Abstract 655: Prognostic relevance of the RANK/RANKL/OPG triad and the IGF1R pathway in osteosarcoma
Authors: van de Luijtgaarden Addy , Leus Manon , Roeffen Melissa , Flucke Uta , van der Geest Ingrid , van der Graaf Winette , Versleijen-Jonkers Yvonne 
Published: February 2011

Abstract
Introduction
Survival in osteosarcoma patients is still limited to 60-70% and new therapeutic options are urgently needed. We examined expression of components of the insulin-like growth factor 1 receptor (IGF1R) axis and the receptor activator of nuclear factor kβ/-ligand/osteoprotegerin(RANK/RANKL/OPG) triad in osteosarcoma tumor biopsies and calculated corresponding prognostic values. This will aid in the selection of future targeted therapies.
Materials and methods
Archival paraffin-embedded therapy-naïve primary osteoblastic osteosarcoma biopsies were immunohistochemically stained for RANK, OPG, IGF1, IGF1R, phosphorylated protein kinase B (pAKT), phosphorylated mammalian target of rapamycin (pmTOR) and phosphorylated extracellular-regulated kinase (pERK). A semiquantitative scoring system was used in which staining of &lt;10% of cells was scored “0”, staining of at least 10% of cells but with an intensity less than positive control was scored “1” and staining intensity equal to or greater than positive control of
≥10% of cells was scored “2”. Influence on event-free and overall survival was tested by the Kaplan-Meier method and Spearman ρ correlations were calculated for response to chemotherapy (&lt; vs.
≥90% necrosis).
Results
Tumors of 28 patients (median follow-up 62 months) were available. Expression of RANK (14% weak, 86% strong), OPG (54% weak, 43% strong), IGF1R (7% weak, 86% strong), IGF1 (96% strong), pmTOR (29% weak, 46% strong), pAKT (50% weak, 39% strong) and pERK (100% strong) was high. Stronger expression of RANK predicted worse event-free survival (EFS median 23 months vs not reached, p=0.049). Absence of pmTOR expression at diagnosis predicted worse overall survival (OS median 26 months vs. not reached, p=0.026) and a trend towards worse response to chemotherapy in pmTOR negative tumors was observed (ρ=0.365, p=0.067).
Discussion
Strong expression of RANK, a key regulator of bone metabolism, on osteosarcoma samples predicted worse EFS. Since pmTOR is involved in the IGF1R axis which is required for osteoblast growth, it is intriguing that absent pmTOR expression was related with worse OS. The trend towards less chemotherapy response in pmTOR negative tumors might reflect the lack of a sufficient proliferation rate which is required for an adequate response to chemotherapy.
Conclusion
Targeting the RANK/RANKL/OPG signaling triad could provide survival benefits in osteosarcoma patients. The mechanism by which absent pmTOR expression predicts worse patient outcome and possibly is related to a worse response to neoadjuvant chemotherapy will be further explored.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 655.