CRG Expression Profiles as Indicators for Drug Efficacy and Mechanism

Due to the essential role of cooperation response genes (CRGs) in malignant cell transformation, CRG expression profiles reflect the causal underpinnings of the malignant state at molecular level. The utility of gene expression profiles for classification of drug function has been established through the work of others. We have developed technologies for in silico screening of cooperation response gene expression profiles in response to drug challenge. In this context, we predict that CRG expression profiles can be effectively used for identification of cancer ablative drugs. This path of investigation is aimed at facilitating translation of our discoveries into clinical application.

Critical Role of Cooperation Response Genes (CRGs) for the Cancer Phenotype

Our discovery that most of the CRGs we identified appear to be critical for the cancer phenotype provides us with the exciting opportunity to establish the entire cohort of CRGs, out of the 100-strong gene set, that is causally relevant to malignancy of colon cancer cells. We are performing comprehensive gene perturbation experiments in malignant murine and human cancer cells targeting all cooperation response genes for which a causative role for the cancer phenotype has not yet been established. The list of CRGs contains many genes with unknown functions and thus represents a considerable novel resource for cancer intervention.

The Cancer Phenotype is Controlled by a Network of CRGs

Neoplastic progression is associated with profound changes in the gene networks that control the functioning of the cell. Interrogation of these networks by specific gene perturbations thus will be required to understand the development and progression of cancer and to identify intervention targets with inherent cancer cell specificity. The discovery of CRGs provides us with unprecedented access to essential components of the mechanisms mediating the malignant phenotype downstream of cooperating oncogenic mutations. We have preliminary evidence to show that regulation of CRG expression by cooperating oncogenic mutations underlies robust hierarchical organization, thus indicating functional relationships between CRGs. We predict that investigation of CRG network architecture provides a rational path to identification of cancer cell-specific vulnerabilities and thus the rational design of multi-targeted cancer intervention strategies.