Insight into the Molecular and Cellular Etiology of the Tumors Responsible for Tumor-Induced Osteomalacia

Presentation Number: OR07-7
Date of Presentation: April 2nd, 2017

Jason A Berglund*1, Rachel I Gafni1, Jonathan A Forsberg2, Alfredo A Molinolo3, Luis Fernandez de Castro1, Kelly G Ten Hagen4, E Tian4, Tarek Metwally5, Diana Overjero Crespo1, William Chong6 and Michael T. Collins1
1Section on Skeletal Disorders and Mineral Homeostasis, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 2Orthopaedics, USU-Walter Reed Department of Surgery, Bethesda, MD, 3University of California San Diego, San Diego, CA, 4Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 5University of Michigan School of Dentistry, Ann Arbor, MI, 6FDA, Silver Spring, MD



Tumor-induced osteomalacia (TIO) is a rare paraneoplastic condition associated with hypophosphatemia, muscle weakness, bone pain, and pathological fracture. It is caused by secretion of FGF23 by phosphaturic mesenchymal tumors (PMTs) with histological features reminiscent of osteogenic cells. The molecular and cellular origins of these tumors have yet to be clearly elucidated, but the recent identification of a fibronectin-fibroblast growth factor receptor 1 (FN1-FGFR1) translocation in a subset of these tumors suggests FGFR1 signaling as a potential tumorogenic driver


In an effort to better understand the pathophysiology of PMTs, 26 tumors clinically proven to cause TIO by cure after resection were assessed. Analyses included: translocation testing with a FN1/FGFR1-specific FISH, immunohistochemical and/or immunofluorescent testing of markers of FGF23 and FGFR1 pathway signaling, and osteogenic cell markers. A comparison was made in vitro of the response in FGF23 production to FGFR and/or mTOR blockade by BGJ398 and rapamycin, respectively, in separate FN1/FGFR1 translocation positive and negative tumors.


14/26 (54%) tumors were successfully assessed by FISH (tumors arising in bone were generally unanalyzable). Of the 14 samples, 4/14 (29%) were positive for a FN1-FGFR1 translocation. All tumors were FGF23 positive. Tumors were positive for various early and late osteogenic lineage markers (including DMP-1, which showed a high level of co-expression with FGF23), the FGF23 UDP-GalNAc transferase, GALNT3, and the FGF23 co-receptor KLOTHO. In vitro, addition of the FGFR inhibitor BGJ-398, with and without presence of the synergistic mTOR inhibitor rapamycin, decreased FGF23 production by 80% in a FN1/FGFR1 translocation positive tumor, but had a negligible effect on a tumor lacking the translocation.


PMTs express osteogenic cell markers consistent with having differentiated from an inducible skeletal stem cell. A significant proportion of PMTs harbor a FN1/FGFR1 translocation, and may be responsive to FGFR pathway blockade. These data suggest a role for FGR1 signaling in tumorigenesis and FGF23 production, and identify the FGFR1 pathway as a potential target for treatment.


Disclosure: RIG: , Shire. Nothing to Disclose: JAB, JAF, AAM, LF, KGT, ET, TM, DO, WC, MTC