Abstract
BackgroundSurvival outcomes for patients with osteosarcoma (OS) have remained stagnant over the past three decades. Insulin-like growth factor 1 receptor (IGF1R) is over-expressed in a number of malignancies, and anti-IGF1R antibodies have and are currently being studied in clinical trials. Understanding the molecular aberrations which result in increased tumor response to anti-IGF1R therapy could allow for the selection of patients most likely to benefit from IGF1R targeted therapy.Methods IGF1R mRNA expression was assessed by RT PCR in OS patient primary tumors, cell lines, and xenograft tumors. IGF1R copy number was assessed by 3 approaches: PCR, FISH, and dot blot analysis. Exons 1–20 of IGF1R were sequenced in xenograft tumors and 87 primary OS tumors, and surface expression of IGF1R was assessed by flow cytometry. Levels of mRNA and protein expression, copy number, and mutation status were compared with tumor response to anti-IGF1R antibody therapy in 4 OS xenograft models.Results IGF1R mRNA is expressed in OS. Primary patient samples and xenograft samples had higher mRNA expression and copy number compared with corresponding cell lines. IGF1R mRNA expression, cell surface expression, copy number, and mutation status were not associated with tumor responsiveness to anti-IGF1R antibody therapy.Conclusions IGF1R is expressed in OS, however, no clear molecular markers predict response to IGF1R antibody-mediated therapy. Additional pre-clinical studies assessing potential predictive biomarkers and investigating targetable molecular pathways critical to the proliferation of OS cells are needed.
Highlights
Osteosarcoma (OS) is the most common primary bone malignancy in children and young adults [1]
OS Xenograft Tumor Response Osteosarcoma xenograft models OS1, OS17, and OS31 were treated with monotherapy anti-Insulin-like growth factor 1 receptor (IGF1R) therapies SCH 717454, BMS 754807, and IMC A12 in previous Pediatric Preclinical Testing Program (PPTP) studies [14,19,20]
IGF1R expression was higher in the primary patient specimens as compared to the OS cell lines
Summary
Osteosarcoma (OS) is the most common primary bone malignancy in children and young adults [1]. Current treatment strategies have achieved a long-term survival rate of approximately 70% in patients with localized disease at presentation [1,2]. Treatment strategies that target biological pathways driving the proliferation and survival of the malignant cells have recently proven successful in hematologic and solid malignancies. The insulin-like growth factor (IGF) pathway is important for regulating cellular growth, proliferation, and stress response in both normal tissue and cancer cells [6]. Survival outcomes for patients with osteosarcoma (OS) have remained stagnant over the past three decades. Insulin-like growth factor 1 receptor (IGF1R) is over-expressed in a number of malignancies, and anti-IGF1R antibodies have and are currently being studied in clinical trials. Understanding the molecular aberrations which result in increased tumor response to anti-IGF1R therapy could allow for the selection of patients most likely to benefit from IGF1R targeted therapy
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