Patient-Derived Xenografts for Prognostication and Personalized Treatment for Head and Neck Squamous Cell Carcinoma

Christina Karamboulas; Jeffrey P Bruce; Andrew J Hope; Jalna Meens; Shao Hui Huang; Natalie Erdmann; Elzbieta Hyatt; Keira Pereira; David P Goldstein; Ilan Weinreb; Jie Su; Brian O'Sullivan; Rodger Tiedemann; Fei-Fei Liu; Trevor J Pugh; Scott V Bratman; Wei Xu; Laurie Ailles

doi:10.1016/j.celrep.2018.10.004

Patient-Derived Xenografts for Prognostication and Personalized Treatment for Head and Neck Squamous Cell Carcinoma

Cell Rep. 2018 Oct 30;25(5):1318-1331.e4. doi: 10.1016/j.celrep.2018.10.004.

Authors

Christina Karamboulas¹, Jeffrey P Bruce¹, Andrew J Hope², Jalna Meens¹, Shao Hui Huang², Natalie Erdmann¹, Elzbieta Hyatt³, Keira Pereira¹, David P Goldstein⁴, Ilan Weinreb⁵, Jie Su⁶, Brian O'Sullivan², Rodger Tiedemann¹, Fei-Fei Liu⁷, Trevor J Pugh⁸, Scott V Bratman⁷, Wei Xu⁹, Laurie Ailles¹⁰

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
² Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON M5G 2M9, Canada.
³ Hospital for Sick Children, Program in Genetics and Genome Biology, Toronto, ON M5G 0A4, Canada.
⁴ Department of Otolaryngology-Head and Neck Surgery, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada; University of Toronto, Toronto, ON M5G 2M9, Canada.
⁵ Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada.
⁶ Division of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
⁷ Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
¹⁰ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: [email protected].

PMID: 30380421
DOI: 10.1016/j.celrep.2018.10.004

Abstract

Overall survival remains very poor for patients diagnosed as having head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcomes. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immunodeficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC, we demonstrate that rapid engraftment into immunocompromised mice is highly prognostic and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4and CDK6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4 and CDK6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients and demonstrates the potential of using PDX models to identify targeted therapies that will benefit patients who have the poorest outcomes.

Keywords: abemaciclib; cyclin D1; engraftment; head and neck squamous cell carcinoma; patient-derived xenografts; preclinical drug testing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / pharmacology
Aminopyridines / therapeutic use
Animals
Base Sequence
Benzimidazoles / pharmacology
Benzimidazoles / therapeutic use
Cyclin D1 / genetics
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase 6 / metabolism
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Female
Humans
Male
Mice, Inbred NOD
Mice, SCID
Middle Aged
Multivariate Analysis
Mutation / genetics
Neoplasm Recurrence, Local / pathology
Precision Medicine*
Prognosis
Regression Analysis
Risk Factors
Squamous Cell Carcinoma of Head and Neck / drug therapy
Squamous Cell Carcinoma of Head and Neck / genetics
Squamous Cell Carcinoma of Head and Neck / pathology
Squamous Cell Carcinoma of Head and Neck / therapy*
Survival Analysis
Treatment Outcome
Xenograft Model Antitumor Assays*

Substances

Aminopyridines
Benzimidazoles
CCND1 protein, human
CDKN2A protein, human
Cyclin-Dependent Kinase Inhibitor p16
Cyclin D1
abemaciclib
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6