In silico approach for the discovery of synergistic combinations
Oss, March 19, 2019 – Successful cancer therapies are often based on drug combinations to halt cancer growth and prevent resistance mechanisms. A good way to find novel, unexpected synergistic drug combinations is unbiased high throughput screening on cancer cell lines, such as the NTRC SynergyScreen™ platform. The effort involved in handling large numbers of possible combinations may constrain broad screening. NTRC therefore launches two additions to its SynergyScreen™ platform: diversity-based library screening and in silico prioritization.
In diversity-based screening, the drug of interest is screened in combination with a set of 42-exemplars that were selected from a library of 162 therapeutics (Uitdehaag et al. , 2016). The library represents the known variety of anti-cancer mechanisms under investigation and approved for clinical use (Figure). Only if synergistic hits are found for an exemplar, the other compounds from the exemplar’s cluster are screened in a second step. In an example for the PARP inhibitor niraparib, screening of 50% less compounds identified more than 70% of the validated synergistic hits from the broad screen.
In the in silico prioritization workflow, the Oncolines™ drug responses of the compound of interest are combined with known clinically validated synthetic lethal interactions (Lee et al., 2018), to generate a list of likely synergistic partners for the single agent. This list is then prioritized for actual combination screening. The in silico prioritization workflow was highly succesful in predicting synergistic pairs that are reported in the combination screening literature, and in NTRC internal screens.
Uitdehaag et al. (2016) Cell Panel Profiling Reveals Conserved Therapeutic Clusters and Differentiates the Mechanism of Action of Different PI3K/mTOR, Aurora Kinase and EZH2 Inhibitors, Molecular Cancer Therapeutics, 15 (12): 3097-3109.
Lee et al. (2018)
Harnessing synthetic lethality to predict the response to cancer treatment, Nature Communications, 9: 2546.
NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing custom-based assays with primary patient material and high-throughput cancer cell line profiling services (Oncolines™, GeneNominator™, SynergyFinder™ and SynergyScreen™), as well as target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. Arginase Gold™ and NFK GreenScreen™ are assay read-outs for the cancer immunotherapy drug targets Arginase-1, and IDO1 and TDO respectively. Assay kits are supplied to clients globally.