Osteosarcoma is the most common malignant tumour of the bone; it is the cause of more than 10% of malignant tumours in young adults. Although the survival rate has improved considerably after the introduction of neoadjuvant chemotherapy and surgery, metastatic or recurrent disease still occurs. Osteosarcoma frequently metastasizes especially to the lung and the 5-year survival rate for patients with metastases at the time of diagnosis is only 20¿28%. For this reason, it is essential to investigate new target therapies for osteosarcoma to increase the survival of the patients. In our previous analysis we found that 15 genes (ALDH1L2, BCLAF1, CLCN1, COG3, DIS3, ERBB4, KARS, OR52N1, PDE6C, PDHX, SCN8A, SP140L, THBS1, UBE4A and ZNF12) were mutated only in patients that did not respond to treatment and that developed metastasis, the so-called ¿not responder¿ patients. In this project, our intention is to analyse these gene by WES in a large coorte of high-grade osteosarcoma patients and to study their gene expression profile by RealTime-PCR to corroborate our hypothesis that these genes are involved in metastatic progression of osteosarcoma patients. The goal will be to improve the knowledge of these genes in osteosarcoma metastatic progression; indeed, 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.
Despite improvements in the clinical management of osteosarcoma patients in recent years, the current clinical trials of osteosarcoma have shown only modest progress. Probably due, first to poor knowledge of the molecular events associated with the development of osteosarcoma and moreover because there is not a true molecular targeted therapy for osteosarcoma. So, clinical outcomes for patients have not improved over the past 30 years and there are currently no approved target antimetastatic therapies for osteosarcoma in wide clinical use. More than 75% of osteosarcoma metastases occur in the lung and these are the cause of most of osteosarcoma -related deaths.
Metastasis is a complex multistep process that is not fully understood, and the sequencing of the exome have become indispensable tools in the study of this tumour to identify mutations involved in metastatic progression and resistance to therapy. Indeed, exome sequencing where the coding region of the genome is sequenced at a deep level has proven to be a cost-effective method to detect tumour-specific mutations. The knowledge of genetic alterations in coding exon regions may result in an easier discovery of new molecular target which could be aimed by personalized therapies.
In this project, the study of genes probably involved in metastasis development and drug resistance could offer the opportunity to identify potential drug targets in order to create a personalized therapy and increase the survival rate among young patients with osteosarcoma.