SKP2缺失致p53/pRb双失功能骨肉瘤中的协同致死作用和机制研究

骨肉瘤是最常见的青少年骨原发恶性肿瘤,预后极差，近40年骨肉瘤患者的生存改善不明显，因此迫切需要探索新的治疗靶点和方法。骨肉瘤的发病机理至今不清，而且缺乏特异性的致癌基因或致癌通路，但我们前期的研究总结发现抑癌因子p53和pRb共同失功能突变是骨肉瘤中最常见的成对抑癌基因突变；同时我们还发现pRb的下游抑制性靶点，SKP2，在骨肉瘤中过表达且提示不良预后。SKP2可能通过其靶蛋白p27对骨肉瘤的发生发展发挥促进作用，而抑制SKP2活性可以抑制骨肉瘤细胞增殖及转移。因此我们拟克服以往采用体外细胞系或人肿瘤异种移植模型的局限性，应用骨组织特异性TP53/RB1双敲除转基因自发骨肉瘤小鼠模型和三维骨肉瘤类器官模型，探讨SKP2是否为p53和pRb双失功能骨肉瘤细胞协同致死的靶点及具体相关机制。该研究有助于为骨肉瘤寻找新的治疗靶点和方式提供信息。

Osteosarcoma (OS) is the most common bone malignancy in children and adolescents with a worse prognosis. Since current intense chemotherapy fails to improve survival, novel approaches, especially those that are independent of response to cytotoxic agents are urgently needed. Studies have shown that inactivation of tumor suppressors pRb and p53 are the most common genetic landscape of OS. Since p53 and pRb cannot be reactivated or re-introduced into the patient’s tumor, their inactivation poses a formidable challenge, making OS very difficult to treat. Our previous studies have shown that SKP2 is a prognostic factor and plays an oncogenic role in OS. In the context of p53/pRb co-inactivation, the addition of SKP2 deletion is synthetic lethal and appears to block tumorigenesis lastingly, suggesting that cancers with combined pRb and p53 alterations such as OS may be particularly susceptible to SKP2 inhibition. Although the oncogenic role of SKP2 has been studied in several human cancers, the mechanistic interactions and therapeutic utility of the SKP2 in OS in the context of p53/pRb inactivation are still largely unexplored. We will test our hypothesis using two clinically relevant models, including genetically engineered mouse model with double knockout of pRb and p53 within cells of the osteoblastic lineage, to define pro-oncogenic mechanisms by which the SKP2 promotes OS tumorigenesis, within the context of p53/pRb co-inactivation. Human-derived OS organoids will be served as the second preclinical model to understand the effect and mechanism by inhibiting SKP2 in p53/pRb -deficient OS as translational therapeutics. Together, leveraging p53/pRb inactivation and SKP2 vulnerabilities to create new therapeutics that can decrease the tumor burden and prolong the survival of OS patients.