Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor β (TGF-β) is one of the most abundant growth factors in bones. The TGF-β signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-β is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-β on carcinoma (epithelial origin) progression, TGF-β seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-β signaling have been developed: neutralizing antibodies that prevent TGF-β binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TβRII) or the type III receptor ((TβRIII), preventing TGF-β from binding to its receptors; antisense nucleotides that reduce TGF-β expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TβRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TβRII antisense genes, or target furin convertase, resulting in reduced TGF-β signaling.

TGF-β antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-β antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

骨肉瘤是一种罕见的骨癌，一半的病例影响 20 岁以下的儿童和青少年。尽管大力努力改善化疗和手术治疗，但转移性骨肉瘤的临床结果仍然不佳。转化生长因子 β (TGF-β) 是骨骼中最丰富的生长因子之一。TGF-β信号通路在人类癌症的发病机制中具有复杂且矛盾的作用。TGF-β主要是一种肿瘤抑制因子，可抑制癌前上皮细胞的增殖并诱导其凋亡。然而，在癌症进展的后期，TGF-β通过促进肿瘤生长、诱导上皮间质转化（EMT）、阻断抗肿瘤免疫反应、增加肿瘤相关纤维化和增强血管生成来发挥转移促进剂的作用。与 TGF-β 对癌（上皮来源）进展的双重作用相反，TGF-β 似乎主要对包括骨肉瘤（间质来源）在内的肉瘤具有促肿瘤作用。许多针对 TGF-β 信号转导的药物已被开发出来：阻止 TGF-β 与受体复合物结合的中和抗体；配体陷阱，采用重组 Fc 融合蛋白，其中含有 II 型 (TβRII) 或 III 型受体 ((TβRIII)) 的可溶性胞外域，防止 TGF-β 与其受体结合；反义核苷酸可降低 TGF-β 在转录位点的表达/翻译水平；I型受体丝氨酸/苏氨酸激酶（TβRI）的小分子抑制剂防止下游信号传导；以及含有用TβRII反义基因转染的细胞系或靶向弗林蛋白酶转化酶的疫苗，从而导致TGF-β信号传导减少。

TGF-β拮抗剂已在体外和体内显示对骨肉瘤有作用。小分子TβRI抑制剂之一Vactosertib目前正在进行1/2期临床试验，以评估其对骨肉瘤的作用。多项 1/2/3 期临床试验表明 TGF-β 拮抗剂是安全且耐受性良好的。例如，Luspatercept（一种 TGF-β 配体捕获剂）已被 FDA 批准用于治疗与环形铁粒幼细胞/突变 SF3B1 相关的骨髓发育不良综合征 (MDS) 相关的贫血， 且安全性可接受。评估 Luspatercept 长期安全性的临床试验正在进行中。