Next generation proteomics with drug sensitivity screening identifies sub-clones informing therapeutic and drug development strategies for multiple myeloma patients

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.

S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

“…Proteome analysis was performed for 35 MM patient samples as described previously (Tierney et al, 2021). Briefly, CD138 + cells were lysed in RIPA buffer (Cell Signaling Technology, Danvers, MA, United States).…”

Ex vivo drug response heterogeneity reveals personalized therapeutic strategies for patients with multiple myeloma

“…Complementary to molecularly guided precision medicine, drug testing directly on patient biopsies is increasingly successfully implemented for personalized treatment selection [40][41][42] and analysis of drug sensitivity [43][44][45] . For MM, several ex vivo drug screening studies have been performed with bulk viability assays informing on possible treatment options, including BCL2 inhibition by venetoclax [46][47][48] . We have recently reported that image-based ex vivo drug testing (called pharmacoscopy; PCY) recommends treatments that lead to significant progression-free survival improvement for patients suffering from relapsed/refractory hematological malignancies, compared to the patient's own responses to previous treatment 40,41,49 .…”

Realm of proteomics in breast cancer management and drug repurposing to alleviate intricacies of treatment

“…However, NGP can narrow down multiple non-specific drugs to targetspecific or patient-specific drugs. For example, with the help of NGP and drug sensitivity score (DSS) determination, Tierney et al constructed a theranostic profile for multiple myeloma patients to predict the least/most sensitive drug among 5 drug molecule panels [133].…”

“…For example, with the help of NGP and drug sensitivity score (DSS) determination, Tierney et al. constructed a theranostic profile for multiple myeloma patients to predict the least/most sensitive drug among 5 drug molecule panels [133]. Additionally, in a multidisciplinary proteomic study, through phosphoproteomics, interactomics, and immunopeptidomics, CT45 (a protein involved in the DNA damage pathway) was reported as an enhancer of chemotherapy and immunotherapy in ovarian cancer [134].…”