Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap

Iancu‐Rubin, Camelia; Mosoyan, Goar; Wang, Jiapeng; Kraus, Thomas; Sung, Victoria; Hoffman, Ronald

doi:10.1016/j.exphem.2012.12.002

Cited by 91 publications

(70 citation statements)

References 32 publications

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“…However, the mechanisms underlying the effect of sotatercept or analogous compounds on erythropoiesis are still poorly understood. Cellular or soluble factors in the bone marrow microenvironment could be involved [11,13] .…”

Section: Activin Inhibitorsmentioning

confidence: 99%

Erythropoietin

Jelkmann¹

2016

Frontiers of Hormone Research

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Total hemoglobin (Hb) mass is an important determinant of aerobic power. The glycoprotein erythropoietin (Epo) promotes the production of red blood cells (RBCs). The present article reviews the regulation of erythropoiesis and ways of its manipulation. The various Epos, e.g. recombinant human (rh)Epo and (epoetin), and their long-acting analogues can be misused by cheating athletes, but the drugs are detectable by chemical tests, because their glycan isoform structures differ from those of endogenous Epo. Still, anti-doping control has become more difficult, since additional erythropoiesis-stimulating agents have become available (Epo mimetics, activin inhibitors, and small-molecule chemical drugs activating EPO expression). A major problem is created by hypoxia-inducible factor (HIF) stabilizers (e.g. α-ketoglutarate competitors and Co2+ salt) which activate HIFs and thus increase EPO expression. Direct EPO transfer is theoretically also possible but medically little advanced. To overcome weaknesses of direct testing of biological fluids, the World Anti-Doping Agency has implemented the Athlete Biological Passport for continuous monitoring of RBC parameters of athletes. Blood doping is assumed when distinct parameters (blood Hb concentration and reticulocytes) change in a nonphysiological way.

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Section: Activin Inhibitorsmentioning

confidence: 99%

Erythropoietin

Jelkmann¹

2016

Frontiers of Hormone Research

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“…88 In the first report of an ongoing trial (NCT01712308) in patients with MF and anemia, sotatercept led to a 36% objective response rate (ORR), which included achievement of TI in some RBC-TD patients. 89 This well-tolerated agent lends itself particularly well to combination with ruxolitinib, and if proven effective in the combination arm of this trial, this class of agents could prove to be a useful addition to the therapeutic armamentarium for anemia of MF, enabling more patients to stay on and receive an optimal dose of ruxolitinib.…”

Section: Rational Ruxolitinib-based Combinations For Mf: Is This the mentioning

confidence: 99%

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Bose

Verstovšek

2017

Blood

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Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.

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“…Its inhibition in mouse models of anemia with ineffective erythropoiesis restores normal erythropoietic differentiation and alleviates anemia. 76 Sotatercept (ACE 011) has the chemical structure of activin receptor IIA (ActRIIA). It has been shown to increase hemoglobin levels in breast cancer patients treated for bone metastasis, and thus was evaluated for erythropoietic stimulating activity, especially in beta-thalassemia, 77 but of course its possible effects in MDS were investigated.…”

Section: Experimental Agents In Esa Failuresmentioning

confidence: 99%

“…75 Three different molecules with anti-TGF-β activity have been evaluated in clinics: sotatercept, luspatercept, and galunisertib. [76][77][78][79][80][81] Two of these target GDF11, a molecule that regulates erythropoiesis. Its inhibition in mouse models of anemia with ineffective erythropoiesis restores normal erythropoietic differentiation and alleviates anemia.…”

Section: Experimental Agents In Esa Failuresmentioning

confidence: 99%

Anemia as the Main Manifestation of Myelodysplastic Syndromes

Santini

2015

Seminars in Hematology

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Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap

Cited by 91 publications

References 32 publications

Erythropoietin

Erythropoietin

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Anemia as the Main Manifestation of Myelodysplastic Syndromes

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