Analysis and validation of gene polymorphisms in osteosarcoma

Osteosarcoma (OS) is an aggressive bone tumor for which the cure rate has not significantly improved in the last 30 years. OS is treated with neoadjuvant chemotherapy regimens, whose effectiveness can be opposed by drug resistance mechanisms that decrease treatment response and cure probability. Moreover, the problem of treatment-related adverse events has to be seriously taken into consideration because it can negatively affect patients' quality of life. It is therefore necessary to identify novel biomarkers, which can distinguish patients who are at risk of developing drug resistance or collateral toxicity due to chemotherapy. In the past years, candidate gene polymorphisms have been indicated to be involved in response to chemotherapy and/or susceptibility to treatment-related toxicity in OS patients, but this information needs further validation. The aim of this PhD project is to validate the clinical impact of candidate gene polymorphisms, which have been highlighted in previous studies and to better define their possible predictive value. Candidate gene polymorphisms, therefore, have been analyzed in a panel of human OS cell lines, either sensitive or resistant to conventional chemotherapy drugs, to confirm their role in the development of drug resistance. Moreover, the same polymorphisms have been evaluated in OS clinical samples to validate their predictiveness for the OS development and their prognostic value. Finally, to study the involvement of these polymorphisms in the development of collateral toxicity due to the use of chemotherapy, a human kidney model has been developed to allow future research aimed to better clarify how single nucleotide polymorphisms may contribute to the development of toxicity in this organ. The results achieved in this project are essential to identify single nucleotide polymorphisms that are important in the development of OS but most of all in treatment unresponsiveness, which may be used to draw more personalized treatments.