TY - JOUR
TI - Ex vivo culture of cells derived from circulating tumour cell xenograft to support small cell lung cancer research and experimental therapeutics
AU - Lallo, A.
AU - Gulati, S.
AU - Schenk, M.W.
AU - Khandelwal, G.
AU - Berglund, U.W.
AU - Pateras, I.S.
AU - Chester, C.P.E.
AU - Pham, T.M.
AU - Kalderen, C.
AU - Frese, K.K.
AU - Gorgoulis, V.G.
AU - Miller, C.
AU - Blackhall, F.
AU - Helleday, T.
AU - Dive, C.
JO - British Journal of Pharmacology
PY - 2019
VL - 176
TODO - 3
SP - 436-450
PB - John Wiley and Sons Inc
SN - 0007-1188, 1476-5381
TODO - 10.1111/bph.14542
TODO - cisplatin;  etoposide;  2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine;  antineoplastic agent;  indazole derivative;  sulfonamide, animal experiment;  animal model;  animal tissue;  Article;  cancer cell culture;  cancer research;  cell assay;  cell proliferation;  cellular thermal shift assay;  chemosensitivity;  circulating tumor cell;  controlled study;  CRISPR-CAS9 system;  disease marker;  drug response;  drug screening;  ex vivo study;  female;  gene expression;  human;  human cell;  image analysis;  immunohistochemistry;  in vivo study;  mouse;  neuroendocrinology;  nonhuman;  pharmacology;  phenotype;  prediction;  priority journal;  RNA sequence;  Sanger sequencing;  small cell lung cancer;  transcriptomics;  tumor xenograft;  Western blotting;  animal;  chemistry;  dose response;  drug effect;  experimental neoplasm;  inbred mouse strain;  lung tumor;  pathology;  preclinical study;  SCID mouse;  small cell lung cancer;  structure activity relation;  tumor cell culture;  tumor embolism, Animals;  Antineoplastic Agents;  Cell Proliferation;  Dose-Response Relationship, Drug;  Drug Evaluation, Preclinical;  Drug Screening Assays, Antitumor;  Humans;  Indazoles;  Lung Neoplasms;  Mice;  Mice, Inbred Strains;  Mice, SCID;  Neoplasms, Experimental;  Neoplastic Cells, Circulating;  Small Cell Lung Carcinoma;  Structure-Activity Relationship;  Sulfonamides;  Tumor Cells, Cultured
TODO - Background and Purpose: Small cell lung cancer (SCLC) is an aggressive disease with median survival of <2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX), which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short-term ex vivo cultures of CDX tumour cells. Experimental Approach: CDX tumours were disaggregated, and the human tumour cells derived were cultured for a maximum of 5 weeks. Phenotypic, transcriptomic and pharmacological characterization of these cells was performed. Key Results: CDX cultures maintained a neuroendocrine phenotype, and most changes in the expression of protein-coding genes observed in cultures, for up to 4 weeks, were reversible when the cells were re-implanted in vivo. Moreover, the CDX cultures exhibited a similar sensitivity to chemotherapy compared to the corresponding CDX tumour in vivo and were able to predict in vivo responses to therapeutic candidates. Conclusions and Implications: Short-term cultures of CDX provide a tractable platform to screen new treatments, identify predictive and pharmacodynamic biomarkers and investigate mechanisms of resistance to better understand the progression of this recalcitrant tumour. © 2018 The British Pharmacological Society
ER -