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A controlled trial of HNSCC patient-derived xenografts reveals broad efficacy of PI3Kα inhibition in controlling tumor growth.
Ruicci, Kara M; Meens, Jalna; Sun, Ren X; Rizzo, Giananthony; Pinto, Nicole; Yoo, John; Fung, Kevin; MacNeil, Danielle; Mymryk, Joe S; Barrett, John W; Boutros, Paul C; Ailles, Laurie; Nichols, Anthony C.
Afiliação
  • Ruicci KM; Department of Otolaryngology - Head and Neck Surgery, Western University, London, Canada.
  • Meens J; Department of Pathology and Laboratory Medicine, Western University, London, Canada.
  • Sun RX; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
  • Rizzo G; Ontario Institute for Cancer Research, Toronto, Canada.
  • Pinto N; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
  • Yoo J; Department of Otolaryngology - Head and Neck Surgery, Western University, London, Canada.
  • Fung K; Department of Otolaryngology - Head and Neck Surgery, Western University, London, Canada.
  • MacNeil D; Department of Otolaryngology - Head and Neck Surgery, Western University, London, Canada.
  • Mymryk JS; Department of Oncology, Western University, London, Canada.
  • Barrett JW; Department of Otolaryngology - Head and Neck Surgery, Western University, London, Canada.
  • Boutros PC; Department of Oncology, Western University, London, Canada.
  • Ailles L; Department of Otolaryngology - Head and Neck Surgery, Western University, London, Canada.
  • Nichols AC; Department of Oncology, Western University, London, Canada.
Int J Cancer ; 145(8): 2100-2106, 2019 10 15.
Article em En | MEDLINE | ID: mdl-30468243
Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K/AKT/mTOR signaling axis, particularly in the PIK3CA gene. PI3K-targeted agents have therefore gained considerable preclinical and clinical interest as emerging therapies for HNSCC. Identification of predictive biomarkers of response would advance the clinical application of PI3K-targeted drugs for patients, in order to achieve maximal benefit. To date, studies of drug biomarkers have largely focused on screening cell lines, with much more limited in vivo testing, usually only as validation. This approach has rarely enabled accurate predictions of clinical efficacy. Recently, clinical trials of PDX models (PDX clinical trials) have been introduced as a preclinical approach to interrogate interpatient response heterogeneity. Already, PDX clinical trial responses have been demonstrated to correlate closely with patient outcomes. Here, using both an HNSCC specific, 28-cell line panel and a PDX clinical trial of 80 xenografts derived from 20 unique HNSCC tumors, we systematically examine patterns of response to PI3K inhibition in HNSCC. We find EGFR, AKT1 and CSMD1 copy number aberrations, but not PIK3CA mutations, to be associated with responsiveness to PI3K-targeted drugs. Further, we reveal PI3Kα inhibition to be almost globally tumoristatic in HNSCC xenografts regardless of PIK3CA mutational status, emphasizing its potential as a stabilizing neoadjuvant therapy for HNSCC patients.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Escamosas / Ensaios Antitumorais Modelo de Xenoenxerto / Classe I de Fosfatidilinositol 3-Quinases / Cetuximab / Neoplasias de Cabeça e Pescoço Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Cancer Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Escamosas / Ensaios Antitumorais Modelo de Xenoenxerto / Classe I de Fosfatidilinositol 3-Quinases / Cetuximab / Neoplasias de Cabeça e Pescoço Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Cancer Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Canadá