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

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

doi:10.1038/s43018-022-00337-6

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

Nat Cancer. 2022 Feb;3(2):232-250. doi: 10.1038/s43018-022-00337-6. Epub 2022 Feb 24.

Authors

Katrin P Guillen^#^{1

2}, Maihi Fujita^#^{1

2}, Andrew J Butterfield^#^{1

2}, Sandra D Scherer^{1

2}, Matthew H Bailey^{2

3}, Zhengtao Chu^{1

2}, Yoko S DeRose^{1

2}, Ling Zhao^{1

2}, Emilio Cortes-Sanchez^{1

2}, Chieh-Hsiang Yang^{1

2}, Jennifer Toner^{1

2}, Guoying Wang^{1

2}, Yi Qiao³, Xiaomeng Huang³, Jeffery A Greenland^{1

2}, Jeffery M Vahrenkamp^{1

2}, David H Lum², Rachel E Factor^{2

4}, Edward W Nelson^{2

5}, Cindy B Matsen^{2

5}, Jane M Poretta^{2

5}, Regina Rosenthal^{2

5}, Anna C Beck^{2

6}, Saundra S Buys^{2

6}, Christos Vaklavas^{2

6}, John H Ward^{2

6}, Randy L Jensen^{1

2

7}, Kevin B Jones^{1

2

8}, Zheqi Li⁹, Steffi Oesterreich⁹, Lacey E Dobrolecki¹⁰, Satya S Pathi^{1

2}, Xing Yi Woo¹¹, Kristofer C Berrett^{1

2}, Mark E Wadsworth^{1

2}, Jeffrey H Chuang^{11

12}, Michael T Lewis¹⁰, Gabor T Marth^{2

3}, Jason Gertz^{1

2}, Katherine E Varley^{1

2}, Bryan E Welm^{13

14}, Alana L Welm^{15

16}

Affiliations

¹ Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
² Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
³ Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT, USA.
⁴ Department of Pathology, University of Utah, Salt Lake City, UT, USA.
⁵ Department of Surgery, University of Utah, Salt Lake City, UT, USA.
⁶ Department of Internal Medicine, Division of Medical Oncology, University of Utah, Salt Lake City, UT, USA.
⁷ Department of Neurosurgery, University of Utah, Salt Lake City, UT, USA.
⁸ Department of Orthopaedics, University of Utah, Salt Lake City, UT, USA.
⁹ Department of Pharmacology and Chemical Biology, University of Pittsburgh, UPMC Hillman Cancer Center, Magee Womens Research Institute, Pittsburgh, PA, USA.
¹⁰ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
¹¹ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
¹² Department of Genetics and Genome Sciences, UCONN-Health, Farmington, CT, USA.
¹³ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. [email protected].
¹⁴ Department of Surgery, University of Utah, Salt Lake City, UT, USA. [email protected].
¹⁵ Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA. [email protected].
¹⁶ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. [email protected].

^# Contributed equally.

Abstract

Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.

Publication types

Case Reports
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Drug Discovery
Heterografts
Humans
Organoids*
Precision Medicine / methods
Triple Negative Breast Neoplasms* / drug therapy
United States
Xenograft Model Antitumor Assays

Abstract

Publication types

MeSH terms

Grants and funding