Evaluation of agents targeting mechanisms involved in repair of drug-induced DNA damages in osteosarcoma

Osteosarcoma (OS) is a highly aggressive bone tumor, which shows high prevalence among children and young adults and often displays drug resistance towards the most common neoadjuvant chemotherapy drugs. Provided that three out of the four drugs used induce DNA damage either directly (cisplatin and ifosfamide) or indirectly (doxorubicin), one of the resistance mechanisms observed in OS is represented by aberrantly activated DNA repair pathways, which allow tumor cells to survive and to cope with DNA damage. A thorough investigation of genetic status involved in such aberrant DNA repair activity, along with emergence of new inhibitors targeting these genes, could provide new treatment strategies to overcome drug resistance in OS. The present project aims to evaluate the efficacy of new inhibitor drugs targeting genes and pathways involved either directly or indirectly in DNA repair in human OS cell lines. Specific categories of inhibitors were examined in light of the important roles covered by targeted genes in OS and for their potential exploitation in treatment of this entity. Moreover, efficacy of PARP inhibitors was prioritized and Talazoparib peaked as most effective agent to be further investigated. Indeed, the selection of human OS cell lines resistant to prioritized DNA repair inhibitor Talazoparib was carried out to provide an experimental model for studying the underlying mechanisms of resistance which may be developed by OS cells. Moreover, potential use of Talazoparib as adjuvant to conventional chemotherapy was assessed in combined treatments with DX and CDDP. Lastly, such in vitro efficacy assessment was accompanied by NGS investigation provided by targeted multimodal sequencing of nucleic acids from human OS cell lines, which yielded preliminary results to be further explored. Such approach was attained in order to shed light on potential biomarkers to be considered for effective translation of new treatment approaches in OS clinical setting.