Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

Abstract

Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.

Activin-A impairs CD8 T cell-mediated immunity and immune checkpoint therapy response in melanoma

“… 12 13 INHBA mRNA is upregulated across diverse tumor types, including various skin malignancies, 14 15 and elevated circulating Activin-A promotes cachexia and correlates with poor prognosis. 16 However, whether Activin-A promotes or inhibits tumor progression depends on context. 14 A dual role has been reported in melanoma, where ALK4 signaling in melanocytes inhibits proliferation and survival, whereas frequent gain of Activin-A secretion by melanoma cells promotes tumor growth and metastasis by inhibiting adaptive antitumor immunity.…”

Cardiac Cachexia: Unaddressed Aspect in Cancer Patients

“…The elevation of the circulating cardiac troponin I [59], the most commonly used biomarker to predict cardiac damage, and alteration of the circulating lipid profile observed in patients with cancer cachexia and chemotherapy-induced cardiac toxicity may be considered to be biomarkers that can be used to gain insight into the cardiovascular status of cancer patients with a cachectic phenotype. Significant increases in activin A levels in lung and colorectal cancer patients with cachexia [60] as well as in heart failure patients [61] reinforce the potential role of activin as a biomarker for cancer-induced cardiac dysfunction. Inflammatory markers include TNF-α, IL-1β, and IL-6.…”

Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer

“…We identified increased tumor expression of Inhba and activation of the TGF-β/ SMAD pathway in the skeletal muscle using unbiased transcriptomics. Activin A has been previously established as a pro-cachectic factor, and ActRIIB-Fc treatment is known to improve muscle mass and survival in cachectic mice bearing tumor allografts [78][79][80][81][82] . In KL mice, ActRIIB-Fc increased lean mass and spontaneous activity, but had no benefit on fat mass or survival unless it was given with an agent that effectively improved appetite (i.e., Ana).…”