Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

Co-production of Public Services:Institutional Barriers to the Involvement of Citizens in Policy Implementation

Co-production refers to the involvement of citizens/service users in the direct implementation of policy. In practice, this means that public servants and citizens act jointly to deliver public services that would traditionally be the domain of the public servant alone. Co-production is increasingly posited as a desirable model of implementation for health and social policies, development and environment programs, and community safety, among other areas. However, while we have some understanding about the role of context in shaping approaches to policy implementation generally, comparatively less attention has been paid to the contextual contingency of co-production. This chapter employs an institutional logics framework to consider the different ways in which co-production plays a role - or not - in policy implementation. In particular, I discuss the way that a community logic, professional logic, market logic, and state logic in different sectors and different contexts shape public servants’ perceptions of their role visà- vis citizens in policy implementation and produce opportunities and barriers for co-production with citizens.</p