Functional drug susceptibility testing using single-cell mass predicts treatment outcome in patient-derived cancer neurosphere models

Abstract

Highlights d In a retrospective study, ex vivo drug testing predicts GBM patient survival d Testing is based on detecting subtle changes in single-cell mass d Predictive power of functional testing is comparable to MGMT promoter methylation d Mass biomarker could be used in situations where genomic biomarkers are unavailable

Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation

“…Adding regorafenib at 1 µM indicated improved response compared to the double combination (Fig. 2 B) [ 6 ]. According to our in vitro experimental results and previous literature on MAPK pathway homeostasis, phosphorylated ERK—the downstream effector of activated MAPK pathway—exerts a negative feedback inhibition on the receptor tyrosine Kinase (RTK).…”

Functional Drug Screening in the Era of Precision Medicine

“…Coupled with AI analysis, spatial omics technology is capable of linking pathology images with spatial gene expression profiles and spatial maps of tumor samples will uncover new potential treatment avenues ( 123 ). Single-cell mass analysis has also emerged as a potentially useful functional medicine tool for prediction of drug response and treatment outcome in patient derived neurosphere models ( 124 ). Integration of proteomic, epigenomic, transcriptomic, genomic, and functional data is necessary for the identification of new biomarker signatures and the most efficient targeting of the disease at hand ( 125 ).…”

Metabolic-imaging of human glioblastoma live tumors: a new precision-medicine approach to predict tumor treatment response early

“…The uniqueness of our approach is to avoid keeping the organoids in culture for extended time to prevent it from undergoing the usual genetic and morphological evolution and divergence from the tumor of origin. Many other in vitro glioblastoma organoid models 6 8 consist of several weeks of culturing, wasting the patients’ precious time who in the meantime progresses in their short-term fatal clinical course. This long culture period is also due to the fact that conventional in vitro drug testing assays require very long application settings and readout times with various biological, molecular, genetic, and chemical assays 45 , that inevitably lead to prolongation of in vitro tumor growth, which in the long term alters an already formed 3D tumor structure, such as a GB-EXP example.…”

“…Recent advances in organoid technology have revolutionized in vitro culture tools for biomedical research by creating powerful 3D-dimensional models, that better preserve the local cytoarchitecture and native cell-cell interactions of original tumors 5 . Despite numerous ex-vivo drug testing approaches leverage on 3d-in vitro GB models, they still have shortcomings and none fully captures the complexity of each individual glioblastoma cellular organization and composition overlooking therefore the relevance of how the tumor microenvironment affects tumor behavior and drug response 6 7 8 . These drug testing approaches have several limiting requirements such as: a) extended time of performance that leads to a long period of in vitro tumor culturing with a consequent molecular and morphological transformation diverging from the parental tumor in vivo 6 ; b) technical measurements requiring dissociation of the original tumoral tissue down to a single cell suspension, losing therefore the tumor cytoarchitecture and cell-cell interaction characteristics 8 ; c) use of non-human animal models which implies laborsome procedures and introduction of biases due to host organism-tumor interactions 9 .…”