Drug Combination Screening Assays
Combination therapies are essential in drug development in oncology, however the volume of possible combinations necessitates the use of screening platforms. Charles River has developed several relevant two-drug combination therapy screening formats to profile combinations of oncology drugs or developmental compounds for synergy or antagonism. These drug combination screening formats include fixed-concentration or fixed-ratio combination and assume that compound effects are additive.
We offer matrix combination analysis based on Bliss Independence, combination index analysis of fixed ratio-combinations according to Chou & Talalay, or curve shift analysis according to Zhao. Combination studies may be run with or without a pre-screen to determine single agent efficacy and to identify an appropriate test range for the combination. Screens before entering further evaluation in e.g., a 5x5 matrix or 9 concentration fixed-ratio design allows you to obtain information about possible synergistic or antagonistic effects, dependent on the mode of action.
Matrix combinations and evaluation based on Bliss Independence analysis allow you to study drug effects in a broad range of combination conditions.
Example Data: Combination Studies
Figure: The combination of Pimasertib (MEK1/2 inhibitor) and XL-765 (PI3K/mTOR inhibitor) tested in a 5x5 matrix layout in 2D monolayer culture shows synergistic effects in KRAS and PIK3CA double mutant DLD-1 cells, which confirms observation in literature (Temraz et al. Int. J. Mol. Sci. 16, 22976-22988, 2015; Haagensen et al. Brit. J. Cancer 106, 1386-1394, 2012).
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Frequently Asked Questions (FAQs) about Combination Therapy Screening
What is combination therapy screening?
Drug combination screening assesses the synergistic and antagonistic interactions between combined therapies, allowing us to identify combinations which will increase the efficacy of novel cancer therapies.
Why should I include combination therapy screening in my oncology drug development?
Combination therapy can increase efficacy by targeting more than one molecular target, and help overcome resistance mechanisms. By including drug combination screening in vitro assays in your oncology drug development you can increase translation into the clinic.
What drugs should I include in my combination therapy screen?
The assay format and drug combinations used in drug combination screening will depend on the mechanism of action, and on whether the drugs are mutually exclusive or non-exclusive. The most common combination in clinical trials is immune checkpoint inhibitors to PD-1 and CTLA-4, but drug combinations can include checkpoint agonists, cancer vaccines, other immunomodulatory agents, and more traditional options such as chemotherapy. Charles River’s oncology team can advise on suitable drug combinations to aid your drug development.