Abstract
With the introduction of novel therapeutic agents, survival in Multiple Myeloma (MM) has increased in recent years. However, drug-resistant clones inevitably arise and lead to disease progression and death. The current International Myeloma Working Group response criteria are broad and make it difficult to clearly designate resistant and responsive patients thereby hampering proteo-genomic analysis for informative biomarkers for sensitivity. In this proof-of-concept study we addressed these challenges by combining an ex-vivo drug sensitivity testing platform with state-of-the-art proteomics analysis. 35 CD138-purified MM samples were taken from patients with newly diagnosed or relapsed MM and exposed to therapeutic agents from five therapeutic drug classes including Bortezomib, Quizinostat, Lenalidomide, Navitoclax and PF-04691502. Comparative proteomic analysis using liquid chromatography-mass spectrometry objectively determined the most and least sensitive patient groups. Using this approach several proteins of biological significance were identified in each drug class. In three of the five classes focal adhesion-related proteins predicted low sensitivity, suggesting that targeting this pathway could modulate cell adhesion mediated drug resistance. Using Receiver Operating Characteristic curve analysis, strong predictive power for the specificity and sensitivity of these potential biomarkers was identified. This approach has the potential to yield predictive theranostic protein panels that can inform therapeutic decision making.
Highlights
With the introduction of novel therapeutic agents, survival in Multiple Myeloma (MM) has increased in recent years
We investigated the response of the CD138+ plasma cell samples from 35 patients, to five anti-myeloma therapies: Bortezomib (PI), Lenolidomide (IMiD), Navitoclax (BCL-2 inhibitor), Quizinostat (HDACi) and the investigational drug PF-04691502
The changes in protein abundance for 35 patients to five MM drug treatments was studied to give a unique insight into drug resistance to these particular treatments from patients at varying stages of disease progression, with the long-term goal of developing individual treatment courses catering to individual patient needs (Supplementary Tables 1 and 2)
Summary
With the introduction of novel therapeutic agents, survival in Multiple Myeloma (MM) has increased in recent years. The current International Myeloma Working Group response criteria are broad and make it difficult to clearly designate resistant and responsive patients thereby hampering proteo-genomic analysis for informative biomarkers for sensitivity. In this proof-of-concept study we addressed these challenges by combining an ex-vivo drug sensitivity testing platform with state-of-the-art proteomics analysis. Comparative proteomic analysis using liquid chromatography-mass spectrometry objectively determined the most and least sensitive patient groups Using this approach several proteins of biological significance were identified in each drug class. Using Receiver Operating Characteristic curve analysis, strong predictive power for the specificity and sensitivity of these potential biomarkers was identified This approach has the potential to yield predictive theranostic protein panels that can inform therapeutic decision making. The immunomodulatory drug (IMiD) Lenalidomide increases T cell p roliferation[9] and by inhibiting tumour necrosis factor-alpha (TNFα)-induced endothelial cell migration, basic Fibroblast Growth Factor (bFGF) and Vascular Endothelial Growth Factor (VEGF), it exhibits anti-angiogenic p roperties[10]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.