Relying on OMICS
Another approach is through omics-based development. Using the tools of proteomics, genomics, and metabolomics, potential biomarkers are sifted out of large quantities of microarray or other high-content data, with an agnostic approach to the mechanism or pathway affected. But omics technologies also have not lived up to expectations.
Research at ArQule comes in somewhere between the two extremes. Neither tightly focused on pathway inhibition alone, nor shotgunning the whole genome or proteome, scientists at ArQule are developing a circuit-based technique to biomarker discovery focusing on cross-talk between pathways.
“If a cell works similarly to an electronic circuit board, if you increase the resistance in one of the circuits, there must be corollary changes of the current, either up or down, in some parallel circuits. You just can’t quietly increase the resistance or take down the electron flow in one part of the circuit and not have something else disturbed in the circuit pathway—hence the idea of cross-talk biomarkers came into being,” explained Thomas Chan, Ph.D., CSO at ArQule.
Dr. Chan’s presentation at CHI’s biomarker conference highlighted ArQule’s recent success in identifying cross-talk biomarkers for several of its kinase inhibitor programs.
As an example, using paired tumor biopsies pre- and post-treatment with their oral c-Met inhibitor (currently in Phase II trials), the researchers found statistically significant inhibition of phosphorylated c-MET and phosphorylated FAK expression. This in-between or “Goldilocks” strategy for biomarker development might be the right-sized strategy for smaller companies that cannot afford a large-scale omics campaign but want to draw upon the overall cell-signaling system rather than isolated signals from one pathway.