RESUMO
Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.
Assuntos
Quimiocinas CXC/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinases/metabolismo , Lenalidomida/farmacologia , Mucina-1/biossíntese , Mieloma Múltiplo/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Estudos de Casos e Controles , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/metabolismo , Quimiocinas CXC/metabolismo , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos SCID , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Mucina-1/metabolismo , Mieloma Múltiplo/sangue , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/metabolismo , Receptores CXCR4/biossíntese , Receptores CXCR4/metabolismo , Transdução de Sinais , Células THP-1RESUMO
The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients.
Assuntos
Antineoplásicos/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/farmacologia , Linhagem Celular Tumoral , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Lenalidomida/administração & dosagem , Lenalidomida/farmacologia , Masculino , Camundongos SCID , Terapia de Alvo Molecular , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Organismos Livres de Patógenos Específicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
B-Cell maturation antigen (BCMA) is a cell membrane receptor expressed on mature B lymphocytes, with elevated serum levels found among patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL). Serum BCMA (sBCMA) levels were measured in 331 untreated, newly diagnosed CLL patients using an enzyme-linked immunosorbent assay with a polyclonal anti-BCMA antibody. Elevated sBCMA levels were found among patients with CLL compared with age- and sex-matched healthy controls and those with more active CLL based on prognostic factors. The relationships between sBCMA, time to first treatment (TTFT), overall survival (OS) and multiple prognostic factors were compared using Mann-Whitney and Kruskal-Wallis tests. The median sBCMA level in the CLL cohort (48.6 ng/mL) was significantly higher (p < 0.001) compared with those of age- and sex-matched healthy subjects (n = 100; 37.8 ng/mL). Serum BCMA correlated with TTFT (hazard ratio [HR] = 2.9, 95% confidence interval 2.0-4.2, p < 0.001) and OS (HR = 2.5, 95% confidence interval: 1.5-4.0, p < 0.001). Multiple models were used to test the predictive effects of sBCMA, sex, CLL International Prognostic Index (CLL-IPI) and International Prognostic Score for early-stage CLL (IPS-E) on TTFT and OS. The addition of sBCMA to CLL-IPI and IPS-E improved their prognostic ability to predict TTFT and OS. Thus, sBCMA is a new promising prognostic biomarker for CLL.
Assuntos
Antígeno de Maturação de Linfócitos B , Leucemia Linfocítica Crônica de Células B , Antígeno de Maturação de Linfócitos B/sangue , Linfócitos B/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/patologia , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
B-cell maturation antigen (BCMA), a tumor necrosis factor receptor (TNFR) family member, is selectively expressed on terminally differentiated B-lymphocytes including multiple myeloma (MM) tumor cells. We sought to determine whether circulating (c)BCMA in MM serum interferes with antiBCMA antibody binding to MM cells. An enzyme-linked immunosorbent assay (ELISA) was used to determine serum (s) BCMA levels among 379 samples from patients with relapsed/refractory MM (RRMM). Furthermore, flow cytometric and immunofluorescent studies were used to examine if concentrations of BCMA in patients' serum were high enough to interfere with the binding of anti-BCMA antibody to MM tumor cells. We have shown that BCMA is elevated in the serum from MM patients and that the median concentration of sBCMA from RRMM patients was 176 ng/mL (n = 379). Additionally, there was a consistent decrease in the binding of anti-BCMA antibody to MM tumor cells with sBCMA level ≥156 ng/mL. Together, these results demonstrate that circulating BCMA levels in most RRMM patients are high enough to interfere with anti-BCMA antibody binding to MM tumor cells and may interfere with BCMA-targeted immune-based therapies.
Assuntos
Anticorpos Monoclonais/metabolismo , Complexo Antígeno-Anticorpo/metabolismo , Antígeno de Maturação de Linfócitos B/metabolismo , Biomarcadores Tumorais/metabolismo , Mieloma Múltiplo/patologia , Anticorpos Monoclonais/imunologia , Afinidade de Anticorpos , Complexo Antígeno-Anticorpo/imunologia , Antígeno de Maturação de Linfócitos B/imunologia , Sítios de Ligação de Anticorpos , Estudos de Casos e Controles , Humanos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , PrognósticoRESUMO
INTRODUCTION: B-cell maturation antigen (BCMA) is a cell membrane bound tumor necrosis factor receptor family member that is expressed exclusively on late stage normal and malignant B-cells and plasma cells. Addition of two of its ligands, B-cell activating factor and a proliferation inducting ligand, to normal B-cells cause B-cell proliferation and antibody production. Serum BCMA is elevated among patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and is a prognostic and monitoring tool for these patients. The first anti-BCMA antibody (Ab) was developed in 2007. Recently, biotech and pharmaceutical companies have created various forms of BCMA-directed Abs (naked Abs, Ab drug conjugates, and bispecific Abs) and cellular therapies (chimeric antigen receptor T-cells) with promising clinical results. Areas covered: This BCMA review encompasses full-text publications of original research articles and abstracts presented at hematology/oncology meetings. Expert commentary: The limited preclinical and ongoing clinical studies published to date evaluating BCMA-directed therapies have shown great promise. It has also been demonstrated that BCMA is solubilized and elevated in the blood of MM, Waldenstrom's macroglobulinemia and CLL patients, and is also responsible for the immune deficiency in MM. Reducing circulating levels may improve the efficacy of these treatments.
Assuntos
Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Antígeno de Maturação de Linfócitos B/sangue , Biomarcadores Tumorais/sangue , Fator Ativador de Células B/sangue , Fator Ativador de Células B/imunologia , Antígeno de Maturação de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Humanos , Imunoterapia Adotiva , Leucemia Linfocítica Crônica de Células B/terapia , Mieloma Múltiplo/terapia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab-drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs. Additionally, there are now three bispecific antibodies in development, which bind to both BCMA and CD3ε on T-cells. This latter binding results in T-cell recruitment and activation, causing target cell lysis. More recently, T-cells have been genetically engineered to recognize BCMA-expressing cells and, in 2013, the first report of anti-BCMA-chimeric antigen receptor T-cells showed that these killed MM cell lines and human MM xenografts in mice. BCMA is also solubilized in the blood (soluble BCMA [sBCMA]) and MM patients with progressive disease have significantly higher sBCMA levels than those responding to treatment. sBCMA circulating in the blood may limit the efficacy of these anti-BCMA-directed therapies. When sBCMA binds to B-cell activating factor (BAFF), BAFF is unable to perform its major biological function of inducing B-cell proliferation and differentiation into Ab-secreting PC. However, the use of γ-secretase inhibitors, which prevent shedding of BCMA from PCs, may improve the efficacy of these BCMA-directed therapies.
Assuntos
Linfócitos B/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Humanos , Mieloma Múltiplo/patologiaRESUMO
TNF receptor-associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IκB kinase (IKK) to regulate the NF-κB and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant-negative (TRAF6dn) peptides were constructed which specifically reduced TRAF6 signaling and activation of IKK. TRAF6 not only reduced cellular growth but also increased the apoptosis of multiple myeloma tumor cells in a concentration-dependent fashion. Because TRAF6 activates IKK through polyubiquitination, independent of its proteasome activity, a TRAF6dn peptide was combined with the proteasome inhibitors bortezomib or carfilzomib to treat multiple myeloma. Importantly, targeting of TRAF6 in the presence of proteasome inhibition enhanced anti-multiple myeloma effects and also decreased TLR/TRAF6/NF-κB-related signaling. Finally, TRAF6dn dose dependently inhibited osteoclast cell formation from CD14+ monocytes, induced with RANKL and mCSF, and markedly reduced bone resorption in dentin pits. In all, these data demonstrate that blocking TRAF6 signaling has anti-multiple myeloma effects and reduces bone loss.Implications: The ability to target TRAF6 signaling and associated pathways in multiple myeloma suggests a promising new therapeutic approach. Mol Cancer Res; 15(5); 598-609. ©2017 AACR.