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Abstract：
Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas.
摘要：
肉瘤是异质性骨和软组织癌症，代表儿童和青少年中第二常见的肿瘤类型。组织学和基因分析发现了100多种亚型，其特征是特殊的分子脆弱性。然而,除标准治疗外,治疗选择有限,仅在少数肉瘤患者中观察到靶向治疗的临床获益.这些肿瘤的稀有性，缺乏可操作的突变，目前靶向治疗的化学成分和局限性阻碍了这些方法在肉瘤中的应用。靶向蛋白降解（TPD）是一种创新的药理学方式，可直接改变蛋白质丰度，在癌症中具有有希望的临床潜力。甚至是不可食用的蛋白质。TPD基于使用称为降解剂或蛋白水解靶向嵌合体（PROTACs）的小分子，引发泛素依赖性降解感兴趣的蛋白质。在这次审查中,我们将讨论PROTAC和PROTAC衍生的遗传系统的主要特征，用于靶标验证和癌症治疗，并关注这些方法克服与肉瘤靶向治疗相关的主要问题的潜力，包括耐药性,目标特异性，和不可用的目标。对这些策略的更深入了解可能为推动分子和个性化医学治疗肉瘤提供新的燃料。
