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Circulating Biomarkers From the Phase 1 Trial of Sirolimus and Autophagy Inhibition for Patients With Lymphangioleiomyomatosis.
Chest 2018 November
BACKGROUND: We have previously conducted the Sirolimus and Autophagy Inhibition in LAM (SAIL) trial, a phase 1 dose-escalation study of the combination of sirolimus and hydroxychloroquine in patients with lymphangioleiomyomatosis (LAM). The goal of the present study was to analyze sera from the SAIL trial to identify novel biomarkers that could shed light into disease pathogenesis and response to therapy.
METHODS: We used the DiscoveryMAP platform from Rules Based Medicine to simultaneously measure 279 analytes in sera collected at each visit from subjects enrolled in the SAIL trial. We used longitudinal regression and pathway analysis to examine analyte rate of change and corresponding effect on lung function and to identify networks and potential nodes of interest.
RESULTS: A total of 222 analytes were included in the analysis. We identified 32 analytes that changed over the treatment period of the study. Pathway analysis revealed enrichment in cytokine-receptor interaction and mechanistic/mammalian target of rapamycin-related pathways, in addition to seemingly unrelated processes such as rheumatoid arthritis. Search Tool for the Retrieval of Interacting Genes/Proteins analysis identified two hubs centered around acetyl-CoA carboxylase alpha and beta and coagulation factor II. In addition, we identified vascular endothelial growth factor receptor-3 and CCL21 as molecules significantly associated with changes in FEV1 during the study period.
CONCLUSIONS: We performed a large-scale analyte study in sera of women with LAM and identified potential markers that could be linked to disease pathogenesis, lung injury, and therapeutic response. These data will enable future investigation into the specific roles of these molecules in LAM.
TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01687179; URL: www.clinicaltrials.gov).
METHODS: We used the DiscoveryMAP platform from Rules Based Medicine to simultaneously measure 279 analytes in sera collected at each visit from subjects enrolled in the SAIL trial. We used longitudinal regression and pathway analysis to examine analyte rate of change and corresponding effect on lung function and to identify networks and potential nodes of interest.
RESULTS: A total of 222 analytes were included in the analysis. We identified 32 analytes that changed over the treatment period of the study. Pathway analysis revealed enrichment in cytokine-receptor interaction and mechanistic/mammalian target of rapamycin-related pathways, in addition to seemingly unrelated processes such as rheumatoid arthritis. Search Tool for the Retrieval of Interacting Genes/Proteins analysis identified two hubs centered around acetyl-CoA carboxylase alpha and beta and coagulation factor II. In addition, we identified vascular endothelial growth factor receptor-3 and CCL21 as molecules significantly associated with changes in FEV1 during the study period.
CONCLUSIONS: We performed a large-scale analyte study in sera of women with LAM and identified potential markers that could be linked to disease pathogenesis, lung injury, and therapeutic response. These data will enable future investigation into the specific roles of these molecules in LAM.
TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01687179; URL: www.clinicaltrials.gov).
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