscal Year
2001
Total Cost
$166,416
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Paddison, Patrick J; Caudy, Amy A; Hannon, Gregory J (2002) Stable suppression of gene expression by RNAi in mammalian cells. Proc Natl Acad Sci U S A 99:1443-8