Patient-derived xenograft models of Fanconi anemia–associated head and neck cancer identify personalized therapeutic strategies
Jennifer R. Grandis, Hua Li, Benjamin A. Harrison, Andrew L.H. Webster, Joanna Pucilowska, Austin Nguyen, Jinho Lee, Gordon B. Mills, Jovanka Gencel-Augusto, Yan Zeng, Steven R. Long, Mi-Ok Kim, Rex H. Lee, David I. Kutler, Theresa Scognamiglio, Margaret Brandwein-Weber, Mark Urken, Inna Khodos, Elisa de Stanchina, Yu-Chien Lin, Frank X. Donovan, Settara C. Chandrasekharappa, Moonjung Jung, Mathijs A. Sanders, Agata Smogorzewska, Daniel E. Johnson
Jennifer R. Grandis, Hua Li, Benjamin A. Harrison, Andrew L.H. Webster, Joanna Pucilowska, Austin Nguyen, Jinho Lee, Gordon B. Mills, Jovanka Gencel-Augusto, Yan Zeng, Steven R. Long, Mi-Ok Kim, Rex H. Lee, David I. Kutler, Theresa Scognamiglio, Margaret Brandwein-Weber, Mark Urken, Inna Khodos, Elisa de Stanchina, Yu-Chien Lin, Frank X. Donovan, Settara C. Chandrasekharappa, Moonjung Jung, Mathijs A. Sanders, Agata Smogorzewska, Daniel E. Johnson
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Research Article Genetics Oncology

Patient-derived xenograft models of Fanconi anemia–associated head and neck cancer identify personalized therapeutic strategies

Abstract

Fanconi anemia (FA) confers a high risk (~700-fold increase) of solid tumor formation, most often head and neck squamous cell carcinoma (HNSCC). FA germline DNA repair defects preclude administration of most chemotherapies, and prior hematopoietic stem cell transplantation limits the use of immunotherapy. Thus, surgery and judicious delivery of radiation offer the only treatment options, with most patients dying from their cancers. A paucity of preclinical models has limited the development of new treatments. Here, we report what to our knowledge are the first patient-derived xenografts (PDXs) of FA-associated HNSCC (FA-HNSCC) and highlight the efficacy of FDA-approved EGFR-targeted therapies in tumors with high EGFR and phosphorylated EGFR levels and the activity of the FDA-approved B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax in a FA-HNSCC PDX overexpressing Bcl-2. These findings support the development of precision medicine approaches for FA-HNSCC.

Authors

Jennifer R. Grandis, Hua Li, Benjamin A. Harrison, Andrew L.H. Webster, Joanna Pucilowska, Austin Nguyen, Jinho Lee, Gordon B. Mills, Jovanka Gencel-Augusto, Yan Zeng, Steven R. Long, Mi-Ok Kim, Rex H. Lee, David I. Kutler, Theresa Scognamiglio, Margaret Brandwein-Weber, Mark Urken, Inna Khodos, Elisa de Stanchina, Yu-Chien Lin, Frank X. Donovan, Settara C. Chandrasekharappa, Moonjung Jung, Mathijs A. Sanders, Agata Smogorzewska, Daniel E. Johnson

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Figure 4

FA-HNSCC PDX exhibits heightened sensitivity to cisplatin.

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FA-HNSCC PDX exhibits heightened sensitivity to cisplatin. (A) Cisplatin...
(A) Cisplatin dose response of FA-HNSCC PDX tumors. Mice harboring FA PDX 1, FA PDX 2, or FA PDX 3 tumors were treated once a week via i.p. injection with vehicle (saline) or varying doses of cisplatin (4 mice/group for FA PDX 1 and FA PDX 3; 5 mice/group for FA PDX 2; 2 tumors/mouse for all). Data represent the mean + SEM. Differences at the final time point in average tumor volumes between treatment groups were determined using Dunnett’s 2-tailed t test ad hoc to control the experiment-wise type I error rate at 5%. (B) Comparison of cisplatin sensitivity in FA-HNSCC PDX models (red) versus sporadic (spor) HNSCC PDX models. The average tumor volume on day 14 after cisplatin treatment (normalized to vehicle treatment) for the FA-HNSCC PDX is compared with the responses we have previously reported for 7 sporadic HNSCC PDX models (20). Mice harboring FA-HNSCC PDX tumors were treated once a week via i.p. injection with vehicle (saline) or cisplatin (5 mg/kg) (4 mice/group for FA PDX 1 and FA PDX 3; 5 mice/group for FA PDX 2; 2 tumors/mouse for all). Data represent the mean + SEM.