Introduction

The receptor activator of nuclear factor kb/-ligand/osteoprotegerin (RANK/RANKL/OPG) triad and insulin-like growth factor 1 receptor (IGF1R) system are potential therapeutic targets in osteosarcoma. We studied the consistency of expression of specific targets over time and across lesions within subjects. This aids to select biomarkers for future therapies and to determine an optimal sequence of targeted and cytotoxic therapy.

Materials and methods

Immunohistochemical staining was performed on paraffin-embedded therapy-naïve biopsies, post-neoadjuvant chemotherapy resection specimens, and metastatic lesions for RANK, OPG, IGF1R, IGF1, phosphorylated protein kinase B (pAKT), mammalian target of rapamycin (pMTOR) and extracellular-regulated kinase (pERK). Staining intensity was scored as absent (0), weak (1) or strong (2). Change of expression between lesions within subjects was interrogated by Wilcoxon signed rank tests.

Results

49 tumor samples of 28 patients were available (staining results presented in table 1). No change in RANK or OPG expression was observed. After chemotherapy pERK (p=0.008) and pMTOR expression (p=0.015) decreased; pERK and IGF1R expression (both p=0.046) were lower in metastases than in primary tumors. Expression of IGF1 and pAKT remained unchanged.

Discussion

The choice for a therapeutic regimen is increasingly guided by presence of specific molecular alterations in tumor tissue. Variation of target expression over time and across lesions within subjects is a known phenomenon in common cancers. In osteosarcomas, we found a rather consistent expression signature with the exception of pERK, pMTOR and IGF1R, which were downregulated after exposure to chemotherapy or in metastatic lesions.

Conclusion

Screening for biomarkers for specific targeted drugs in osteosarcoma should not be limited to a single tumor sample. It is likely from our data that an optimal sequence of targeted therapies and cytotoxic drugs exists.

Table 1:

Staining results (%)

 Biopsy (n=28)Resection (n=13)Metastasis (n=8)
Intensity 
RANK 14 86 15 85 13 88 
OPG 54 43 39 54 25 50 25 
IGF1 96 21 79 100 
IGF1R 86 15 77 14 57 29 
pmTOR 25 29 46 69 15 15 43 14 43 
pAKT 11 50 39 31 39 31 29 71 
pERK 100 54 46 50 50 
 Biopsy (n=28)Resection (n=13)Metastasis (n=8)
Intensity 
RANK 14 86 15 85 13 88 
OPG 54 43 39 54 25 50 25 
IGF1 96 21 79 100 
IGF1R 86 15 77 14 57 29 
pmTOR 25 29 46 69 15 15 43 14 43 
pAKT 11 50 39 31 39 31 29 71 
pERK 100 54 46 50 50 

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 1599.