A renal cell carcinoma tumorgraft platform to advance precision medicine

Roy Elias; Vanina T Tcheuyap; Akash K Kaushik; Nirmish Singla; Ming Gao; Oscar Reig Torras; Alana Christie; Aditi Mulgaonkar; Layton Woolford; Christina Stevens; Kavitha Priya Kettimuthu; Andrea Pavia-Jimenez; Lindsey K Boroughs; Allison Joyce; Marianna Dakanali; Hollis Notgrass; Vitaly Margulis; Jeffrey A Cadeddu; Ivan Pedrosa; Noelle S Williams; Xiankai Sun; Ralph J DeBerardinis; Orhan K Öz; Hua Zhong; Somasekar Seshagiri; Zora Modrusan; Brandi L Cantarel; Payal Kapur; James Brugarolas

doi:10.1016/j.celrep.2021.110055

A renal cell carcinoma tumorgraft platform to advance precision medicine

Cell Rep. 2021 Nov 23;37(8):110055. doi: 10.1016/j.celrep.2021.110055.

Authors

Roy Elias¹, Vanina T Tcheuyap², Akash K Kaushik³, Nirmish Singla⁴, Ming Gao², Oscar Reig Torras², Alana Christie⁵, Aditi Mulgaonkar⁶, Layton Woolford², Christina Stevens², Kavitha Priya Kettimuthu⁷, Andrea Pavia-Jimenez², Lindsey K Boroughs³, Allison Joyce², Marianna Dakanali⁶, Hollis Notgrass⁸, Vitaly Margulis⁴, Jeffrey A Cadeddu⁴, Ivan Pedrosa⁹, Noelle S Williams¹⁰, Xiankai Sun⁹, Ralph J DeBerardinis¹¹, Orhan K Öz¹², Hua Zhong¹³, Somasekar Seshagiri¹⁴, Zora Modrusan¹⁴, Brandi L Cantarel¹⁵, Payal Kapur¹⁶, James Brugarolas¹⁷

Affiliations

¹ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
² Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Division of Biostatistics, Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁹ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁰ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹¹ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹² Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹³ Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁴ Department of Microchemistry, Proteomics, Lipidomics and NGS, Genentech, Inc., South San Francisco, CA, USA.
¹⁵ Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁷ Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: james.brugarolas@utsw.edu.

Abstract

Renal cell carcinoma (RCC) encompasses a heterogenous group of tumors, but representative preclinical models are lacking. We previously showed that patient-derived tumorgraft (TG) models recapitulate the biology and treatment responsiveness. Through systematic orthotopic implantation of tumor samples from 926 ethnically diverse individuals into non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice, we generate a resource comprising 172 independently derived, stably engrafted TG lines from 148 individuals. TG lines are characterized histologically and genomically (whole-exome [n = 97] and RNA [n = 102] sequencing). The platform features a variety of histological and oncogenotypes, including TCGA clades further corroborated through orthogonal metabolomic analyses. We illustrate how it enables a deeper understanding of RCC biology; enables the development of tissue- and imaging-based molecular probes; and supports advances in drug development.

Keywords: BAP1; HIF; NGS; PET; PT2385; TAK-243; VHL; animal models; belzutifan; biomarkers; iPET; immunoPET; kidney cancer; metabolomics; molecular imaging; radiotracer; patient-derived xenograft (PDX); renal cell carcinoma (RCC).

Publication types

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

MeSH terms

Animals
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / metabolism*
Carcinoma, Renal Cell / physiopathology
Cell Line, Tumor
Humans
Kidney Neoplasms / genetics
Mice
Mice, Inbred NOD
Mice, SCID
Precision Medicine / methods
Xenograft Model Antitumor Assays / methods*

Abstract

Publication types

MeSH terms

Grants and funding