Project description:Background: Development of target specific therapeutics greatly benefits from simultaneous identification of biomarkers to determine aspects of bioactivity, drug safety and efficacy or even treatment outcome. This is particularly important when targeting pleiotropic factors such as the TGFbeta system. TGFbeta has become a prime target for cancer therapeutics since inhibition of TGFbeta signaling simultaneously attacks the tumor and its microenvironment. Methods: Here we introduce blood transcriptomics followed by a defined set of validation assays as a promising approach to identify novel biomarkers for monitoring TGFbeta therapy. Findings: Our initial genome-wide analysis of transcription in peripheral blood revealed 12 candidate genes specifically regulated in peripheral blood by the TGFbeta receptor I kinase inhibitor LY2109761. In subsequent in vitro and in vivo molecular and immunological analyses, the combined monitoring of gene regulation of three genes, namely TMEPAI, OCIAD2, and SMAD7 was established as novel biomarkers for anti-TGFbeta based therapies. Interpretation: Overall, the proposed algorithm of biomarker identification is easily adapted towards other drug candidates for which gene regulation can be established in peripheral blood. CD4+ T cells were serum-deprived for 12 hours followed by 8 hours incubation with the indicated compounds, total of 22 samples.
Project description:Background: Development of target specific therapeutics greatly benefits from simultaneous identification of biomarkers to determine aspects of bioactivity, drug safety and efficacy or even treatment outcome. This is particularly important when targeting pleiotropic factors such as the TGFbeta system. TGFbeta has become a prime target for cancer therapeutics since inhibition of TGFbeta signaling simultaneously attacks the tumor and its microenvironment. Methods: Here we introduce blood transcriptomics followed by a defined set of validation assays as a promising approach to identify novel biomarkers for monitoring TGFbeta therapy. Findings: Our initial genome-wide analysis of transcription in peripheral blood revealed 12 candidate genes specifically regulated in peripheral blood by the TGFbeta receptor I kinase inhibitor LY2109761. In subsequent in vitro and in vivo molecular and immunological analyses, the combined monitoring of gene regulation of three genes, namely TMEPAI, OCIAD2, and SMAD7 was established as novel biomarkers for anti-TGFbeta based therapies. Interpretation: Overall, the proposed algorithm of biomarker identification is easily adapted towards other drug candidates for which gene regulation can be established in peripheral blood.
Project description:Treatment of latent tuberculosis infection (LTBI) in individuals at greatest risk for reactivation is an important component of TB control and elimination strategies. However, blood biomarkers for monitoring LTBI treatment have not been identified. We performed a microarray analysis to identify the gene expression profile in whole blood from healthy individuals reactive to the tuberculin skin test (TST) with/without a positive in-house interferon-γ release assay (IGRA) before and after isoniazid (INH) prophylactic therapy.
Project description:In this study we wanted to identify baseline predictors of successful anti-TNF and vedolizumab therapy in patients with inflammatory bowel disease (based on tissue transcriptomics and CD4/CD14 transcriptomics)
Project description:About 40% IBD patients treated with anti-TNF antibodies do not respond to therapy. Baseline biomarkers of response are therefore of interest. By combining computational deconvolution of gene expression and meta-analysis approaches we identified cellular biomarkers in tissue (validated in 2 cohorts by IHC of biopsies), and investigated associated gene biomarkers in blood. This dataset provides data from the validation cohort III (blood).
