title: CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients.
abstract: OBJECTIVE
  CD44, a cell surface glycoprotein, plays important roles in the development, progression, and metastasis of various tumor types. The aim of this study was to investigate how the expression of CD44 isoforms influences the interaction with hyaluronic acid (HA) and how differential isoform expression impacts antitumoral responses in vivo to treatment with RG7356, a humanized anti-CD44 antibody inhibiting CD44-HA interaction.
  
  
  METHODS
  CD44 isoform expression on various tumor cell lines was analyzed by RNASeq while data on patients with different tumor types were obtained from the publicly available TCGA RNASeq dataset as well as a phase I clinical study (NCT01358903). We analyzed the link between HA production and CD44 isoform expression as well as the consequences of blocking the CD44-mediated cell adhesion to HA using RG7356. The correlation between CD44 isoform expression and antitumor response to RG7356 treatment was investigated in the corresponding murine xenograft in vivo models as well as in a subset of patients treated with RG7356 from a recently completed phase I clinical trial.
  
  
  RESULTS
  CD44 isoform expression, in particular expression of CD44s, is associated with HA production and predicts response to treatment with RG7356 in tumor xenograft models. Furthermore, patient data suggest that CD44 isoform status is a potential predictive biomarker for clinical response to treatment with RG7356.
  
  
  CONCLUSIONS
  We provide new insights into the close interplay between CD44 and HA and a potential biomarker to enrich patient responses to RG7356 in the clinic.
authors.affiliation: Roche Innovation Center Penzberg, Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Penzberg, Germany. Fabian.birzele@roche.com.
authors.forename: Fabian
authors.initials: F
authors.lastname: Birzele
authors.affiliation: Roche Innovation Center Penzberg, Oncology Division, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Voss
authors.affiliation: Roche Innovation Center Penzberg, Oncology Division, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Nopora
authors.affiliation: Roche Innovation Center Penzberg, Oncology Division, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Honold
authors.affiliation: Roche Innovation Center Penzberg, Oncology Division, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Heil
authors.affiliation: Roche Innovation Center Penzberg, Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Lohmann
authors.affiliation: VU MEDISCH CENTRUM, Department of Medical Oncology, Amsterdam, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Verheul
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: Department of Medicine, Institut Claudius Regaud, Toulouse, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.affiliation: UMC St Radboud, Medical Oncology Department, Nijmegen, the Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: van Herpen
authors.affiliation: Cancer Therapy and Research Center, San Antonio, Texas.
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.affiliation: University of WA Medical Center, Seattle, Washington.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Coveler
authors.affiliation: Roche innovation Center Basel, Oncology Division, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Meresse
authors.affiliation: Roche Innovation Center Penzberg, Large Molecule Research, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Weigand
authors.affiliation: Roche Innovation Center Penzberg, Oncology Division, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Valeria
authors.initials: V
authors.lastname: Runza
authors.affiliation: Roche Innovation Center Penzberg, Oncology Division, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Cannarile
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D060066:Protein Interaction Maps; D020033:Protein Isoforms; D014158:Transcription, Genetic; D014162:Transfection; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; C576196:RG7356; D006820:Hyaluronic Acid