A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

Author:

Guillen Katrin P.,Fujita Maihi,Butterfield Andrew J.,Scherer Sandra D.,Bailey Matthew H.,Chu Zhengtao,DeRose Yoko S.,Zhao Ling,Cortes-Sanchez Emilio,Yang Chieh-Hsiang,Toner Jennifer,Wang Guoying,Qiao Yi,Huang Xiaomeng,Greenland Jeffery A.,Vahrenkamp Jeffery M.,Lum David H.,Factor Rachel E.,Nelson Edward W.,Matsen Cindy B.,Poretta Jane M.,Rosenthal Regina,Beck Anna C.,Buys Saundra S.,Vaklavas Christos,Ward John H.,Jensen Randy L.,Jones Kevin B.,Li Zheqi,Oesterreich Steffi,Dobrolecki Lacey E.,Pathi Satya S.,Woo Xing Yi,Berrett Kristofer C.,Wadsworth Mark E.,Chuang Jeffrey H.ORCID,Lewis Michael T.,Marth Gabor T.,Gertz Jason,Varley Katherine E.,Welm Bryan E.,Welm Alana L.

Abstract

AbstractModel systems that recapitulate the complexity of human tumors and the reality of variable treatment responses are urgently needed to better understand cancer biology and to develop more effective cancer therapies. Here we report development and characterization of a large bank of patient-derived xenografts (PDX) and matched organoid cultures from tumors that represent some of the greatest unmet needs in breast cancer research and treatment. These include endocrine-resistant, treatment-refractory, and metastatic breast cancers and, in some cases, multiple tumor collections from the same patients. The models can be grown long-term with high fidelity to the original tumors. We show that development of matched PDX and PDX-derived organoid (PDxO) models facilitates high-throughput drug screening that is feasible and cost-effective, while also allowing in vivo validation of results. Our data reveal consistency between drug screening results in organoids and drug responses in breast cancer PDX. Moreover, we demonstrate the feasibility of using these patient-derived models for precision oncology in real time with patient care, using a case of a triple negative breast cancer with early metastatic recurrence as an example. Our results uncovered an FDA-approved drug with high efficacy against the models. Treatment with the PDxO-directed therapy resulted in a complete response for the patient and a progression-free survival period more than three times longer than her previous therapies. This work provides valuable new methods and resources for functional precision medicine and drug development for human breast cancer.Graphical Abstract

Publisher

Cold Spring Harbor Laboratory

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