title: High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.
abstract: Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Korn
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ferretti
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Monahan
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Youzhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Mallika
authors.initials: M
authors.lastname: Singh
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Guizhi
authors.initials: G
authors.lastname: Yang
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: O Alejandro
authors.initials: OA
authors.lastname: Balbin
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Barbe
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Cai
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Fergal
authors.initials: F
authors.lastname: Casey
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Shannon
authors.initials: S
authors.lastname: Chuai
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Cogan
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Collins
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Ernesta
authors.initials: E
authors.lastname: Dammassa
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ebel
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Millicent
authors.initials: M
authors.lastname: Embry
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: John
authors.initials: J
authors.lastname: Green
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Kauffmann
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Kowal
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Leary
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehar
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Lorenzana
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: E
authors.initials: E
authors.lastname: Robert McDonald
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Merkin
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Naylor
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Montesa
authors.initials: M
authors.lastname: Patawaran
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Röelli
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ruddy
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Salangsang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Santacroce
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Angad P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Tinetto
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Tobler
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Velazquez
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Venkatesan
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Von Arx
authors.affiliation: Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Hui Qin
authors.initials: HQ
authors.lastname: Wang
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Zongyao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wyss
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Fiona
authors.initials: F
authors.lastname: Xu
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Lees
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: China Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Keen
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Cozens
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Michael Rugaard
authors.initials: MR
authors.lastname: Jensen
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Pryer
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Williams
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D015203:Reproducibility of Results; D012878:Skin Neoplasms / Q000188:drug therapy; D013274:Stomach Neoplasms / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents