Monter Cancer Center, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY, USA.
Expert Opin Investig Drugs. 2013 Jan;22(1):87-101. doi: 10.1517/13543784.2013.738666. Epub 2012 Nov 6.
Antagonists of activin receptor signaling may be beneficial for cancer-related anemia and bone disease caused by malignancies such as multiple myeloma and solid tumors.
We review evidence of dysregulated signaling by activin receptor pathways in anemia, myeloma-associated osteolysis, and metastatic bone disease, as well as potential involvement in carcinogenesis. We then review properties of activin receptor antagonists in clinical development.
Sotatercept is a novel receptor fusion protein that functions as a soluble trap to sequester ligands of activin receptor type IIA (ActRIIA). Preclinically, the murine version of sotatercept increased red blood cells (RBC) in a model of chemotherapy-induced anemia, inhibited tumor growth and metastasis, and exerted anabolic effects on bone in diverse models of multiple myeloma. Clinically, sotatercept increases RBC markedly in healthy volunteers and patients with multiple myeloma. With a rapid onset of action differing from erythropoietin, sotatercept is in clinical development as a potential first-in-class therapeutic for cancer-related anemia, including those characterized by ineffective erythropoiesis as in myelodysplastic syndromes. Anabolic bone activity in early clinical studies and potential antitumor effects make sotatercept a promising therapeutic candidate for multiple myeloma and malignant bone diseases. Antitumor activity has been observed preclinically with small-molecule inhibitors of transforming growth factor-β receptor type I (ALK5) that also antagonize the closely related activin receptors ALK4 and ALK7. LY-2157299, the first such inhibitor to enter clinical studies, has shown an acceptable safety profile so far in patients with advanced cancer. Together, these data identify activin receptor antagonists as attractive therapeutic candidates for multiple diseases.
激活素受体信号通路的拮抗剂可能对癌症相关贫血和多发性骨髓瘤和实体瘤等恶性肿瘤引起的骨疾病有益。
我们综述了激活素受体通路在贫血、骨髓瘤相关溶骨性疾病和转移性骨疾病中的失调信号，以及其在肿瘤发生中的潜在作用。然后，我们回顾了临床开发中激活素受体拮抗剂的特性。
Sotatercept 是一种新型受体融合蛋白，作为激活素受体 IIA（ActRIIA）配体的可溶性陷阱发挥作用。在临床前研究中，鼠源 sotatercept 可增加化疗诱导性贫血模型中的红细胞（RBC）数量，抑制肿瘤生长和转移，并在多发性骨髓瘤的多种模型中对骨骼产生合成代谢作用。在临床上，sotatercept 可显著增加健康志愿者和多发性骨髓瘤患者的 RBC。与促红细胞生成素的作用机制不同，sotatercept 的作用迅速，作为癌症相关贫血的潜在同类首创治疗药物正在临床开发中，包括骨髓增生异常综合征等无效性红细胞生成的贫血。早期临床研究中的骨合成代谢活性和潜在的抗肿瘤作用使 sotatercept 成为多发性骨髓瘤和恶性骨疾病的有前途的治疗候选药物。临床前研究观察到小分子转化生长因子-β受体 I（ALK5）抑制剂具有抗肿瘤活性，也能拮抗密切相关的激活素受体 ALK4 和 ALK7。LY-2157299 是首个进入临床研究的此类抑制剂，迄今为止在晚期癌症患者中显示出可接受的安全性。综上所述，这些数据表明激活素受体拮抗剂是多种疾病的有吸引力的治疗候选药物。
