Strategies to Target Change in Anti Cancer Therapies by Finding Agents That Can Potentially Perturb an Unstable Pathway

Pathways that tend to change their cohesiveness in tumor-containing versus normal tissues represent interesting targets for anti-cancer therapy, making it highly desirable to locate agents with the potential to specifically disrupt these pathways. The previously discussed relationship between compound cytotoxic response to pathways and MOAs through gene expression patterns can now be brought to bear on specific cancer pathway targets (58). Compound clusters derived from growth inhibition data (GI50) that are significantly correlated with a pathway can potentially perturb that pathway. Therefore, for each of the pathways with a change in gene expression coherence, we have found the SOM cluster that is associated with the pathway (58).

The compounds that are the most significantly correlated with these pathways are mostly clustered in the SOM regions F, P, V, and N. This is not surprising because we have found previously that the P-region contains agents with kinase/phosphotase targeting as their putative MOA (18,79), and many of the pathways that tend to change their cohesiveness are signaling pathways. Some clades contain compounds that can potentially perturb both "up" and "down" pathways, such as clades F2, P1, and P2, whereas other clades contain compounds that appear to perturb specifically "up" or "down" pathways.

Most notably, compounds clustered in clades P4 and M3 are associated only with "up" pathways, and those in clades N9, P6, F6, F8, and V1 are associated predominantly with "down" pathways and with very few or no "up" pathways. Most clinically used compounds in anti-cancer therapies are located in regions M and S, essentially targeting the proliferation stage of a cancer cell. Our analysis, however, points to a much more diverse set of compounds different from traditional cancer therapy and with the potential to disrupt a wide spectrum of cellular processes that are characteristic of cancer cells.

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