Osteosarcoma is the most common pediatric primary bone tumor. The survival rate has improved considerably with neoadjuvant chemotherapy, but metastatic disease still occurs. The survival of patients is related to the response to chemotherapy and development of metastases. The osteosarcoma chemotherapy is still based on not selective cytotoxic drugs so a more efficacious treatments for osteosarcoma patients are clearly needed.
Osteosarcoma karyotype is complex, and this determines the generations of neo-antigens that can be recognized by the immune system. However, therapy with checkpoint inhibitors turned out to be a failure in osteosarcoma. The CXCL12-CXCR4 signalling is involved in various biological and pathological processes.
Aberrant changes in CXCL12 expression can result in alteration in cell migration and local proliferation in osteosarcoma and it has been hypothesized that alteration of this signalling could be the cause of the failure of the use of checkpoint inhibitors in osteosarcoma immunotherapy. Moreover, in our previous study we found that CXCL12 gene expression was modulated in osteosarcoma cell lines after KMT2C mRNA silencing, a gene coding a chromatin-modifying and remodelling protein. The aim of this project is to stratify osteosarcoma patients on CXCL12 and CXCR4 gene and protein expression on primary tumour and on blood samples (liquid biopsy) during follow-up to identify patients that could be eligible for the combined treatment (anti-CXCL12-CXCR4 plus checkpoint inhibitors). The goal will be to improve the knowledge of CXCL12-CXCR4 axis in osteosarcoma metastatic progression to give a tailored combined immunotherapy for each patient based on his CXCL12-CXCR4 profile. The project seeks to accelerate research in osteosarcoma treatment, will permit closer therapy monitoring and might help to identify patients at risk earlier to develop metastasis, allowing to a personalized treatment.