title: A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option.
abstract: Patient-derived xenograft (PDX) models have shown to reflect original patient tumors better than any other preclinical model. We embarked in a study establishing a large panel of head and neck squamous cell carcinomas PDX for biomarker analysis and evaluation of established and novel compounds. Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel, cetuximab, methotrexate, carboplatin, 5-fluorouracil and everolimus. Further, tumors were subjected to sequencing analysis and gene expression profiling of selected mTOR pathway members. Most frequent response was observed for docetaxel and cetuximab. Responses to carboplatin, 5-fluorouracil and methotrexate were moderate. Everolimus revealed activity in the majority of PDX. Mutational profiling and gene expression analysis did not reveal a predictive biomarker for everolimus even though by trend RPS6KB1 mRNA expression was associated with response. In conclusion we demonstrate a comprehensively characterized panel of head and neck cancer PDX models, which represent a valuable and renewable tissue resource for evaluation of novel compounds and associated biomarkers.
authors.affiliation: Department of Hematology and Oncology, Charité University Medicine, Berlin, Germany; Department of Experimental Pharmacology, Max Delbrueck Center, Berlin, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Klinghammer
authors.forename: Jan-Dirk
authors.initials: JD
authors.lastname: Raguse
authors.forename: Thomas
authors.initials: T
authors.lastname: Plath
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Albers
authors.forename: Korinna
authors.initials: K
authors.lastname: Joehrens
authors.forename: Andre
authors.initials: A
authors.lastname: Zakarneh
authors.forename: Bernadette
authors.initials: B
authors.lastname: Brzezicha
authors.forename: Annika
authors.initials: A
authors.lastname: Wulf-Goldenberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
authors.forename: Jens
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D004252:DNA Mutational Analysis; D000068338:Everolimus; D005260:Female; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D052162:Human papillomavirus 16 / Q000502:physiology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: HNSCC; PDX; PI3K; everolimus; head and neck cancer; mTor; patient avatar; xenograft