Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes

Verma, Amit; Suragani, Rajasekhar Nvs; Aluri, Srinivas; Shah, Nishi; Bhagat, Tushar D.; Alexander, Mark J.; Komrokji, Rami; Kumar, Ravi

doi:10.1172/jci133678

Cited by 39 publications

(39 citation statements)

References 55 publications

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“…Like its native counterpart, it can bind activins A and B, myostatin, GDF11, and some BMPs. It has been investigated in clinical trials in patients with thalassemia [115] and myelodysplastic syndromes [116]. With respect to cancer, it was tested in multiple myeloma patients with osteolytic lesions [117] and for treatment of chemotherapy-induced anemia in patients with metastatic cancer [94].…”

Section: Targeting Approaches For Activin Amentioning

confidence: 99%

“…However, the company is not further pursuing these applications and focuses currently on pulmonary arterial hypertension (PAH), where promising interim results of a phase II study with sotatercept were recently obtained (NCT03496207). Luspatercept (ACE-536) is a ligand trap based on the extracellular domain of ActRIIB and has lower affinity for activin A compared to sotatercept [116]. It has recently become the first activin receptor-based drug to gain regulatory approval by the FDA for the treatment of anemia associated with βthalassemia.…”

Section: Targeting Approaches For Activin Amentioning

confidence: 99%

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Activin A: an emerging target for improving cancer treatment?

Ries

Schelch

Falch

et al. 2020

Expert Opinion on Therapeutic Targets

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Introduction: Activin A is involved in the regulation of a surprisingly broad number of processes that are relevant for cancer development and treatment; it is implicated in cell autonomous functions and multiple regulatory functions in the tumor microenvironment. Areas covered: This article summarizes the current knowledge about activin A in cell growth and death, migration and metastasis, angiogenesis, stemness and drug resistance, regulation of antitumor immunity, and cancer cachexia. We explore the role of activin A as a biomarker and discuss strategies for using it as target for cancer therapy. Literature retrieved from Medline until 25 June 2020 was considered. Expert opinion: While many functions of activin A were investigated in preclinical models, there is currently limited experience from clinical trials. Activin A has growth-and migration-promoting effects, contributes to immune evasion and cachexia and is associated with shorter survival in several cancer types. Targeting activin A could offer the chance to simultaneously limit tumor growth and spreading, improve drug response, boost antitumor immune responses and improve cancer-associated or treatment-associated cachexia, bone loss, and anemia. Nevertheless, defining which patients have the highest likelihood of benefiting from these effects is challenging and will require further work.

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Section: Targeting Approaches For Activin Amentioning

confidence: 99%

Section: Targeting Approaches For Activin Amentioning

confidence: 99%

Activin A: an emerging target for improving cancer treatment?

Ries

Schelch

Falch

et al. 2020

Expert Opinion on Therapeutic Targets

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“…Though initially thought to exert its activity via inactivating GDF11, recent genetic studies called into question this mechanism of action ( Guerra et al., 2019 ). A number of other TGFβ ligands, including BMPs, activins, and GDF8 may play role ( Verma et al., 2020 ). Preventing signaling downstream of these ligands can have a profound impact on the BME.…”

Section: Current Therapiesmentioning

confidence: 99%

Targeting the Microenvironment in MDS: The Final Frontier

et al. 2020

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Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal.

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“…Members of the transforming growth factor β (TGF-β) superfamily ligands, including growth differentiation factors and activins, have been shown to act as inhibitors of late-stage erythropoiesis [41][42][43][44]. Activin receptor ligand traps, namely sotatercept and luspatercept, through their ability to reduce SMAD2/3 signaling, improve anemia in disorders characterized by ineffective erythropoiesis, such as β-thalassemia [45] and myelodysplastic syndromes (MDS) [46] (Fig. 1a).…”

Section: Activin II Receptor Trapsmentioning

confidence: 99%

Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation

Motta

Bou‐Fakhredin

Taher

et al. 2020

Drugs

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Hemoglobinopathies are among the most common monogenic diseases worldwide. Approximately 1-5% of the global population are carriers for a genetic thalassemia mutation. The thalassemias are characterized by autosomal recessive inherited defects in the production of hemoglobin. They are highly prevalent in the Mediterranean, Middle East, Indian subcontinent, and East and Southeast Asia. Due to recent migrations, however, the thalassemias are now becoming more common in Europe and North America, making this disease a global health concern. Currently available conventional therapies in thalassemia have many challenges and limitations. A better understanding of the pathophysiology of β-thalassemia in addition to key developments in optimizing transfusion programs and iron-chelation therapy has led to an increase in the life span of thalassemia patients and paved the way for new therapeutic strategies. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. In this review, we provide an overview of the novel therapeutic approaches that are currently in development for β-thalassemia.

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Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes

Cited by 39 publications

References 55 publications

Activin A: an emerging target for improving cancer treatment?

Activin A: an emerging target for improving cancer treatment?

Targeting the Microenvironment in MDS: The Final Frontier

Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation

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