April 2012
Principal Investigator: Alexander Nikitin
Co-Principal Investigator: Zeynep Gumus
Department of Biomedical Sciences (Nikitin); Department of Physiology and Biophysics, Weill Cornell Medical College (Gumus)
Contact Information: Email: an58@cornell.edu; Phone: 607-253-4347
Sponsor: Cornell University Ithaca-Weill Cornell Medical College Seed Grants Program
Grant Number: N/A
Title: Discovery of Cancer-specific Synthetic Lethal Pathways
Annual Direct Cost: $50,000
Project Period: 07/01/2012-06/30/2013
DESCRIPTION (provided by applicant): Synthetic lethality concept is based on the identification of genetic and epigenetic alterations which individually can be tolerated by cells but lead to their death if present together. Since cancer cells frequently have mutations in critical cellular pathways, disruption of complementary pathways may be detrimental to malignant but not normal cells, thus making these pathways ideal therapeutic targets. This approach has been successfully used for identification of several pathways, with targeting PARP in BRCA1 and 2 mutant cells most extensively studied. However, extensive functional searches aimed to identify additional synthetically lethal combinations have so far had limited success. Recently we have made a serendipitous observation that in mouse primary cells simultaneous inactivation of the tumor suppressor genes p53 and Rb affects expression of much fewer clinically important human cancer genes, as compared to those altered by inactivation of p53 or Rb alone. Based on these observations we hypothesize that cancer-specific synthetic lethal pathways can be identified by a comparative oncogenomic approach based on meta-analysis of gene expression profiles obtained from primary mouse cells subjected to controlled genetic alterations. The following Specific Aims are proposed to test this hypothesis:
- To test if gene sets which are expressed differently only after a single, but not double, p53 and Rb mutations will result in synthetic lethality in p53 and Rb deficient background, which is common for a broad variety of cancers. This Aim may result in identification of clinically relevant targets.
- To identify additional candidates for synthetic lethality in the context of altered p53 and Rb pathways by performing genome-wide search. This Aim will also facilitate fine-tuning of our novel comparative oncogenomic approach.
