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Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.

ABSTRACT: Synthetic lethal screens are used to discover new combination treatments for cancer. In traditional high-throughput synthetic lethal screens, compounds are tested at a single dose, and hit selection is based on threshold activity values from the variance of the efficacy of the compounds tested. The limitation of the single-dose screening for synthetic lethal screens is that it does not allow for the robust detection of differential activities from compound collections with a broad range of potencies and efficacies. There is therefore a need to develop screening approaches that enable the identification of compounds with synthetic lethal effects based on changes in both potency and efficacy. Here we describe the implementation of a dose response-based synthetic lethal screen to find drugs that enhance or mitigate the cytotoxic effect of an immunotoxin protein (HA22). We developed a data analysis framework for the selection of compounds with enhancing or mitigating cytotoxic activities based on the use of dose-response parameters. The data analysis framework includes an ensemble ranking approach that allows the use of multiple dose-response parameters in a nonparametric fashion. Quantitative high-throughput screening (HTS) enables the identification of compounds with synthetic lethal activity not identified by single-dose HTS.

SUBMITTER: Guha R

PROVIDER: S-EPMC7876566 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.

Guha Rajarshi R Mathews Griner Lesley A LA Keller Jonathan M JM Zhang Xiaohu X Fitzgerald David D Antignani Antonella A Pastan Ira I Thomas Craig J CJ Ferrer Marc M

Journal of biomolecular screening 20160425 9

Synthetic lethal screens are used to discover new combination treatments for cancer. In traditional high-throughput synthetic lethal screens, compounds are tested at a single dose, and hit selection is based on threshold activity values from the variance of the efficacy of the compounds tested. The limitation of the single-dose screening for synthetic lethal screens is that it does not allow for the robust detection of differential activities from compound collections with a broad range of poten ...[more]

PMID: 27112173

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Project description:BACKGROUND:Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy. MATERIALS AND METHODS:We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. RESULTS:Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies. CONCLUSION:A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.

Dataset Information

Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.

Publications

Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.

Similar Datasets

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