Drug response signatures and the identification of potential responder populations across diseases
File(s)
Author(s)
Badi, Yusef Eamon
Type
Thesis
Abstract
Background: Diseases with unmet treatment needs may benefit from repurposing of drugs successfully used to treat related diseases. Severe refractory asthma has unmet treatment needs. Exploring related chronic inflammatory diseases like atopic dermatitis (AD) and psoriasis (PS) and their clinically effective drugs may indicate potential asthma responder populations.
Objective: To study and establish shared pathological features across diseases (AD, PS and asthma) to establish relation. To molecularly characterise clinical response to treatment from biologic and small molecule inhibitors in diseases related to asthma. To identify potential responders in asthma.
Methods: Through collaborating with world leading AD clinical researchers at the Icahn School of Medicine at Mount Sinai (New York City, New York, USA) I derived AD disease signatures and several drug response signatures from clinically responding patients for dupilumab (anti-IL-4/anti-IL-13), a novel anti-IL-22 drug (fezakinumab) and a novel JAK/STAT and SYK drug (gusacitinib). Public data was also used to generate psoriasis disease and anti-IL-17RA (brodalumab), anti-IL-12/anti-IL-23 (ustekinumab), anti-IL-23 (guselkumab) and anti-JAK/STAT (tofacitinib) drug signatures. Bioinformatics approaches were used to probe U-BIOPRED and ADEPT asthma data with these signatures to identify and characterise potential responders.
Results: I successfully derived disease and drug-response signatures for both biologic and small molecule drugs and utilised these to characterise asthma patients with shared immunopathological features with AD and PS and stratify asthma patients into predicted responder and non-responder populations. Clinical and omics analyses led to the successful phenotyping of these patients.
Conclusions: I have demonstrated a novel method of identifying patients which may respond to interventions already established in related diseases. Validation in animal models and clinical trials is required. My novel approach methodology and findings may aid in the development of better patient pre-selection approaches for clinical trials and may be extended to other diseases.
Objective: To study and establish shared pathological features across diseases (AD, PS and asthma) to establish relation. To molecularly characterise clinical response to treatment from biologic and small molecule inhibitors in diseases related to asthma. To identify potential responders in asthma.
Methods: Through collaborating with world leading AD clinical researchers at the Icahn School of Medicine at Mount Sinai (New York City, New York, USA) I derived AD disease signatures and several drug response signatures from clinically responding patients for dupilumab (anti-IL-4/anti-IL-13), a novel anti-IL-22 drug (fezakinumab) and a novel JAK/STAT and SYK drug (gusacitinib). Public data was also used to generate psoriasis disease and anti-IL-17RA (brodalumab), anti-IL-12/anti-IL-23 (ustekinumab), anti-IL-23 (guselkumab) and anti-JAK/STAT (tofacitinib) drug signatures. Bioinformatics approaches were used to probe U-BIOPRED and ADEPT asthma data with these signatures to identify and characterise potential responders.
Results: I successfully derived disease and drug-response signatures for both biologic and small molecule drugs and utilised these to characterise asthma patients with shared immunopathological features with AD and PS and stratify asthma patients into predicted responder and non-responder populations. Clinical and omics analyses led to the successful phenotyping of these patients.
Conclusions: I have demonstrated a novel method of identifying patients which may respond to interventions already established in related diseases. Validation in animal models and clinical trials is required. My novel approach methodology and findings may aid in the development of better patient pre-selection approaches for clinical trials and may be extended to other diseases.
Version
Open Access
Date Issued
2022-04
Date Awarded
2023-03
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Adcock, Ian
Chung, Kian
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
GlaxoSmithKline
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)