title: Activin receptor antagonists for cancer-related anemia and bone disease.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Monter Cancer Center, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY, USA.
authors.forename: Scott Z
authors.initials: SZ
authors.lastname: Fields
authors.forename: Shiroo
authors.initials: S
authors.lastname: Parshad
authors.forename: Madhurima
authors.initials: M
authors.lastname: Anne
authors.forename: Haralambos
authors.initials: H
authors.lastname: Raftopoulos
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Alexander
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Sherman
authors.forename: Abderrahmane
authors.initials: A
authors.lastname: Laadem
authors.forename: Victoria
authors.initials: V
authors.lastname: Sung
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
mesh_terms: D029404:Activin Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D029404:Activin Receptors