Abstract
Simple SummaryTreatment of osteosarcoma, apart from chemotherapy modifications, has not changed for approximately 30 years. Similarly, as in other tumors, mutations in the TP53 gene are often observed in osteosarcoma. In this article, we highlight the possibility of targeting p53 in the treatment of osteosarcoma. We collected data on mutations in this gene founded in patients-derived samples. We describe animals with TP53 dysfunction, which may constitute preclinical models. We put emphasis on several molecules which act on p53 protein or its activity. We also highlight gene therapy approaches. Although many of the therapies are at an early stage, they offer hope for a change in the approach to osteosarcoma treatment based on TP53 targeting in the future.The TP53 gene is mutated in 50% of human tumors. Oncogenic functions of mutant TP53 maintain tumor cell proliferation and tumor growth also in osteosarcomas. We collected data on TP53 mutations in patients to indicate which are more common and describe their role in in vitro and animal models. We also describe animal models with TP53 dysfunction, which provide a good platform for testing the potential therapeutic approaches. Finally, we have indicated a whole range of pharmacological compounds that modulate the action of p53, stabilize its mutated versions or lead to its degradation, cause silencing or, on the contrary, induce the expression of its functional version in genetic therapy. Although many of the described therapies are at the preclinical testing stage, they offer hope for a change in the approach to osteosarcoma treatment based on TP53 targeting in the future.
Highlights
Osteosarcoma (OS) is a primary malignant tumor of the skeleton, characterized by the formation of immature bone or osteoid tissue by the sarcoma cells that develop mostly in the long bones
Li–Fraumeni syndrome (LFS) is a rare, autosomal dominant hereditary disorder— where mutations in the TP53 gene occur in about 70% of the cases [96,97]
No clinical data on treatment with heat shock protein 90 (Hsp90) inhibitors in OS patients are available. Another way to target p53 is treatment with substances that exclusively inhibit pathways involved in the proliferation of p53-mutated cells, including Chk1, polo-like kinase 1 (Plk1), and wee1 kinase (Wee1) [200]
Summary
Osteosarcoma (OS) is a primary malignant tumor of the skeleton, characterized by the formation of immature bone or osteoid tissue by the sarcoma cells that develop mostly in the long bones. P53G245C and p53R273H mutations were reported to promote a more aggressive phenotype with an enhanced malignant potential, high cell viability, and proliferation, enhanced cell migration [10,11,12]. All these molecular data suggest that TP53 is a promising therapeutic target in OS. The development of clinical trials including small molecules that could restore the wild-type conformation of p53 and gene therapy combined with chemotherapy, radiation therapy, or conventional surgery are expected in the future. We review the OS animal models useful for studying TP53-targeted treatments
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