Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. ...We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo. We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.
ObjectiveThis study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC).Design, setting and participantsThis is a phase ...1–1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion.InterventionsPatients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation.Outcome measuresThe phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab.Results33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study.ConclusionsSabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types.Trial registration numberNCT02608268.
Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the ...safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.
Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.
Enrolled patients (
= 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (
= 133) or sabatolimab plus spartalizumab (
= 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12-27 months) in colorectal cancer (
= 2), non-small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3-positive staining, including one patient with NSCLC who received prior PD-1 therapy.
Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
Runx2 is a master regulator of bone development and has also been described as an oncogene. Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα), both implicated in bone metabolism and ...breast cancer, have been shown to share common transcriptional targets. Here, we show that ERα is a positive regulator of Runx2-I transcription. Moreover, ERRα can act as a transcriptional activator of Runx2-I in presence of peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α). In contrast, ERRα behaves as a negative regulator of Runx2-I transcription in presence of PGC-1β. ERα and ERRα cross-talk via a common estrogen receptor response element on the Runx2-I promoter. In addition, estrogen regulates PGC-1β that in turn is able to modulate both ERα and ERRα transcriptional activity.
The importance of insulin-like growth factor I (IGF-I) on maintenance of skeletal integrity has been widely recognized. Although osteoblasts secrete some IGF-I, the liver is the primary endocrine ...source for IGF-I. We have studied the regulation of the human IGF-I promoter in the hepatocyte cell line Hep3B, and we have shown that the IGF-I promoter, when co-transfected in Hep3B cells together with an estrogen receptor (ER)-α expression vector, was transcriptionally regulated by raloxifene or raloxifene-like molecules but not by 17β-estradiol and 4(OH)-tamoxifen. The induction mediated by raloxifene is antagonized by 17β-estradiol and mediated selectively by ER-α, but not by ER-β. Transfer of IGF-I promoter sequences from −733 to −65 or from −375 to −65 to a minimal Fos promoter resulted in a comparable responsiveness to raloxifene. This region contains two CAAT/enhancer-binding protein sites and an activator protein 1 site, both of which have been shown to be involved in estrogen receptor-mediated transactivation. When the CAAT/enhancer-binding protein sites were mutated in a construct bearing the sequence from −375 to −65 in front of the minimal Fos promoter, raloxifene induction was reduced, whereas mutation of the other elements did not affect induction. In addition, using chimeric proteins, we delineated the domains of ER-α that confer to ER-α transactivation abilities on the IGF-I promoter that are not exhibited by ER-β. These data shed new light on the mechanism of action of antiestrogens and might help explain, at least in part, the bone-protective effects observed for some antiestrogens in ovariectomized animals.
The importance of insulin-like growth factor I (IGF-I) on maintenance of skeletal integrity has been widely recognized. Although
osteoblasts secrete some IGF-I, the liver is the primary endocrine ...source for IGF-I. We have studied the regulation of the
human IGF-I promoter in the hepatocyte cell line Hep3B, and we have shown that the IGF-I promoter, when co-transfected in
Hep3B cells together with an estrogen receptor (ER)-α expression vector, was transcriptionally regulated by raloxifene or
raloxifene-like molecules but not by 17β-estradiol and 4(OH)-tamoxifen. The induction mediated by raloxifene is antagonized
by 17β-estradiol and mediated selectively by ER-α, but not by ER-β. Transfer of IGF-I promoter sequences from â733 to â65
or from â375 to â65 to a minimal Fos promoter resulted in a comparable responsiveness to raloxifene. This region contains
two CAAT/enhancer-binding protein sites and an activator protein 1 site, both of which have been shown to be involved in estrogen
receptor-mediated transactivation. When the CAAT/enhancer-binding protein sites were mutated in a construct bearing the sequence
from â375 to â65 in front of the minimal Fos promoter, raloxifene induction was reduced, whereas mutation of the other elements
did not affect induction. In addition, using chimeric proteins, we delineated the domains of ER-α that confer to ER-α transactivation
abilities on the IGF-I promoter that are not exhibited by ER-β. These data shed new light on the mechanism of action of antiestrogens
and might help explain, at least in part, the bone-protective effects observed for some antiestrogens in ovariectomized animals.
Angiogenesis is a fundamental process in skeletal development and repair, and previous studies indicate that vascular endothelial growth factor (VEGF), an endothelial cell-specific angiogenic factor, ...may be involved in bone formation and repair Therefore, we studied the hormonal regulation of VEGF expression in SaOS-2 osteoblast-like cells, both at the protein level, and at the transcriptional level by transient transfection experiments. 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3, increased VEGF expression by approximately 3-fold, and the increase was dose dependent, with maximum stimulation between 1.0 and 10 nM of 1,25-(OH)2D3. Up-regulation of VEGF protein was detected already after 6 h of treatment. VEGF up-regulation was also observed in ROS-17/2.8 and OHS-4 osteoblast-like cells but not in MCF-7 and MDA-MB231 breast carcinoma cells. Dexamethasone (Dex) decreased VEGF expression to 40% of the control, but when added together with 1,25-(OH)2D3, had no effects on the up-regulation of VEGF by 1,25-(OH)2D3. PTHi-34 stimulated weakly VEGF expression, but combined with 1,25-(OH)2D3, resulted in a close to 5-fold stimulation. A 4-day pretreatment of the cells with Dex increased the vitamin D3 receptor expression and resulted in a stronger stimulation of VEGF by 1,25-(OH)2D3, alone or in combination with PTHi-34. The results show that the VEGF promoter is a target of 1,25-(OH)2D3 regulation in osteoblasts, despite the lack of classical vitamin D3 responsive elements. The up-regulation of VEGF in osteoblast-like cells by calciotropic hormones provides additional evidence of the involvement of VEGF in bone metabolism.
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