Assuntos
Bortezomib/agonistas , Carcinoma Hepatocelular/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Proteína 28 com Motivo Tripartido/farmacologia , Bortezomib/uso terapêutico , Linhagem Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Proteína 28 com Motivo Tripartido/uso terapêuticoRESUMO
Therapeutically targeting CD138, a define multiple myeloma (MM) antigen, is not yet approved for patients. We here developed and determined the preclinical efficacy of VIS832, a novel therapeutic monoclonal antibody (MoAb) with differentiated CD138 target binding to BB4 that is anti-CD138 MoAb scaffold for indatuximab ravtansine (BT062). VIS832 demonstrated enhanced CD138-binding avidity and significantly improved potency to kill MM cell lines and autologous patient MM cells regardless of resistance to current standard-of-care therapies, via robust antibody-dependent cellular cytotoxicity and phagocytosis mediated by NK and macrophage effector cells, respectively. Specifically, CD38-targeting daratumumab-resistant MM cells were highly susceptible to VIS832 which, unlike daratumumab, spares NK cells. Superior maximal cytolysis of VIS832 vs. daratumumab corresponded to higher CD138 vs. CD38 levels in MM cells. Furthermore, VIS832 acted synergistically with lenalidomide or bortezomib to deplete MM cells. Importantly, VIS832 at a sub-optimal dose inhibited disseminated MM1S tumors in vivo as monotherapy (P < 0.0001), and rapidly eradicated myeloma burden in all mice concomitantly receiving bortezomib, with 100% host survival. Taken together, these data strongly support clinical development of VIS832, alone and in combination, for the therapeutic treatment of MM in relapsed and refractory patients while pointing to its potential therapeutic use earlier in disease intervention.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Bortezomib/farmacologia , Imunoconjugados/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Sindecana-1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/imunologia , Bortezomib/agonistas , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Maitansina/agonistas , Maitansina/análogos & derivados , Maitansina/farmacologia , Camundongos , Camundongos SCID , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/imunologia , Sindecana-1/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Multiple myeloma stem-like cells (MMSCs) are responsible for initiation and relapse, though novel treatment paradigms that effectively eradicate MMSCs are yet to be developed. Selective inhibition of the cell cycle regulatory kinase Wee1 by MK1775 is being explored as a potential anti-cancer therapeutic. We report that higher expression of Wee1 is correlated with poor survival in multiple myeloma (MM). The MM models and patient-derived CD138+ plasma cells are particularly sensitive to the growth-inhibitory effects of the Wee1 inhibitor MK1775. MK1775 induces Mus81-Eme1 endonuclease-mediated DNA damage in S-phase cell cycle that results in a blockade of replication and then apoptosis. Furthermore, MK1775 strongly suppresses the features of stemness in vitro, in vivo and in primary CD138+ cells by decreasing ALDH1+ cell fraction and the expression of ALDH1. In addition, co-treatment of MK1775 with bortezomib is synergistic in vitro and in vivo. Bortezomib, although it enhances ALDH1+ cells, when combined with MK1775 abrogates this stimulatory effect on stemness. Considering MM as an invariably incurable malignancy due to the presence of heterogenic myeloma stem-like cells, our study presents inhibition of Wee1 as a promising targeted therapy for MM and provides a compelling rationale to further investigate the activity of MK1775 against myeloma in clinical settings.
Assuntos
Bortezomib/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Mieloma Múltiplo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Animais , Bortezomib/agonistas , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/enzimologia , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirazóis/agonistas , Pirimidinonas/agonistas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Quercetin, a bioflavonoid contained in several vegetables daily consumed, has been studied for long time for its antiinflammatory and anticancer properties. Quercetin interacts with multiple cancer-related pathways such as PI3K/AKT, Wnt/ß-catenin and STAT3. These pathways are hyperactivated in primary effusion lymphoma (PEL), an aggressive B cell lymphoma whose pathogenesis is strictly linked to the oncogenic virus Kaposis' Sarcoma-associated Herpesvirus (KSHV). In this study, we found that quercetin inhibited PI3K/AKT/mTOR and STAT3 pathways in PEL cells, and as a consequence, it down-regulated the expression of the prosurvival cellular proteins such as c-FLIP, cyclin D1 and cMyc. It also reduced the release of IL-6 and IL-10 cytokines, leading to PEL cell death. Moreover, quercetin induced a prosurvival autophagy in these cells and increased the cytotoxic effect of bortezomib, a proteasomal inhibitor, against them. Interestingly, quercetin decreased also the expression of latent and lytic KSHV proteins involved in PEL tumorigenesis and up-regulated the surface expression of HLA-DR and calreticulin, rendering the dying cells more likely detectable by the immune system. The results obtained in this study indicate that quercetin, which does not exert any cytotoxicity against normal B cells, may represent a good candidate for the treatment of this aggressive B cell lymphoma, especially in combination with autophagy inhibitors or with bortezomib.