Journal articles on the topic 'RAP-011'
To see the other types of publications on this topic, follow the link: RAP-011.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 25 journal articles for your research on the topic 'RAP-011.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Carrancio, Soraya, Jennifer A. Markovics, Piu Wong, Carla Heise, Tom O. Daniel, Rajesh Chopra, and Victoria Sung. "Sotatercept Promotes Differentiation and Survival Of Erythroid Progenitors By Blocking Inhibitory Effects Of TGFβ Superfamily Members." Blood 122, no. 21 (November 15, 2013): 944. http://dx.doi.org/10.1182/blood.v122.21.944.944.
Full textAbstract:
Abstract Erythropoiesis, the process of cell proliferation and differentiation that produces erythrocytes, is a tightly regulated process, but apart from early progenitor development and the EPO-dependent response, very little is known about other molecular signals which control cellular fate during RBC production. Members of the transforming growth factor beta (TGFβ) superfamily have been studied as potential regulators of erythropoiesis, iron regulation and globin expression. Sotatercept, an ActRIIA ligand trap, binds to and inhibits activin and other members of the TGFβ superfamily to induce a rapid increase in red cell number and hemoglobin in healthy volunteers. Pharmacological findings demonstrate that RAP-011, a murine ortholog of sotatercept, stimulates RBC parameters in mice through a mechanism distinct from EPO. We conducted the current study to evaluate if RAP-011 may stimulate expansion of a late-stage erythroblast population that is not normally expanded and/or may induce faster differentiation of erythroid precursors. In order to determine if RAP-011 promotes proliferation or differentiation during erythropoiesis, the number of cell divisions was quantified by CFSE staining. During in vitro erythroid differentiation, RAP-011 did not appear to alter the number of cell divisions; however, the percentage of cells that underwent the last division was higher in cultures treated with RAP-011, suggesting that the drug induced faster cellular maturation/differentiation. We also analyzed cell viability of GPA+ cells at the end of the differentiation process and observed that the percentage of apoptotic death was higher in control vs. RAP-011-treated cells. This suggests that RAP-011 may promote survival of late-stage precursors. To assess potential candidates which may mediate the erythropoietic effects of RAP-011, we selected three high affinity RAP-011 ligands, Activin A, Activin B and GDF-11, and proceeded to evaluate their effects on Smad signaling and on erythroid differentiation of human bone marrow progenitors. First, we observed that RAP-011 blocked ligand-induced Smad2/3 phosphorylation in the bone marrow-derived cells. Secondly, RAP-011 rescued activin A-induced inhibition of BFU-E colony formation. Finally, when mature CD36+ cells were differentiated in liquid media containing each of the three ligands, RAP-011 was able to reverse GDF-11- and Activin A-induced inhibition of of erythroid cell proliferation. GDF-11 and Activin A also significantly decreased the percentage of GPA-positive cells in culture, while significantly increasing the percentage of CD45-positive cells. Consistent with proliferation results, RAP-011 blocked these ligand effects. Treatment of CD36+ cells with Activin B did not alter growth or differentiation. These data suggest that GDF-11 and Activin A may contribute, in part, to the erythropoietic stimulatory effects of RAP-011. Several members of the TGFβ superfamily of ligands have been implicated as negative growth regulators, or “chalones”, functioning in homeostasis to maintain specific, mature tissue size. The results from our studies using the ActRIIA-Fc ligand trap, RAP-011, suggest that GDF-11 and Activin A, as well as other sotatercept ligands, may also be “chalones” for the blood, specifically regulating homeostasis of mature RBCs. We suggest that sotatercept increases red blood cell maturation and survival by blocking the negative growth regulation by TGFβ members. In pathologic states such as ineffective erythropoiesis, sotatercept may have an even greater impact than in the healthy, homeostatically-balanced environment. Disclosures: Carrancio: Celgene Corp.: Employment. Markovics:Celgene Corp.: Employment. Wong:Celgene Corp.: Employment. Heise:Celgene: Employment, Equity Ownership. Daniel:Celgene Corp.: Employment, Equity Ownership. Chopra:Celgene: Employment, Equity Ownership. Sung:Celgene Corp.: Employment.
2
Carrancio, Soraya, Jennifer A. Markovics, Piu Wong, Jim Leisten, Matthew C. Groza, Heather K. Raymon, Carla Heise, Rajesh Chopra, Tom O. Daniel, and Victoria Sung. "Sotatercept, an Activin Receptor IIa Ligand Trap, Acts Through Bone Marrow Accessory Cells to Promote Late-Stage Erythropoiesis and a Rapid Induction of Red Blood Cell Number and Hemoglobin." Blood 120, no. 21 (November 16, 2012): 372. http://dx.doi.org/10.1182/blood.v120.21.372.372.
Full textAbstract:
Abstract Abstract 372 The regulation of erythropoiesis requires stem cell factor and erythropoietin (EPO) for the proliferation and survival of erythroid progenitor and early precursor cells. While recombinant EPO is widely used for treating various types of anemia, it often lacks efficacy in cases of anemia due to ineffective erythropoiesis in which immature erythroid precursors undergo apoptosis. Thus, there is an need for new therapies to treat the later stages of erythropoiesis. Members of the transforming growth factor beta (TGFβ) superfamily have been studied as potential regulators of erythropoiesis, iron regulation and globin expression. Sotatercept (ACE-011), a recombinant fusion protein consisting of the extracellular domain of the human activin receptor IIA (ActRIIA) linked to the human immunoglobulin G1 (IgG1) Fc domain, is a ligand trap which binds a number of TGFβ superfamily ligands including activin A, activin B, growth differentiation factor-11 (GDF-11) and bone morphogenetic protein-10 (BMP-10). Administration of sotatercept led to substantial increases in red cell number and hemoglobin in human subjects, but the mechanism is not fully understood. We utilized both mouse in vivo and human in vitro models to investigate the mechanism of sotatercept in promoting erythropoiesis. In order to compare the effects of RAP-011 (the murine version of sotatercept) to EPO on red blood cell (RBC) parameters, C57/Bl mice were dosed with RAP-011, EPO or control vehicle. RAP-011-treated mice had a rapid and statistically significant increase in hematocrit, hemoglobin, and RBC number in less than 72-hours. As rapidly as 24 hours after treatment, RAP-011 induced a significant increase in RNA-negative, enucleated cells in the bone marrow (BM). RAP-011 also rapidly increased BM BFU-e and CFU-e erythroid progenitors, while EPO was more effective on spleen-derived progenitors. These data suggest that RAP-011 acts primarily on both bone marrow progenitor cells and late erythroblasts to promote erythropoiesis. In order to investigate the cellular mechanism by which RAP-011 increases red blood cell parameters, we conducted a series of in vitro experiments and found no evidence to support direct effects of RAP-011 on human CD34+ cells assessed in colony formation assays and in erythroid differentiation in liquid culture. As both clinical and pharmacological findings point to a clear role for RAP-011 in stimulating RBC parameters, we hypothesized that RAP-011 effects may be mediated by accessory cells in the BM microenvironment. Human CD36+ cells, which are highly enriched for erythroid progenitors, were co-cultured with long-term BM cultures and erythroid differentiation was assessed following 6 days of culture in EPO (2U/mL)-supplemented media. At day 6 the output of these cultures was predominantly characterized as EryA (∼basophilic erythroblast) but with the addition of RAP-011 (50μM), a significant fraction of CD36+ cells matured into EryB/C cells (polychromatic/orthochromatic erythroblasts), suggesting that factors produced by BM accessory cells mediate RAP-011 erythropoietic effects and that, in contrast to EPO, RAP-011 may play a role in the latter stages of erythroblast maturation. To identify cytokines that may mediate RAP-011 effects, CD36+ cells were treated with several activin receptor IIA ligands. GDF-11 treatment significantly decreased proliferation of GPA+ cells during the differentiation process and RAP-011 effectively reversed this effect, but had no consequence on untreated cells. These data suggest that GDF-11 may mediate the erythroipoietic stimulatory effects of RAP-011. In summary, RAP-011 induced a rapid increase in RBC parameters in mice (reflected in the number of enucleated cells found in the bone marrow), likely mediated by BM accessory cells. Our data also suggest that effects of sotatercept may be mediated at least partly by GDF-11, acting as a potential negative regulator of the terminal stages of erythropoiesis. The ability of sotatercept to reverse this inhibition would lead to a rapid release of terminal erythroid cells into the circulation. These data support the rationale to develop sotatercept for the treatment of anemia and ineffective erythropoiesis, especially in patients who may not respond to EPO. Disclosures: Carrancio: Celgene Corporation: Employment. Markovics:Celgene Corporation: Employment. Wong:Celgene Corporation: Employment. Leisten:Celgene Corporation: Employment. Groza:Celgene Corporation: Employment. Raymon:Celgene Corporation: Employment. Heise:Celgene Corporation: Employment. Chopra:Celgene Corp: Employment, Equity Ownership. Daniel:Celgene Corporation: Employment. Sung:Celgene Corporation: Employment.
3
Malek, Mehnaz, Carla Heise, Rajesh Chopra, Tom O. Daniel, and Victoria Sung. "Sotatercept, An Activin Receptor-2a Ligand Trap, Modulates Hepcidin Levels In Primary Human Hepatocytes." Blood 122, no. 21 (November 15, 2013): 3441. http://dx.doi.org/10.1182/blood.v122.21.3441.3441.
Full textAbstract:
Abstract Sotatercept, a recombinant human fusion protein containing the extracellular domain of ActRIIA binds to and inhibits activin and other members of the TGFß superfamily to induce a rapid increase in red cell number and hemoglobin. We sought to investigate if RAP-011, the murine ortholog of sotatercept, might regulate iron availability, which is important for erythropoiesis, through modulating hepcidin levels. Hepcidin is a circulating peptide hormone that negatively regulates iron transport into the plasma membrane by binding the iron transporter, ferroportin, and causing degradation of the complex. Hepcidin is primarily secreted by hepatocytes and also by hematopoietic cells, macrophages, kidney, heart, pancreas, and adipose cells (Gantz, T., Blood, 2003). The hepcidin promoter can be activated by both SMAD-4 and STAT-3, downstream targets of BMP-6 and IL-6 respectively (Andriopoulos Jr, B., Nature Genetics, 2009). BMP-6 binds its receptor, triggering downstream SMAD-1/5/8 signaling leading to SMAD-4 activation and initiation of HAMP (the gene encoding hepcidin) transcription. SMAD-4 signaling is also implicated in STAT-3 activation of HAMP transcription downstream of inflammatory signals such as IL-6 (Wang, R.H., Cell Metabolism, 2005). In the current study, we evaluated the effect of RAP-011 on hepcidin expression and regulation in primary human hepatocytes. Consistent with its role as an activin receptor ligand trap, RAP-011 reduced baseline p-SMAD 1/5/8 expression and subsequently decreased HAMP expression. Next, we asked whether RAP-011 could also decrease HAMP expression under conditions of exogenous BMP-6 stimulation. When hepatocytes were treated with 50 ng BMP-6, an approximately 50-fold induction of HAMP was observed; interestingly, RAP-011 treatment decreased this induction by half. Similarly, treatment of the hepatocytes with the inflammatory cytokine IL-6 led to nearly a 7-fold induction of HAMP which was reduced to baseline levels following the addition of RAP-011. Hepcidin protein levels, although much more variable, mirrored that of HAMP expression following BMP-6 and combined BMP-6 + RAP-011 treatment. Protein changes following IL-6 stimulation were less apparent; this may be due to the fact that the peak of IL-6-stimulated HAMP expression occurred earlier than the 48 hours post-treatment at which the protein was assayed. Our data demonstrate that RAP-011 can modulate SMAD signaling and HAMP expression in primary human hepatocytes and suggests that RAP-011 may allow for increased iron availability for erythropoiesis. Importantly, RAP-011 was able to rescue IL-6-induced HAMP expression, suggesting that the drug might be able to restore iron availability in antinflammatory environment. Anemia of inflammation is associated with diseases such as renal, Castleman’s, and Rheumatoid arthritis. Hepcidin has been shown to play a role in restricting iron and promoting anemia in these pathologies (Steinbicker, A.U., Blood, 2011). In summary, RAP-011, through a yet unknown mechanism, may help to regulate iron availability by regulating hepcidin in pathological situations such as inflammation, iron restriction, or stress erythropoiesis. Disclosures: Malek: Celgene Corp.: Employment. Heise:Celgene: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Daniel:Celgene Corp.: Employment, Equity Ownership. Sung:Celgene Corp.: Employment, Equity Ownership.
4
Mulivor, Aaron W., Denise Barbosa, Ravi Kumar, Matthew Leigh Sherman, Jas Seehra, and R. Scott Pearsall. "RAP-011, a Soluble Activin Receptor Type IIa Murine IgG-Fc Fusion Protein, Prevents Chemotherapy Induced Anemia." Blood 114, no. 22 (November 20, 2009): 161. http://dx.doi.org/10.1182/blood.v114.22.161.161.
Full textAbstract:
Abstract Abstract 161 Anemia is a common and often severe side-effect of chemotherapy treatment that can alter treatment regimens and can frequently require patients to receive blood transfusions. The majority of therapies approved for anemia target the erythropoietin (EPO) pathway. However, recent studies suggest an increased risk of mortality associated with recombinant erythropoietin (EPO) and its derivatives, which may stimulate tumor progression and increase the occurrence of thromboembolic events. The TGF-β superfamily of proteins has been reported to play a role in red blood cell (RBC) development, but works via a different pathway from EPO. RAP-011 is a murine fusion protein based on the activin receptor type IIA (ActRIIA) that binds to and prevents signaling of certain members of the TGF-β superfamily through the ActRIIA receptor. The purpose of the current study is to evaluate the effect of RAP-011 on chemotherapy induced anemia (CIA) in a mouse model. To investigate the ability of RAP-011 to prevent anemia, six week old C57BL/6 mice (30/dose group) were treated with Vehicle (VEH), or RAP-011 (1 mg/kg, 10 mg/kg, 30 mg/kg) 7 days prior to chemotherapy (Day -7). On Day 0, the mice received a single dose of paclitaxel (25 mg/kg) to induce CIA. 10 mice from each treatment group were sacrificed on Days 0, 3 and 7 and blood was collected for complete blood cell counts. On study day 0, immediately prior to CIA induction, VEH treated mice had an average hematocrit of 41.6% and RAP-011 treated mice had significantly increased hematocrits compared to the VEH cohort (1 mg/kg 43.4%, P<0.001; 10 mg/kg 42.7%, P<0.001; 30 mg/kg 43.59%, P<0.001). Similarly, VEH treated mice had an average hemoglobin level of 154.4 g/l and RAP-011 treated mice had significantly increased levels compared to the VEH cohort (1 mg/kg 167.2 g/l, P<0.001; 10 mg/kg 167.1 g/l, P<0.001; 30 mg/kg 170.1 g/l, P<0.001). 3 days following CIA the hematocrit in VEH treated mice was decreased to 38.3%. The hematocrit in RAP-011 treated groups decreased as well, but was significantly greater than VEH controls (1 mg/kg 41.0%, P<0.001; 10 mg/kg 42.9%, P<0.001; 30 mg/kg 42.3%, P<0.001). Hemoglobin measurements followed a similar pattern with VEH treated mice being decreased (137.0 g/l) whereas all of the RAP-011 treated cohorts were decreased but were significantly greater than the VEH cohort (1 mg/kg 150.8 g/l, P<0.001; 10 mg/kg 154.3 g/l, P<0.001; 30 mg/kg 151.2 g/l, P<0.001). One week following CIA the hematocrit in VEH treated mice was still decreased compared to the baseline measurements (40.7%, P<0.001). The lowest dose RAP-011 treated group was decreased as well (1 mg/kg 42.9%, P<0.001). However, the higher RAP-011 dosed cohorts had returned to their baseline values and were significantly higher than the VEH treated cohort (10 mg/kg 44.6%, P<0.001; 30 mg/kg 43.8%, P<0.001). Hemoglobin levels in the VEH cohort returned to baseline levels (150.5 g/l) and all of the RAP-011 treated cohorts were significantly increased compared to VEH (1 mg/kg 161.4 g/l, P<0.05; 10 mg/kg 171.7 g/l, P<0.001; 30 mg/kg 167.2 g/l, P<0.001). These data suggest that altering signaling in the TGFβ superfamily by use of a soluble ActRIIA receptor might act as a novel anemia therapy in patients receiving chemotherapy. Towards this end, ACE-011, the human analog of RAP-011, is currently in clinical development for the treatment of chemotherapy induced anemia. Disclosures: Mulivor: Acceleron Pharma: Employment. Barbosa:Acceleron Pharma: Employment. Kumar:Acceleron Pharma: Employment. Sherman:Acceleron: Employment, Equity Ownership. Seehra:Acceleron Pharma: Employment. Pearsall:Acceleron Pharma: Employment.
5
Dussiot, Michael, Thiago Maciel, Aurelie Fricot, Joel Veiga, Etienne Paubelle, Emmanuel Payen, Yves Beuzard, et al. "Modulation of Activin Signaling by RAP-011 (ActRIIA-IgG1) Improve Anemia, Increases Hemoglobin Levels and Corrects Ineffective Erythropoiesis in β-Thalassemia." Blood 120, no. 21 (November 16, 2012): 247. http://dx.doi.org/10.1182/blood.v120.21.247.247.
Full textAbstract:
Abstract Abstract 247 Background: β-thalassemia is associated with ineffective erythropoiesis, accelerated erythroid differentiation and apoptosis resulting in anemia and iron overload. The molecular mechanism involved is still incompletely understood. Members of the TGF-β superfamily participate in both proliferation and differentiation of erythroid progenitors. However, the role of these molecules in models of ineffective erythropoiesis has not been addressed so far. RAP-011 is a ligand trap consisting of the extracellular domain of ActRIIA linked to mouse IgG1 Fc domain. We aimed to study the role of ActRIIA signaling in the ineffective erythropoiesis of β-thalassemia and to evaluate the therapeutic impact of RAP-011. Methods: Hbbth1/th1 mice (a model of β-thalassemia intermedia) were subcutaneously treated with RAP-011 (10mg/kg body weight) twice a week for 30–60 days and biological and biochemical parameters were followed. Results: RAP-011 treatment significantly increased hemoglobin levels, red blood cell counts, MCV, MCH and hematocrit with a concomitant decrease in bilirubin levels and reticulocyte counts (since 10 days of treatment and sustained until day 60 of follow up). Flow cytometry analysis showed that RAP-011 significantly decreased late basophilic and polychromatic erythroblast cell numbers in both bone marrow and spleen indicating that RAP-011 corrects ineffective erythropoiesis. We next evaluated the expression of putative ActRIIA ligand(s) in β-thalassemia. Increased expression of Growth Differentiation Factor 11 (GDF11) was observed in cultured erythroblasts and in spleen sections of thalassemic mice. RAP-011 treatment decreased these elevated GDF11 levels in both bone marrow and spleen. We further investigated how BMP/Activin signaling was involved in ineffective erythropoiesis. Anti-GDF11 antibodies, follistatin (activin and GDF11 antagonist) and dorsomorphin (a small molecule inhibitor of SMAD1/5/8 phosphorylation) reduced differentiation, induced FAS-L expression and apoptosis in erythroblasts both in vivo and in vitro whereas noggin (a BMP-2/4 antagonist) had no effect on erythroblast differentiation. Altogether, these data suggest that Activin/BMP signaling controls erythroblast differentiation and targeting BMP type II /activin type II receptors can decrease ineffective erythropoiesis of β-thalassemia. Summary: Sotatercept (a humanized version of RAP-011) is currently in phase II clinical trials for treatment of anemia in patients with Myeloma Bone Disease and End Stage Renal Disease and data from our non-clinical findings support a newly initiated β-thalassemia clinical trial. Our results suggest that sotatercept would be a potential therapeutic tool to improve anemia, increase hemoglobin levels and correct ineffective erythropoiesis and its side effects in β-thalassemic patients. Disclosures: Daniel: Celgene Corporation: Employment. Chopra:Celgene Corp: Employment, Equity Ownership. Sung:Celgene: Employment.
6
Ear, Jason, Haigen Huang, Zahra Tehrani, Victoria Sung, Thomas Daniel, Rajesh Chopra, and Shuo Lin. "RAP-011 Efficiently Rescues Erythropoiesis In Zebrafish Models Of Diamond Blackfan Anemia." Blood 122, no. 21 (November 15, 2013): 3702. http://dx.doi.org/10.1182/blood.v122.21.3702.3702.
Full textAbstract:
Abstract Diamond Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count but normal levels of platelets and white blood cells. Ribosomal mutations in RPS19, RPS26, RPL5, and RPL11 have been identified in approximately 50% of all DBA cases. Corticosteriod therapy and bone marrow transplantion are the most common treatment options for DBA patients. However, corticosteroids have severe side effects and bone marrow transplantation is risky; thus, novel therapeutics for DBA are needed. Sotatercept (ACE-011), an activin receptor IIA ligand trap which rapidly increased hemoglobin and hematocrit in both pharmacologic models and in healthy volunteers, is currently being evaluated in diseases of ineffective erythropoiesis such as ß-thalassemia and MDS. Non-clinical studies in mice have demonstrated that RAP-011, a murine ortholog of sotatercept, stimulates RBC parameters in mice through stimulating expansion of late-stage erythroblasts through a mechanism distinct from EPO. Here, we evaluated the effect of RAP-011 in zebrafish models of ribosome insufficiency in RPS19 and RPL11 that recapitulate the anemic phenotype seen in DBA patients. Treatment with RAP-011 treatment dramatically restored hemoglobin levels compromised by ribosome stress. Furthermore, the beneficial effect of RAP-011 is synergistic with corticosteriod treatment. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by altering the microenvironment of erythroid cells, reducing p21 levels through a p53-independent manner. These findings uncover a novel signaling pathway in the pathogenesis of DBA and support the potential use of Sotatercept for the treatment of DBA patients with ribosomal disorders. Our studies also demonstrate, for the first time, that protein drugs can be effectively evaluated in zebrafish human disease models, which offer a unique opportunity to identify the targets and study their mechanisms of action. Disclosures: Sung: Celgene Corp.: Employment. Daniel:Celgene: Employment. Chopra:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding.
7
Vallet, Sonia, Kishan Patel, Diana Cirstea, Katie Luly, Samantha Pozzi, Loredana Santo, Homare Eda, et al. "Lenalidomide In Combination with the Activin Receptor Type II Murine Fc Protein RAP-011: Preclinical Rationale for a Novel Anti-Myeloma Strategy." Blood 116, no. 21 (November 19, 2010): 4075. http://dx.doi.org/10.1182/blood.v116.21.4075.4075.
Full textAbstract:
Abstract Abstract 4075 The introduction of novel treatment strategies targeting tumor cells within their microenvironment have resulted in prolonged survival for Multiple Myeloma (MM) patients. Lenalidomide belongs to this category of agents working via tumoricidal, anti-osteoclast and immunomodulatory activities. However, lenalidomide lacks bone anabolic effects. We have recently reported that activin A mediates osteoblast inhibition in MM and neutralizing activin A via a soluble receptor, RAP-011 (murinized form of ACE-011) (Acceleron Pharma, Cambridge, MA), restores bone architecture and reduces tumor burden in vivo. We therefore hypothesized that the combination with RAP-011 may potentiate lenalidomide effects and vice versa as they act via complementary mechanisms. Our previous data demonstrates that 50% of MM patients have increased bone marrow (BM) levels of activin A that correlate with osteolytic burden. Here, we observed that 2 and 10 μ M lenalidomide (Selleck Chemicals, Houston, TX) upregulated activin A in 3 out 6 bone marrow stromal cell (BMSC) samples by 1.9 and 2.8 fold (average ± st.dev. 1052 ± 190 and 1667 ± 732 pg/ml respectively, compared to 734 ± 553 in control, p=0.2). There was no time-dependent upregulation of activin A. Of note, no augmentation of activin A was noted in BMSC which already expressed high baseline levels of the cytokine (average ± st.dev 3638 ± 3755 pg/ml in control vs 3074 ± 2997 after lenalidomide 10 μ M). Previous data suggest that high concentrations of activin A induce growth arrest and apoptosis in myeloma and breast cancer cells and may therefore mediate lenalidomide cytotoxicity. To ensure that inhibition of activin would not antagonize lenalidomide anti-tumor effects, we investigated whether activin A inhibition affected the cytotoxic and anti-proliferative effects of lenalidomide on MM cells alone and in co-culture with BMSC. As previously demonstrated, RAP-011 did not exert any direct anti-tumor effects. Lenalidomide 10 μ M induced between 20 and 40% of apoptosis in several myeloma cell lines, such as MM1.S, LR5, DOX40 and RPMI, independent of activin A inhibition. Similarly, lenalidomide almost completely reversed the proliferative advantage conferred by BMSC to tumor cells. Combining lenalidomide and RAP-011 was not antagonistic to the inhibition of the proliferative advantage conferred by BMSC to myeloma cells, suggesting that lenalidomide's direct anti-tumor activity is not mediated through activin A. Finally we assessed OB differentiation in the presence of both RAP-011 and lenalidomide. We have previously reported that activin A inhibitory effects on OB differentiation are reversed by RAP-011 treatment. Here, we noted diminished alkaline phosphatase (ALP, a marker of osteoblast activity) expression during osteoblastogenesis in the presence of increasing concentrations of lenalidomide (17% ± 3 decrease by 2 μ M and 26% ± 11 by 10 μ M compared to control, p=0.01 and 0.06 respectively). In contrast, combination with RAP-011 restored the osteogenic potential by increasing ALP expression close to control levels in healthy donor-derived BMSC and above control levels in MM-derived BMSC. These preliminary data suggest that lenalidomide results in upregulation of activin A expression in MM BMSCs which have low baseline levels. Combining lenalidomide with RAP-011 results in restored osteogenesis presumably by inhibiting activin signaling. Importantly, we observed no antagonistic effect of RAP-011 on lenalidomide's anti-tumor activity, confirming that activin A does not mediate the anti-tumor activity of lenalidomide. Ongoing in vivo studies using a murine model of myeloma will confirm the efficacy of this promising combination. Our results provide a preclinical rationale for combining lenalidomide with ACE-011 to target myeloma by manipulating the microenvironmental compartment, specifically the bone compartment. Disclosures: Seehra: Acceleron Pharma: Employment. Scadden:Fate Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Raje:Celgene, Novartis: Consultancy; Astrazeneca, Acetylon: Research Funding; Celgene, Amgen: Membership on an entity's Board of Directors or advisory committees.
8
Ear, Jason, Haigen Huang, Tianna Wilson, Zahra Tehrani, Anne Lindgren, Victoria Sung, Abderrahmane Laadem, Thomas O. Daniel, Rajesh Chopra, and Shuo Lin. "RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1." Blood 126, no. 7 (August 13, 2015): 880–90. http://dx.doi.org/10.1182/blood-2015-01-622522.
Full text
9
Vallet, Sonia, Siddhartha Mukherjee, Nileshwari Vaghela, Samantha Pozzi, Loredana Santo, Diana Cirstea, Mariateresa Fulciniti, et al. "Restoration of Bone Balance Via Activin a Inhibition Results in Anti-Myeloma Activity." Blood 112, no. 11 (November 16, 2008): 645. http://dx.doi.org/10.1182/blood.v112.11.645.645.
Full textAbstract:
Abstract A distinct feature of multiple myeloma (MM) is the tight interaction between malignant plasma cells and their bone microenvironment, creating a niche suitable for MM growth. In particular, MM cells inhibit osteoblast (OB) differentiation and stimulate osteoclast (OC) function, resulting in imbalanced bone remodeling and osteolytic bone disease. Here we studied a novel cytokine, activin A, identified from a broad range of cytokines, in the development of MM bone disease. We next asked whether activin A inhibition could restore bone balance and suppress tumor growth. Activin, a member of the TNF-α superfamily, is a pleiotropic cytokine involved in bone remodeling. Here, we observed, that MM patients with multiple osteolytic lesions had a 4-fold increase in activin A expression levels in bone marrow plasma compared to MM patients with one or less osteolytic lesions and non-MM patients (average 123.6 ± 136 vs 26.4 ± 21.4 vs 30.6 ± 25.1 pg/ml respectively, p<0.05). Interestingly, our data demonstrate that the main source of activin in the MM niche are bone marrow stromal cells (BMSCs), followed by OCs, and OBs (average levels in 72h culture supernatant are 1884, 1300, 299 pg/ml, respectively). In contrast, MM cells did not secrete activin, but stimulated its secretion in coculture by BMSC (by 1.3 to 2 fold increase). Activin A stimulated OC differentiation in synergy with RANKL and M-CSF via induction of a three-fold increase in precursor cell proliferation. Moreover, activin A had a potent inhibitory effect on OB differentiation as verified by ALP activity (reduced by 30% compared to control, p<0.05) and OB function, assessed with alizarin red (80% inhibition, p< 0.01). To test the role of targeting activin A with therapeutic intent, we used both a neutralizing antibody and a soluble receptor fusion, RAP-011 (Acceleron Pharma Inc., Cambridge). In effect, both strategies enhanced OB differentiation and activity (5 fold increase in calcium deposition at day 21, p<0.05). This was confirmed by quantitative-PCR analysis of ALP and osteocalcin gene expression. Importantly, RAP-011 promoted OB differentiation even in the presence of INA6 MM cells and reversed the inhibitory effects of the stroma-dependent MOLP5 MM cells as well as patient derived MM cells on OB. Enhanced OB differentiation by RAP-011 resulted in inhibition of MM cell proliferation compared to BMSCs and mature OB. These data thus suggest that manipulating the bone niche may result in reduced tumor growth. To further verify if these results translated in reduced tumor growth in vivo, we used the SCID-hu mouse model consisting of INA6 MM cells injected in a subcutaneously implanted fetal human bone. RAP-011 treatment resulted in a decrease in the number of osteolytic lesions assessed by CT imaging accompanied by improved bone density. These effects translated in reduced MM cell growth, analyzed by soluble human IL6 receptor levels, in the treated group compared to the control (p<0.02). These data therefore suggest that activin A is involved in development of MM bone disease and can be effectively targeted by a novel clinical grade compound. RAP-011 demonstrated bone-anabolic effects via inhibition of OC formation and stimulation of OB differentiation resulting in restoration of bone balance within the MM niche, which translated in in-vivo inhibition of MM cell growth. These effects of RAP-011 support the use of the human ACE-011 as an attractive approach for the treatment of MM.
10
Morse, Alyson, Tegan L. Cheng, Lauren Peacock, Kathy Mikulec, David G. Little, and Aaron Schindeler. "RAP-011 augments callus formation in closed fractures in rats." Journal of Orthopaedic Research 34, no. 2 (September 1, 2015): 320–30. http://dx.doi.org/10.1002/jor.22985.
Full text
11
Little, D. G., A. Morse, L. Peacock, K. Mikulec, M. McDonald, and A. Schindeler. "Rap-011 augments callus formation in closed fractures in rats." Bone 48 (May 2011): S101. http://dx.doi.org/10.1016/j.bone.2011.03.152.
Full text
12
De Rosa, Gianluca, Immacolata Andolfo, Roberta Marra, Francesco Manna, Barbara Eleni Rosato, Achille Iolascon, and Roberta Russo. "RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway." International Journal of Molecular Sciences 21, no. 15 (August 4, 2020): 5577. http://dx.doi.org/10.3390/ijms21155577.
Full textAbstract:
Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B-silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B-silenced K562 cells with RAP-011, a “murinized” ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II.
13
Langdon, Jacqueline M., Sangjucta Barkataki, Alan E. Berger, Chris Cheadle, Qian-Li Xue, Victoria Sung, and Cindy N. Roy. "RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice." American Journal of Hematology 90, no. 1 (October 25, 2014): 8–14. http://dx.doi.org/10.1002/ajh.23856.
Full text
14
Scott Pearsall, R., Michelle Mangini, Milton Cornwall-Brady, Travis Monnell, Tod Marvell, Brendan Haigis, Ravindra Kumar, Kathryn W. Underwood, and Jasbir Seehra. "Treatment with RAP-011 (A soluble activin receptor type IIA) increases bone mineral density in mice with prior bisphosphonate exposure." Bone 42 (March 2008): S82. http://dx.doi.org/10.1016/j.bone.2007.12.154.
Full text
15
Mulivor, Aaron, Ravi Kumar, Amelia Pearsall, Kathryn Underwood, Jeff Ucran, Matthew Sherman, Jasbir Seehra, and R. Scott Pearsall. "P51. RAP-011, a soluble activin receptor type IIA IgG-Fc-fusion protein, is a novel bone anabolic agent that prevents bone loss and skeletal metastases in a mouse model of metastatic breast cancer." Cancer Treatment Reviews 34 (2008): 39–40. http://dx.doi.org/10.1016/j.ctrv.2008.03.110.
Full text
16
Mulivor, A. W., D. Barbosa, R. Kumar, A. E. Pearsall, K. W. Underwood, J. A. Ucran, J. Seehra, and R. Pearsall. "RAP-011, a soluble activin receptor type IIA murine IgG-Fc fusion protein, is a novel bone anabolic agent that prevents bone loss and skeletal metastases in a mouse model of metastatic breast cancer." Bone 44 (June 2009): S221—S222. http://dx.doi.org/10.1016/j.bone.2009.03.066.
Full text
17
Patel, K. D. "Novel Epoxy Resin—Part 2." High Performance Polymers 8, no. 2 (June 1996): 301–5. http://dx.doi.org/10.1088/0954-0083/8/2/011.
Full textAbstract:
A novel epoxy resin, namely diglycidyl ether (DGE) of 2,4-dihydroxyacetophenone (i.e. resacetophenone, RAP) was prepared and characterized. The curing of DGE–RAP by various diamines was studied kinetically by differential scanning calorimetry (DSC). The cured neat products have been characterized by IR spectral studies and thermogravimetric analysis (TGA). The glass-reinforced composites based on such a novel epoxy resin–diamine system have also been prepared and characterized.
18
Bose, Prithviraj, Naval Daver, Elias J. Jabbour, Allison Pike, Kate J. Newberry, Lingsha Zhou, Sherry Pierce, Xuemei Wang, Hagop M. Kantarjian, and Srdan Verstovsek. "Phase-2 Study of Sotatercept (ACE-011) in Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia." Blood 128, no. 22 (December 2, 2016): 478. http://dx.doi.org/10.1182/blood.v128.22.478.478.
Full textAbstract:
Abstract Introduction: Anemia is common in MPN-associated myelofibrosis (MF), and current therapies (e.g., erythropoiesis stimulating agents, androgens, danazol, immune modulatory drugs and corticosteroids) are unsatisfactory. Furthermore, anemia is not improved and initially worsened by ruxolitinib, an important MF therapy. New drugs with novel mechanisms of action are needed. Sotatercept is a first-in-class activin receptor type IIA (ActRIIA) ligand trap consisting of the extracellular domain of ActIIRA linked to the human IgG1 Fc domain. Sotatercept binds to and sequesters ligands of the transforming growth factor beta (TGF-ß) superfamily, thus relieving their blockade of terminal erythroid differentiation. Pre-clinically, sotatercept corrects ineffective erythropoiesis in ß-thalassemia (Dussiot, M. et al. Nat Med 2014) and its murine ortholog RAP-011 improves erythropoiesis in Diamond Blackfan anemia (Ear, J. et al. Blood 2015). Clinical trials in persons with lower risk myelodysplastic syndromes (Komrokji, R. et al. ASH 2014) and chemotherapy-induced anemia (Raftopoulos, H. et al. Support Care Cancer 2016) have shown promising results. Methods: This is an ongoing phase-2 study of sotatercept, 0.75 or 1 mg/kg subcutaneously every 3 weeks (1 cycle), in subjects with MF, whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). Subjects must be RBC-transfusion-dependent (Gale, R.P. et al. Leuk Res 2011), have hemoglobin <10 g/dL on every determination during the 84 days preceding study entry without RBC transfusions, or have hemoglobin <10 g/dL despite intermittent RBC transfusions without fulfilling the criteria for transfusion dependence. Primary endpoints include anemia response and safety. Secondary endpoints include time to and duration of anemia response. Anemia response is a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions). Subjects must have received ≥5 cycles of sotatercept to be evaluable for response. Results: 18 subjects are enrolled to date. 1 subject received 6 cycles at a sub-therapeutic dose of 0.3 mg/kg and was not considered for efficacy evaluation, but was evaluable for safety. Of the remaining 17 subjects, 11 received 0.75 mg/kg and 6, 1 mg/kg. Median age was 67 years (range, 47-84 years); 10 were male and 7 female. 14 had PMF and 3, post-ET MF. 12 subjects had JAK2 V617F, 1 had MPLW515L and 2 had CALR exon 9 mutations. 1 subject was triple negative and 1 subject had no JAK2 or MPL mutation but was not tested for CALR mutations. All 17 subjects had intermediate-2 or high risk disease by the Dynamic International Prognostic Scoring System. Table 1 summarizes baseline variables for these 17 subjects. Median number of cycles of sotatercept received is 5 (range, 1-13). 14 of the 17 subjects received ≥5 cycles and were evaluable for response. The 3 other subjects received 1, 2 and 2 cycles and discontinued due to unrelated medical problems, hypertension and stem cell transplant (SCT), respectively. 5 of 14 (36%) evaluable subjects have responded; 4 of whom continue on study in ongoing response. All responders are female and all female subjects evaluable for response responded. Responses occurred across phenotypic driver mutation categories and in both transfusion-dependent (n=3) and -independent (n=2) subjects. 40% and 25% of evaluable patients responded in the 0.75 mg/kg and 1 mg/kg dose cohorts, respectively. Most adverse events (AEs) were grades 1 or 2. The only AEs possibly attributable to sotatercept include grade 3 hypertension leading to discontinuation, and grade 1 myalgia, bone pain, pain in extremity and injection site reaction. 5 subjects remain on study. 12 have discontinued because of no response (5), SCT (2), unrelated medical problems (1), hypertension (1), disease progression (1), transformation to AML (1) and withdrawal of consent (1). Conclusion: Sotatercept improves anemia and RBC-transfusion-dependence in persons with MF and is well-tolerated. Enrollment to the trial is ongoing; updated results will be presented. A separate cohort of subjects receiving ruxolitinib has been added and will also be discussed. Based on the preponderance of responses at the 0.75 mg/kg dose, this dose has been selected for the combination cohort. Disclosures Daver: Incyte: Consultancy, Other: Advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.
19
Cappellini, Maria-Domenica, John Porter, Raffaella Origa, Gian Luca Forni, Adberrahmane Laadem, Frédéric Galacteros, Dimana Miteva, et al. "A Phase 2a, Open-Label, Dose-Finding Study To Determine The Safety and Tolerability Of Sotatercept (ACE-011) In Adults With Beta (β)-Thalassemia: Interim Results." Blood 122, no. 21 (November 15, 2013): 3448. http://dx.doi.org/10.1182/blood.v122.21.3448.3448.
Full textAbstract:
Abstract Background Beta (β)-thalassemia is characterized by ineffective erythropoiesis leading to anemia, bone marrow erythroid hyperplasia, iron overload, and organ failure. Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor (ActRIIA) fusion protein that increases the release of mature erythrocytes into circulation by acting mainly on late-stage erythropoiesis (Carrancio S, et al. Blood. 2012;120:abstract 372). Clinical data in healthy volunteers have shown that treatment with sotatercept results in increased red blood cell (RBC) parameters, including hemoglobin level (Ruckle J, et al. J Bone Miner Res. 2009;24:744-52). RAP-011, a murine ortholog of sotatercept, was efficacious in a mouse model of β-thalassemia intermedia, reducing ineffective erythropoiesis as well as significantly improving anemia and decreasing bilirubin levels, supporting the clinical development of sotatercept (Dussiot M et al. Blood 2012;120:abstract 247). Methods This is an ongoing phase 2a, multicenter, open-label, dose-finding study to determine a safe and active dose level of sotatercept in adult patients with RBC-transfusion dependent (TD) β-thalassemia major or patients with β-thalassemia intermedia who are either TD or non-transfusion dependent (NTD). The dose levels of sotatercept studied to date are 0.1, 0.3, and 0.5 mg/kg, given subcutaneously once every 3 weeks. Safety is assessed according to NCI-CTC grading. Efficacy is assessed by hemoglobin increase from baseline and/or reduction in transfusion burden. Secondary endpoints include assessment of biomarkers for erythropoiesis, hemolysis, iron metabolism, and bone metabolism, as well as in vitro dyserythropoiesis. Dose escalation to higher dose levels is planned contingent on data review and favorable safety profile as determined by the Steering Committee. Results Patient demographics. A total of 25 patients have been enrolled as of July 26, 2013; 8 in the 0.1 mg/kg cohort, 9 in the 0.3 mg/kg cohort, and 8 in the 0.5 mg/kg cohort. Treatment and analysis for the 0.5 mg/kg cohort is underway and will be updated and presented. In the 0.1 and 0.3 mg/kg cohorts, 3 (18%) patients had β-thalassemia major and 14 (82%) had β-thalassemia intermedia (12 of whom were NTD and 2 of whom were TD). Of the 12 NTD β-thalassemia intermedia patients, 6 were treated at the 0.1 mg/kg dose level and 6 at the 0.3 mg/kg dose level. Median baseline hemoglobin for these NTD patients was 8.6 g/dL (range 5.8 to 10.7 g/dL). Median number of sotatercept doses administered was 4 (range 2 to 7) in the 0.1 mg/kg cohort and 8 (range 3 to 9) in the 0.3 mg/kg cohort; 13/17 (76%) patients remained on treatment. Safety.Sotatercept was generally well tolerated. There were no dose-limiting toxicities reported. Two serious adverse events were reported in the 0.1 mg/kg cohort: a grade 2 phlebitis in an NTD patient with a history of high D-dimer at baseline, and a worsening grade 3 bone pain in a TD β-thalassemia major patient with a history of osteoporosis; both were considered possibly study drug-related. Hemoglobin levels/transfusion requirements. Among NTD patients, preliminary data showed that 1 (17%) patient in the 0.1 mg/kg cohort and all 6 (100%) patients in the 0.3 mg/kg cohort had at least a 1 g/dL increase in hemoglobin level from baseline; among these, 1 patient treated with sotatercept 0.3 mg/kg showed a 2 g/dL hemoglobin level increase from baseline as well as a decrease in total bilirubin level from 2.7 × upper limit of normal (ULN) at baseline to 1.8 × ULN. No other relevant decrease in total bilirubin level was reported at the lower dose levels (0.1 mg/kg or 0.3 mg/kg). Three TD patients were still receiving treatment (2 β-thalassemia intermedia and 1 β-thalassemia major). There had been no appreciable reduction in transfusion burden in the 0.1 and 0.3 mg/kg cohorts to date; however further follow up is warranted and an update will be presented. Conclusion Based on these preliminary data, sotatercept administered subcutaneously every 3 weeks may improve anemia via a novel mechanism of action with a favorable safety profile, thereby addressing a significant unmet medical need for patients with NTD β-thalassemia intermedia. The current data suggest a dose-dependent response that supports further evaluation of the exposure–effect relationship of sotatercept in patients with NTD β-thalassemia intermedia. The first, second, and last authors contributed equally to this abstract. Disclosures: Cappellini: Genzyme: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Off Label Use: Sotatercept is an investigational agent that is being assessed for efficacy and safety in beta-thalassemia. Porter:Novartis: Consultancy, Research Funding; Shire: Consultancy; Celgene: Honoraria. Forni:Celgene: Research Funding; Shire: Research Funding; Novartis Pharma: Research Funding. Laadem:Celgene Corp.: Employment, Equity Ownership. Galacteros:Celgene: Consultancy. Miteva:Celgene Corp.: Employment. Sung:Celgene Corp.: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Klesczewski:Celgene Corp.: Employment. Attie:Acceleron Pharma: Employment. Hermine:Celgene Corporation: Consultancy, Research Funding.
20
Vallet, Sonia, Siddhartha Mukherjee, Nileshwari Vaghela, Teru Hideshima, Mariateresa Fulciniti, Samantha Pozzi, Loredana Santo, et al. "Molecular Sequaele of Activin A-Dependent Osteoblast Inhibition in Myeloma." Blood 114, no. 22 (November 20, 2009): 1789. http://dx.doi.org/10.1182/blood.v114.22.1789.1789.
Full textAbstract:
Abstract Abstract 1789 Poster Board I-815 Understanding the pathogenesis of cancer-related bone disease is critical to the discovery of new therapies. The development of osteolytic lesions in multiple myeloma (MM) results from unopposed osteoclast activity due to decreased osteoblast (OB) function. We recently demonstrated that activin A contributes to MM-mediated OB inhibition. The availability of a clinical-grade activin A inhibitor that reduces tumor burden by restoring the bone structure in vivo, underscores the relevance of this pathway in the development of MM-bone disease. Here, we characterize the signaling pathway mediating OB inhibition by activin A. Activin A secretion by bone marrow stromal cells (BMSC) is enhanced in the presence of MM cells which was completely abrogated and using a transwell system. To identify the receptors and pathways involved in activin A secretion, we used neutralizing antibody against several integrins, CD40 and osteopontin. Only VLA4 neutralizing antibodies partially inhibited activin secretion by about 20% (range 10-30%, p<0.05). Since activin A promoter contains a cJUN-binding sequence, we explored the relations between JNK and activin. We show that upon MM cell binding to BMSC, stromal-derived JNK is phosphorylated and SP600125 (20 μM), a specific JNK inhibitor, impairs activin A secretion by BMSC both at basal conditions and in the presence of MM (40% and 54%, respectively; p<0.01). These results suggest that activin secretion requires JNK activation induced by cell-to-cell contact. We next investigated the mechanism underlying activin-mediated OB inhibition by assessing the activity of several signaling pathways critical to OB differentiation. First, we showed that activin A induces SMAD2 phosphorylation, while no effects were noted on SMAD1, β-catenin, pP65 and pERK. Then, using a doxycycline-inducible β-catenin system, we demonstrate that β-catenin activation overcomes activin A inhibition of OB differentiation. These results suggest that activin/SMAD2 and β-catenin modulate OB differentiation by affecting a common downstream target. We next evaluated the expression of two candidates, the transcription factors RUNX2 and DLX5. Only DLX5 expression was downregulated by exogenous activin A (5 fold decrease at 96 hours, p< 0.01). Specific inhibition of SMAD2 via shRNA-mediated knock-down upregulated basal DLX5 and ALP mRNA expression (1.5 and 4.7 fold increase respectively, p<0.05), and partially overcame activin A inhibitory effects. In turn, DLX5 knock-down abrogated OB differentiation without additive effects by exogenous activin A. The clinical relevance of DLX5 was confirmed by the strong correlation between its expression levels in BM biopsies from MM patients and activin A levels in BM serum. Finally, we demonstrate by in vitro and in-vivo studies that MM-mediated DLX5 inhibition is restored by treatment with RAP-011, the specific activin inhibitor. In conclusion, we show that MM cell engagement of BMSC enhances activin A secretion via adhesion-mediated JNK activation and activin A, in turn, inhibits osteoblast differentiation via SMAD2-dependent DLX5 downregulation. This study identifies a novel pathway relevant to OB differentiation and amenable to drug targeting. Disclosures Chauhan: Nereus Pharmaceuticals, Inc: Consultancy. Seehra:Acceleron Pharma: Employment. Anderson:Celgene : Research Funding; Novartis: Research Funding; Millennium: Research Funding. Scadden:Fate Therapeutics: Consultancy. Raje:Astrazeneca, Novartis, Celgene: Research Funding.
21
Gazzano, M., M. Soccio, N. Lotti, L. Finelli, and A. Munari. "Crystallization kinetics, melting behavior, and RAP of novel etheroatom containing naphthyl polyesters." Journal of Thermal Analysis and Calorimetry 110, no. 2 (November 1, 2011): 907–15. http://dx.doi.org/10.1007/s10973-011-1985-8.
Full text
22
Bassan, M., B. Buonomo, E. Coccia, D. Blair, S. D'Antonio, G. Delle Monache, D. Di Gioacchino, et al. "Acoustic detection of particles, the RAP experiment: present status and results." Journal of Physics: Conference Series 39 (May 1, 2006): 46–48. http://dx.doi.org/10.1088/1742-6596/39/1/011.
Full text
23
Ma, Baoguo, Haifeng Wang, and Dingbang Wei. "Performance of RAP in the system of cold inplace recycling of asphalt pavement." Journal of Wuhan University of Technology-Mater. Sci. Ed. 26, no. 6 (December 2011): 1211–14. http://dx.doi.org/10.1007/s11595-011-0392-0.
Full text
24
Terpos, Evangelos, Dimitrios Christoulas, Efstathios Kastritis, Maria Gkotzamanidou, Maria Gavriatopoulou, Evangelos Eleutherakis-Papaiakovou, Magdalini Migkou, Maria Roussou, Athanasios Papatheodorou, and Meletios A. Dimopoulos. "Elevated Levels of Circulating Activin-A Correlate with Features of Advanced Disease, Extensive Bone Involvement and Inferior Survival In Patients with Multiple Myeloma." Blood 116, no. 21 (November 19, 2010): 2967. http://dx.doi.org/10.1182/blood.v116.21.2967.2967.
Full textAbstract:
Abstract Abstract 2967 Activin-A is a member of the transforming-growth factor-beta superfamily most commonly associated with embryogenesis and gonadal hormone signaling. Activin-A is also involved in bone homeostasis having growth stimulatory effects on osteoclasts, but unclear effects on osteoblast function. A recent study showed that, in multiple myeloma (MM) microenvironment, activin-A is a stromally derived osteoblast inhibitor induced by myeloma cells and thus it seems to be implicated into the pathogenesis of myeloma bone disease (Vallet et al, PNAS 2010;107:5124). The aim of this study was to evaluate the circulating levels of activin-A in newly-diagnosed and relapsed patients with MM and explore possible correlations with clinical and laboratory data, including lytic bone disease and survival. We studied 113 MM patients (63M/50F, median age 69 years, range 31–92 years): 98 newly-diagnosed patients (13 with asymptomatic and 85 with symptomatic MM) and 15 patients with relapsed MM after previous response to front-line therapy, who received the combination of lenalidomide and high-dose dexamethasone (RD). All symptomatic patients received frontline treatment with novel agent-based regimens. For newly-diagnosed patients, serum was stored at -80°C at the time of diagnosis, while for relapsed patients serum was stored on day 1 of the first RD cycle and then on day 28 of the 4th cycle. Serum activin-A was measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA) along with a series of markers of bone resorption (C-terminal cross-linking telopeptide of collagen type-1, CTX and tartate-resistant acid phosphatase isoform-5b, TRACP-5b) and bone formation (bone-specific alkaline phosphatase and osteocalcin). Evidence of bone involvement was documented using plain radiographs in patients at diagnosis and at the time of relapse. Activin-A and the above bone markers were also measured in 10 MGUS patients and in 17, gender- and age-matched, healthy controls. Circulating levels of activin-A of newly-diagnosed patients with symptomatic MM (median: 555 pg/mL, range: 129–2336 pg/mL) and of relapsed patients (677 pg/mL, 272–2088 pg/mL) were increased compared to controls (393 pg/mL, 204–899 pg/mL; p<0.001 for both comparisons). There was no significant difference between asymptomatic patients (462 pg/mL, 255–840 pg/mL), MGUS patients (457 pg/mL, 361–839 pg/mL) and controls. Circulating levels of activin-A strongly correlated with disease stage at diagnosis; the median values (range) for ISS-1, ISS-2 and ISS-3 were: 462 pg/mL (255-840 pg/mL), 536 pg/mL (210-1183 pg/mL) and 681 pg/mL (302-2336 pg/mL), respectively; p(ANOVA)=0.002. Activin-A levels also significantly correlated with serum creatinine (r=0.519, p<0.001), beta2-microglobulin (r=0.450, p<0.001) and LDH (r=0.247, p=0.034) at diagnosis. Regarding bone markers, serum activin-A showed strong correlations with both markers of bone resorption: CTX (r=0.574, p<0.001) and TRACP-5b (r=0.481, p<0.001), but no correlation with markers of bone formation. Patients with extensive bone disease (more than 3 osteolyses and/or a fracture) had higher levels of circulating activin-A (618 pg/mL, 211–2043 pg/mL) compared to all others (477 pg/mL, 129–2336 pg/mL; p=0.03). The median survival of newly-diagnosed, symptomatic MM patients was 63 months. In the univariate analysis, low levels of activin-A were associated with superior overall survival: the median survival of patients who had a serum activin-A of <442 pg/mL (lower quartile, n=24 patients) has not been reached yet, while the median survival of all other patients was 59 months (p=0.04). However, in the multivariate model, activin-A was not an independent factor for survival, possibly due to its strong correlation with beta2-microglobulin. In relapsed patients, treatment with RD did not reduce circulating activin-A levels, which remained elevated (710 pg/mL, 302–2384 pg/mL) after 4 cycles of therapy compared to controls (p<0.001). We conclude that circulating activin-A is elevated in patients with newly-diagnosed symptomatic MM and in patients with relapsed MM. High activin-A levels correlated with advanced disease features and high bone resorption. These results reveal activin-A as a possible target (i.e. by using RAP-011, a soluble activin-A receptor) for the development of novel anti-myeloma therapies. Disclosures: No relevant conflicts of interest to declare.
25
Joshi, Sachindra R., Jun Liu, R. Scott Pearsall, Patrick Andre, Gang Li, and Kumar Ravindra. "Abstract 14397: Sotatercept Analog RAP-011 Inhibits Right Ventricular Remodeling and Restores Function in a Mouse Model of Pressure Overload." Circulation 142, Suppl_3 (November 17, 2020). http://dx.doi.org/10.1161/circ.142.suppl_3.14397.
Full textAbstract:
IIntroduction: Right ventricular (RV) failure is the primary cause of death in patients with pulmonary arterial hypertension (PAH). Beneficial effects of sotatercept - an activin receptor type IIA-Fc fusion protein that traps activins and growth differentiation factors - have been reported in PAH patients treated with standard-of-care therapies in a recent phase 2 study (PULSAR). We have reported that therapeutic treatment with sotatercept analog RAP-011 reverses RV remodeling and function in rats with severe angio-obliterative PAH, providing benefits on top of standard care. Hypothesis: To determine whether RAP-011 exerts a direct cardioprotective effect in a mouse model of pressure overload-induced RV failure. Methods: RV failure was induced in male C57BL/6 mice by pulmonary artery banding (PAB). RAP-011 or vehicle were administered subcutaneously twice weekly for 3 weeks beginning one day post surgery. RV remodeling and function were assessed by echocardiography and RV pressure measured by catheterization. RV fibrosis was assessed by Masson’s trichrome staining. Results: PAB caused RV hypertrophy and increased RV wall thickness in comparison to sham surgery. RAP-011 treatment markedly attenuated these PAB-induced changes (by 72% and 41%, respectively; P < 0.0001). PAB significantly reduced tricuspid annular plane systolic excursion (0.68 ± 0.03 vs. 0.98 ± 0.03 mm), which was partially restored by RAP-011 (0.84 ± 0.04 mm; P < 0.01). In addition, the PAB-induced increase in myocardial performance index was reversed by RAP-011 (1.86 vs. 1.48, P < 0.0001). RAP-011 attenuated PAB-induced RV developed pressure (by 82%, P < 0.0001) and partially normalized peak rates of RV pressure change (+dP/dt max and -dP/dt min , P < 0.05). RAP-011 also reduced the extent of PAB-induced RV fibrosis (19.5% vs. 10.5%, P < 0.001). Conclusions: Consistent with our previous findings in a rat model of severe angio-obliterative PAH, RAP-011 treatment reduces RV remodeling and improves function in a PAB model, thus implicating direct cardioprotective actions of RAP-011 as an important component of its therapeutic effects in severe experimental PAH.