Identification of Vulnerabilities in Lung Cancer Using shRNA Screening
The clinical success of targeted therapies along with technological advances in genome-wide profiling have spurred large-scale efforts to systematically map the molecular landscape of human cancers. These approaches nominate candidate essential or tumor suppressor genes, but are not able to identify all types of acquired vulnerabilities, such as synthetic lethal relationships between aberrantly regulated pathways.
Functional studies are therefore an essential complement to these approaches, serving both to confirm the biological roles of candidate cancer genes, and also to identify other vulnerabilities that are acquired as a consequence of observed genetic alterations.
Pooled short hairpin RNAi screening is proving to be a powerful method by which loss-of-function studies can identify new cancer targets. We are developing novel in vivo methods to identify genes which are essential for lung tumorigenesis, using mini-libraries of short hairpins against selected genes of interest.
Identifying and Characterizing c-Myc Dependent Lung Cancers
In addition to pooled short hairpin screening, we are also using a targeted approach to determine the functional importance of known oncogenes. For example, MYC is overexpressed and in some cases amplified in lung cancer. However, it is unknown whether some lung cancers are dependent on MYC expression for their survival and tumorigenic phenotype.
We are working to identify lung cancers that are dependent on MYC, determine their oncogenotype and molecular properties, and identify “acquired vulnerabilities” that would provide both novel therapeutic targets as well as biomarkers to identify patients with MYC-dependent tumors.