Dialogos Commentary From Correlation to Causation to Control: Utilizing Preclinical Disease Models to Improve Cancer Target Discovery

Abstract

Adaptation of genomic and proteomic methods to preclinical animal cancer models promises to revolutionize cancer drug target discovery. Preclinical cancer models uniquely permit focusing on the salient aspect of a drug target, genes, and proteins associated with changes in established tumors. We have identified a direct and rapid manner to use animal cancer models to identify proteins associated with efficacy. The method commences with altered gene expression of tumor-controlling proteins in specific tumor pathways to perturb the growth of established tumors. The resulting tumor perturbation is used to obtain a differential measure of the genes and proteins associated with tumor growth dynamics. Recent advances in efficient nucleic acid delivery tools with low background biological activity enable the concept. First, methods for systemic expression of plasmids at the liver permit separation of gene expression activity and tumor response. Local administration of genes and oligonucleotide inhibitors without proteinaceous viral vectors permit local effects with minimal background biological activity. The second step of the concept is application of genomic and proteomic technologies to tumors with growth rate changes to reveal the genes and proteins correlating with efficacy processes. The third and final step utilizes nucleic acid delivery to alter the expression of efficacy-associated genes in the same or different animal cancer models to validate the genes for efficacy. The targets validated in this manner can then be studied with the standard genomic, proteomic, and pharmacological methods for toxicity in a narrow focused manner to complete their validation as cancer drug targets