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.
Although the advances in understanding of the aetiology and biology of OS, the recent clinical trials of OS have shown only modest progress. Clinical outcomes for patients have not improved over the past 30 years and there are currently no approved target antimetastatic therapies for OS in wide clinical use. More than 75% of OS metastases occur in the lung and these are the cause of most of OS-related deaths. Moreover, despite the excellent clinical response obtained in some tumours using immune checkpoint inhibitors, no promising results were obtained in osteosarcoma with the use of immunotherapy, and it is supposed that the mechanisms underlying this resistance may relate to the CXCL12/CXCR4 axis. So, to obtain a valid therapeutic approach in the treatment of osteosarcoma patients, the blockade of CXCL12/CXCR4 axis, through selective CXCR4 antagonist, should be used synergistically with immunotherapy approach.
We will try to go beyond the specific problems posed in therapy development for rare diseases, that include the small and dispersed patient populations and the limited market for such therapies that provides a low commercial return. So, the project seeks to accelerate research in novel marker and drug development in immunotherapy through the identification of patients at risk earlier to develop metastasis, allowing to a personalized treatment.