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Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment.

ABSTRACT: Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs' recapitulation of human tumors.

SUBMITTER: Sun H

PROVIDER: S-EPMC8384880 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment.

Sun Hua H Cao Song S Mashl R Jay RJ Mo Chia-Kuei CK Zaccaria Simone S Wendl Michael C MC Davies Sherri R SR Bailey Matthew H MH Primeau Tina M TM Hoog Jeremy J Mudd Jacqueline L JL Dean Dennis A DA Patidar Rajesh R Chen Li L Wyczalkowski Matthew A MA Jayasinghe Reyka G RG Rodrigues Fernanda Martins FM Terekhanova Nadezhda V NV Li Yize Y Lim Kian-Huat KH Wang-Gillam Andrea A Van Tine Brian A BA Ma Cynthia X CX Aft Rebecca R Fuh Katherine C KC Schwarz Julie K JK Zevallos Jose P JP Puram Sidharth V SV Dipersio John F JF Davis-Dusenbery Brandi B Ellis Matthew J MJ Lewis Michael T MT Davies Michael A MA Herlyn Meenhard M Fang Bingliang B Roth Jack A JA Welm Alana L AL Welm Bryan E BE Meric-Bernstam Funda F Chen Feng F Fields Ryan C RC Li Shunqiang S Govindan Ramaswamy R Doroshow James H JH Moscow Jeffrey A JA Evrard Yvonne A YA Chuang Jeffrey H JH Raphael Benjamin J BJ Ding Li L

Nature communications 20210824 1

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver e ...[more]

PMID: 34429404

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Project description:BackgroundThe survival rate of patients with advanced high-grade serous ovarian carcinoma (HGSOC) remains disappointing. Clinically translatable orthotopic cell line xenograft models and patient-derived xenografts (PDXs) may aid the implementation of more personalised treatment approaches. Although orthotopic PDX reflecting heterogeneous molecular subtypes are considered the most relevant preclinical models, their use in therapeutic development is limited by lack of appropriate imaging modalities.MethodsWe developed novel orthotopic xenograft and PDX models for HGSOC, and applied a near-infrared fluorescently labelled monoclonal antibody targeting the cell surface antigen CD24 for non-invasive molecular imaging of epithelial ovarian cancer. CD24-Alexa Fluor 680 fluorescence imaging was compared to bioluminescence imaging in three orthotopic cell line xenograft models of ovarian cancer (OV-90luc+, Skov-3luc+ and Caov-3luc+, n = 3 per model). The application of fluorescence imaging to assess treatment efficacy was performed in carboplatin-paclitaxel treated orthotopic OV-90 xenografts (n = 10), before the probe was evaluated to detect disease progression in heterogenous PDX models (n = 7).FindingsApplication of the near-infrared probe, CD24-AF680, enabled both spatio-temporal visualisation of tumour development, and longitudinal therapy monitoring of orthotopic xenografts. Notably, CD24-AF680 facilitated imaging of multiple PDX models representing different histological subtypes of the disease.InterpretationThe combined implementation of CD24-AF680 and orthotopic PDX models creates a state-of-the-art preclinical platform which will impact the identification and validation of new targeted therapies, fluorescence image-guided surgery, and ultimately the outcome for HGSOC patients.FundingThis study was supported by the H2020 program MSCA-ITN [675743], Helse Vest RHF, and Helse Bergen HF [911809, 911852, 912171, 240222, HV1269], as well as by The Norwegian Cancer Society [182735], and The Research Council of Norway through its Centers of excellence funding scheme [223250, 262652].

Dataset Information

Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment.

Publications

Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment.

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