Multicomponent/combination drug therapies have found tremendous clinical utility. Coincidentally, the down-regulation of two targets or pathways offers a means to bypass pathway redundancies and/or causes a synergistic cellular response that is greater than either agent can accomplish individually. Conditions ranging from CNS disorders to infectious diseases have utilized drug pairings and the standards-of-care for diseases such as AIDS and cancer, in particular, now rely heavily on drug combinations. The discovery of drug combinations, however, is often the result of clinical speculation or trial-by-error strategies that result in a preponderance of failures. When discovered, however, the synergy of two targeted therapies can yield spectacular results. We have spearheaded the development of an advanced small molecule library containing high-value small molecule tools, chemical biology probes, and approved and candidate drugs for screening in matrix format. Pilot studies have been initiated in several cancer lines, and an experimental flow that defines single agent IC50 values followed by 4X4 matrix assessment of active agents, followed by 10X10 matrix assessment of agent combinations with putative synergy, has yielded a high-throughput strategy for defining novel pharmacological combinations.
National Cancer Institute
Lou Staudt, M.D., Ph.D.
Public Health Impact
This program offers researchers access to a screening methodology capable of identifying new drug-drug combinations for deciphering overlapping pathways in systems biology and potential clinical examinations.