Prediction of combination therapies based on topological modeling of the immune signaling network in Multiple Sclerosis

Abstract

One sentence summary:A new approach to predict combination therapies based on modeling signaling networks using phosphoproteomics from Multiple Sclerosis patients identifies deregulated pathways and new drug combinations. Significance statementMultiple Sclerosis (MS) is a major health problem, leading to significant disability and patient suffering. Although chronic activation of the immune system is a hallmark of the disease, its pathogenesis is poorly understood. Further, current treatments only ameliorate the disease and may produce severe side effects.Here, we applied a network-based modeling approach based on phosphoproteomic data upon perturbation with ligands and drugs of healthy donors and MS patients to create donor-specific models. The models uncover the differential activation in signaling wiring between healthy donors, untreated patients and those under different treatments.Further, based in the patient-specific networks, a new approach identifies drug combinations to revert signaling to a healthy-like state.

MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis

“…The phosphoproteomic assays were designed to study signaling deregulation using dynamic network modeling. This linked study compiled and presented a manually curated immune-and MS-based signaling network (10). After topological analysis, we screened the 70 antibodies for the xMAP assays that maximized coverage of that network, identifying 30 antibodies with good signalto-noise ratio.…”

“…With this approach, proinflammatory and prosurvival pathways were found to be deregulated. Further, these pathways were used for combination therapy prediction and subsequently validated (10). Hence, both studies jointly demonstrate that such differential activation can potentially benefit from new immunomodulatory therapies for MS and other autoimmune diseases using approved and novel kinase inhibitors.…”

“…Such pathways are known to be critical for cell survival and proliferation, cell adhesion and chemotaxis, and the proinflammatory response of the immune cells. The phosphoproteomic data were generated to perform logic network modeling (10). With this approach, proinflammatory and prosurvival pathways were found to be deregulated.…”

“…Data and Materials Availability. The phosphoproteomic dataset can be found at https://github.com/saezlab/combiMS, together with the code allowing network modeling of signaling pathways (10).…”

Prediction of combination therapies based on topological modeling of the immune signaling network in multiple sclerosis

“…The data from clinical studies has been published by Kotelnikova et al in [ 26 ], while the data from the EGCG clinical trial has been published by Bellmann-Strobl et al in [ 27 ]. All data generated in this study are available on Github ( http://github.com/saezlab/combiMS ) [ 73 ], including all data transformations from xMAP raw measurements to modelling-transformed as shown in Fig. 2 .…”