CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients

• Published in: Clinical cancer research Vol. 21; no. 12; pp. 2753 - 2762
• Main Authors: Birzele, Fabian, Voss, Edgar, Nopora, Adam, Honold, Konrad, Heil, Florian, Lohmann, Sabine, Verheul, Henk, Le Tourneau, Christophe, Delord, Jean-Pierre, van Herpen, Carla, Mahalingam, Devalingam, Coveler, Andrew L, Meresse, Valerie, Weigand, Stefan, Runza, Valeria, Cannarile, Michael
• Format: Journal Article
• Language: English
• Published: United States 15.06.2015
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - metabolism; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Disease Models, Animal; Female; Gene Expression; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Hyaluronic Acid - metabolism; Male; Mice; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Protein Binding; Protein Interaction Maps; Protein Isoforms; Transcription, Genetic; Transfection; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-2141

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. 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. 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. 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.