Patient-derived tumor-like cell clusters for drug testing in cancer therapy

Abstract

Several patient-derived tumor models emerged recently as robust preclinical drug-testing platforms. However, their potential to guide clinical therapy remained unclear. Here, we report a model called patient-derived tumor-like cell clusters (PTCs). PTCs result from the self-assembly and proliferation of primary epithelial, fibroblast, and immune cells, which structurally and functionally recapitulate original tumors. PTCs enabled us to accomplish personalized drug testing within 2 weeks after obtaining the tumor samples. The defined culture conditions and drug concentrations in the PTC model facilitate its clinical application in precision oncology. PTC tests of 59 patients with gastric, colorectal, or breast cancers revealed an overall accuracy of 93% in predicting their clinical outcomes. We implemented PTC to guide chemotherapy selection for a patient with mucinous rectal adenocarcinoma who experienced recurrence with metastases after conventional therapy. After three cycles of a nonconventional therapy identified by the PTC, the patient showed a positive response. These findings need to be validated in larger clinical trials, but they suggest that the PTC model could be prospectively implemented in clinical decision-making for therapy selection.

Progress towards non-small-cell lung cancer models that represent clinical evolutionary trajectories

“…Although not yet applied to NSCLC, patient-derived tumour cell clusters have been developed which allow short-term cell expansions from primary tumours, including immune and fibroblast populations, allowing the investigation of hundreds of therapeutic options per patient in a manner that correlated with the clinical performance [122]. Of course, a caveat of these strategies might be tumour complexity with regards to intra-tumour heterogeneity and sampling bias.…”

Functional drug susceptibility testing based on biophysical measurements predicts patient outcome in glioblastoma patient-derived neurosphere models

“…Although no functional assays have yet reached clinical implementation, most published approaches have used metabolic readouts to measure the response of cells to ex vivo drug exposure. Perhaps the most commonly-used metabolic assay for measuring ex vivo drug response is CellTiter-Glo (Promega), a commercially-available assay that measures ATP levels as a proxy for numbers of viable, metabolicallyactive cells under different conditions of drug exposure (7,8,10,11). Changes in ATP levels reflect cell growth inhibition, and can be used as a readout of ex vivo drug response.…”

“…After allowing 24 hours for cells to re-aggregate into neurospheres, the cells were exposed to either 20 μM temozolomide (a dose comparable to IC50 values reported previously (22)) or a vehicle control. Neurospheres were monitored for two weeks after TMZ exposure, with functional readouts being taken either continuously (IncuCyte assay) or at fixed timepoints (3,5,7,10,12, and 14 days of TMZ exposure, for the SMR mass assay and CellTiter-Glo assay) with feeding at regular intervals over the course of drug exposure. For the SMR mass assay, neurospheres were dissociated to single cells prior to measurement by treatment with Accutase.…”

“…Most studies linking functional testing to patient outcome have only performed functional testing on tumor samples with matched patient outcomes for small numbers of patients (n = 4-9 patients per study with matched clinical outcomes (6)(7)(8)(9)). One recent study has shown promise in statistically relevant retrospective patient cohorts: Yin et al (10) used the CellTiter-Glo assay to perform ex vivo drug susceptibility testing on "patient-derived tumor-like cell clusters" established from 59 gastric, colorectal, and breast tumors with matched clinical outcomes, and found that the assay achieved good performance in predicting clinical outcomes for a range of drugs.…”

Electrochemical Detection and Point-of-Care Testing for Circulating Tumor Cells: Current Techniques and Future Potentials

“…Besides, CTC could be used to assess the patient prognosis and evaluate the treatment outcome in real-time [5,11]. The isolation, culture, and sequencing of CTC could also help us to determine patients' drug resistance and find potential therapeutic targets [12][13][14][15].…”