SynergyFinder™ helps to ensure that new therapies are combined in the best way possible. Combination therapies are applied to halt cancer growth and to overcome emerging resistance mechanisms. To identify the right combination of your lead compound with standards of care or new drugs, NTRC has developed SynergyFinder™.
Synergy drug screening via fixed ratio combination experiments uses equipotent mixtures of the anti cancer drugs. The mixtures contain fixed ratios of Compound A at IC50 and Compound B at IC50. Since Compound A and Compound B are equipotent (viz. both are at IC50), they are interchangeable and there is no dilution effect of mixing the compounds. To expedite synergy testing, NTRC has predetermined IC50 values, curve shapes and efficacy parameters of many relevant anti cancer drugs, covering the relevant anti cancer drug classes. The anti cancer drugs have been profiled in the full OncolinesTM panel, so the IC50 values of these drugs are available for 102 cancer cell lines.
The goal of a SynergyFinderTM experiment is to identify cases where the joint effect of a compound combination is improved compared to the additive effects of the individual compounds (Uitdehaag et al., 2015). At NTRC we have developed two experimental set-ups to measure synergy, the fixed IC50 ratio experiment and the fixed dose combination experiment.
The service SynergyFinder™ is highly suitable for small-scale, custom-based studies as well as large combinatorial screens. Small-scale studies can be performed for a selection of Oncolines™ cell lines and selected combinations of your compound with anti-cancer agents. Usually these studies are based on hypotheses regarding genetic background and targeting of compounds. Examples are provided by Uitdehaag et al. (2015) and Canté-Barrett et al. (2016).
Large combinatorial screens, referred to as SynergyScreen™, are generally performed for combinations of your compound with representatives of the diverse anti cancer drug classes that are covered in the compound database. We have identified 42 exemplars covering approved and novel targets. You can also screen the full library of 160 pre-profiled anti cancer drugs, with the purpose to look broadly for opportunities that may go beyond rationalisation.
Synthetic lethal combinations are identified by a computational approach, referred to as SynergyPredict™. The approach consists of several steps. First, gene expression analysis is performed on drug IC50 data according to GeneNominator™. Gene expression markers, viz. genes for which high expression significantly correlates to drug response are identified for your anti cancer drug. Via a database search, ‘combination genes’ are identified that result in synthetic lethality when combined to your compound’s gene markers (Lee et al., 2018). The identification of gene markers is explained in GeneNominator™. As a last step, compounds are selected for which the ‘combination genes’ are gene expression markers via a query in NTRC’s anti cancer drug database.
Uitdehaag et al. (2015) Selective Targeting of CTNNB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs, PLoS ONE, 10 (5): e0125021.
Zhao et al. (2004) Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses, Clinical Cancer Research, 10 (23): 7994-8004.
Chou, T. (2010) Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method, Cancer Research, 70 (2): 440-446.
Haagensen et al. (2012) The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition, British Journal of Cancer, 106: 1386-1394.
Canté-Barrett et al. (2016) MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia, Leukemia, 30: 1832-1843.
Lee et al. (2018) Harnessing synthetic lethality to predict the response to cancer treatment, Nature Communications, 9: 2546.