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2.
Nat Chem Biol ; 15(7): 681-689, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31133756

RESUMO

The mechanisms by which cells adapt to proteotoxic stress are largely unknown, but are key to understanding how tumor cells, particularly in vivo, are largely resistant to proteasome inhibitors. Analysis of cancer cell lines, mouse xenografts and patient-derived tumor samples all showed an association between mitochondrial metabolism and proteasome inhibitor sensitivity. When cells were forced to use oxidative phosphorylation rather than glycolysis, they became proteasome-inhibitor resistant. This mitochondrial state, however, creates a unique vulnerability: sensitivity to the small molecule compound elesclomol. Genome-wide CRISPR-Cas9 screening showed that a single gene, encoding the mitochondrial reductase FDX1, could rescue elesclomol-induced cell death. Enzymatic function and nuclear-magnetic-resonance-based analyses further showed that FDX1 is the direct target of elesclomol, which promotes a unique form of copper-dependent cell death. These studies explain a fundamental mechanism by which cells adapt to proteotoxic stress and suggest strategies to mitigate proteasome inhibitor resistance.


Assuntos
Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Inibidores de Proteassoma/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteassoma/química , Bibliotecas de Moléculas Pequenas/química
4.
bioRxiv ; 2023 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-37577538

RESUMO

The development of targeted therapy for patients with Multiple Myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chr1q (Amp1q) is the most frequent arm-level copy number gain in patients with MM, and it is associated with higher risk of progression and death despite recent advances in therapeutics. Thus, developing targeted therapy for patients with MM and Amp1q stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with Amp1q and showed increased sensitivity to the combination of MCL1 and PI3K inhibitors. Using single-cell RNA sequencing, we compared subclones with and without Amp1q within the same patient tumors and showed that Amp1q is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number for part of the chr1q arm, we showed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with Amp1q.

5.
Stem Cells ; 28(11): 2109-20, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20882532

RESUMO

Disseminating tumors are one of the gravest medical problems. Here, we combine the tumor-specific apoptosis-inducing activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with the ability of mesenchymal stem cells (MSCs) to infiltrate both tumor and lymphatic tissues to target primary tumors as well as disseminated cancer cells in a human pancreatic cancer mouse model. Furthermore, we targeted X-linked inhibitor of apoptosis protein (XIAP) by RNA interference (RNAi) inside the cancer cells to make use of the apoptosis sensitization as well the antimetastatic effect that is afforded by XIAP silencing. We generated MSCs, termed MSC.sTRAIL, that express and secrete a trimeric form of soluble TRAIL (sTRAIL). MSC.sTRAIL triggered limited apoptosis in human pancreatic carcinoma cells that were resistant to soluble recombinant TRAIL, which is most likely due to the enhanced effect of the direct, cell-mediated delivery of trimeric TRAIL. MSC.sTRAIL-mediated cell death was markedly increased by concomitant knockdown of XIAP by RNAi in the cancer cells. These findings were confirmed in xenograft models, in which tumors from the parental pancreatic carcinoma cells showed only growth retardation on treatment with MSC.sTRAIL, whereas tumors with silenced XIAP that were treated with MSC.sTRAIL went into remission. Moreover, animals with XIAP-negative xenografts treated with MSC.sTRAIL were almost free of lung metastasis, whereas animals treated with control MSCs showed substantial metastatic growth in the lungs. In summary, this is the first demonstration that a combined approach using systemic MSC-mediated delivery of sTRAIL together with XIAP inhibition suppresses metastatic growth of pancreatic carcinoma.


Assuntos
Células-Tronco Mesenquimais/metabolismo , Neoplasias Pancreáticas/terapia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Apoptose/fisiologia , Western Blotting , Diferenciação Celular , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Camundongos , Camundongos Nus , Ligante Indutor de Apoptose Relacionado a TNF/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
6.
Nat Cancer ; 1(5): 493-506, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-33409501

RESUMO

Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK+ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14+ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.


Assuntos
Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Mieloma Múltiplo Latente , Animais , Humanos , Camundongos , Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/genética , Análise de Sequência de RNA , Microambiente Tumoral/genética
7.
Nanoscale ; 11(43): 20485-20496, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31650133

RESUMO

Monitoring malignant progression and disease recurrence post-therapy are central challenges to improving the outcomes of patients with multiple myeloma (MM). Whereas current detection methods that rely upon bone marrow examination allow for precise monitoring of minimal residual disease and can help to elucidate clonal evolution, they do not take into account the spatial heterogeneity of the tumor microenvironment. As such, they are uninformative as to the localization of malignant plasma cells and may lead to false negative results. With respect to the latter challenge, clinically-available imaging agents are neither sufficiently sensitive nor specific enough to detect minute plasma cell populations. Here, we sought to explore methods by which to improve detection of MM cells within their natural bone marrow environment, using whole-animal magnetic resonance imaging to longitudinally monitor early-stage disease as well as to enhance tumor detection after systemic therapy. We conducted a proof-of-concept study to demonstrate that ultra-small (<5 nm) gadolinium-containing nanoparticles bound to full-length antibodies against the B-cell maturation antigen (BCMA) exhibit rapid tumor uptake followed by renal clearance, improving the signal-to-noise ratio for MM detection beyond levels that are currently afforded by other FDA-approved clinical imaging modalities. We anticipate that when combined with bone marrow or blood biopsy, such imaging constructs could help to augment the effective management of patients with MM.


Assuntos
Anticorpos/química , Mieloma Múltiplo/diagnóstico , Nanopartículas/química , Animais , Anticorpos/imunologia , Anticorpos/metabolismo , Antígeno de Maturação de Linfócitos B/imunologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Meios de Contraste/química , Meios de Contraste/farmacocinética , Modelos Animais de Doenças , Detecção Precoce de Câncer , Gadolínio/química , Humanos , Imageamento por Ressonância Magnética , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Mieloma Múltiplo/patologia , Nanopartículas/metabolismo , Neoplasia Residual/diagnóstico , Plasmócitos/metabolismo , Plasmócitos/patologia , Razão Sinal-Ruído , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Distribuição Tecidual
8.
J Clin Invest ; 128(6): 2487-2499, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29558366

RESUMO

Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression is the expansion of regulatory T cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type 1 interferon (IFN). Blocking IFN α and ß receptor 1 (IFNAR1) on Tregs significantly decreases both myeloma-associated Treg immunosuppressive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of MM patients, we found that Tregs were expanded and activated in the BM microenvironment at early stages of myeloma development. Selective depletion of Tregs led to a complete remission and prolonged survival in mice injected with myeloma cells. Further analysis of the interaction between myeloma cells and Tregs using gene sequencing and enrichment analysis uncovered a feedback loop, wherein myeloma-cell-secreted type 1 IFN induced proliferation and expansion of Tregs. By using IFNAR1-blocking antibody treatment and IFNAR1-knockout Tregs, we demonstrated a significant decrease in myeloma-associated Treg proliferation, which was associated with longer survival of myeloma-injected mice. Our results thus suggest that blocking type 1 IFN signaling represents a potential strategy to target immunosuppressive Treg function in MM.


Assuntos
Proliferação de Células , Tolerância Imunológica , Mieloma Múltiplo/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Receptor de Interferon alfa e beta/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Bloqueadores/farmacologia , Anticorpos Antineoplásicos/farmacologia , Linhagem Celular , Camundongos , Camundongos Knockout , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/patologia
9.
Org Lett ; 17(7): 1672-5, 2015 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-25774456

RESUMO

A build-couple-pair strategy, including double-reductive amination macrocyclization, has been used to generate decorated macrocycles (eannaphanes) with an embedded triazole and monosaccharide. Biological screening led to the identification of an inducer of apoptosis in leukemic cells, which acts at least partially as a 5-HT2 antagonist.

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