RESUMO
Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.
Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Sequenciamento do Exoma/métodos , Mieloma Múltiplo/genética , Células Neoplásicas Circulantes , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Variações do Número de Cópias de DNA/genética , Progressão da Doença , Feminino , Humanos , Biópsia Líquida/métodos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Mutação/genética , Medicina de Precisão/métodosRESUMO
Multiple myeloma (MM) is a plasma cell tumor marked by clonal evolution and preceded by a premalignant stage, which progresses via molecular pathway deregulation, including MYC activation. This activation relates to translocation or gain of the MYC locus and deregulation of upstream pathways such as IRF4, DIS3/LIN28B/let-7, or MAPK. Precision medicine is an approach to predict more accurately which treatment strategies for a particular disease will work in which groups of patients, in contrast to a "one-size-fits-all" approach. The knowledge of mechanisms responsible for MYC deregulation in MM enables identification of vulnerabilities and therapeutic targets in MYC-driven tumors. MYC can be targeted directly or indirectly, by interacting with several of its functions in cancer. Several such therapeutic strategies are evaluated in clinical trials in MM. In this review, we describe the mechanism of MYC activation in MM, the role of MYC in cancer progression, and the therapeutic options to targeting MYC.
Assuntos
Mieloma Múltiplo/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/fisiologia , Apoptose , Replicação do DNA , Humanos , Fatores Imunológicos/uso terapêutico , Fatores Reguladores de Interferon/fisiologia , Mieloma Múltiplo/etiologia , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas ras/fisiologiaRESUMO
The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.
Assuntos
Medula Óssea/metabolismo , Matriz Extracelular/metabolismo , Mieloma Múltiplo/metabolismo , Proteoma , Anexina A2/metabolismo , Estudos de Casos e Controles , Galectina 1/metabolismo , Perfilação da Expressão Gênica , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Análise de Sobrevida , Microambiente TumoralRESUMO
MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC-dependent cancers as well.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mieloma Múltiplo/genética , Interferência de RNA , Proteínas de Ligação a RNA/genética , Animais , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Genes myc , Xenoenxertos , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Proteínas de Ligação a RNA/metabolismoRESUMO
Current trajectory of clinical care is heading in the direction of personalized medicine. In an ideal scenario, clinicians can obtain extensive diagnostic and prognostic information via minimally-invasive assays. Information available in the peripheral blood has the potential to bring us closer to this goal. In this review we highlight the contributions of circulating tumor cells and circulating tumor DNA and RNA (ctDNA/ctRNA) towards cancer therapeutic field. We discuss clinical relevance, summarize available and upcoming technologies, and hypothesize how future care could be impacted by a combined study.
Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Neoplasias/sangue , Células Neoplásicas Circulantes/metabolismo , DNA de Neoplasias/genética , Humanos , Mutação , Neoplasias/genética , Medicina de PrecisãoRESUMO
The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.
Assuntos
Mieloma Múltiplo/patologia , Neovascularização Patológica/tratamento farmacológico , Animais , Anticorpos/uso terapêutico , Medula Óssea , Movimento Celular , Células Clonais/patologia , Progressão da Doença , Células Endoteliais/patologia , Camundongos , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Prevenção Secundária , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologiaRESUMO
Waldenström's macroglobulinemia (WM) is a rare, low-grade malignancy with no established standard of care. Rituximab regimens are most commonly used, supported by their efficacy in hematologic malignancies, including WM. A growing number of investigational regimens for WM have been evaluated in phase II clinical trials, including single-agent and combination strategies that include newer-generation monoclonal antibodies (ofatumumab and alemtuzumab), proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory agents (thalidomide and lenalidomide), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), a Bruton's tyrosine kinase inhibitor (ibrutinib), and a histone deacetylase inhibitor (panobinostat). Other novel agents are in early-stage development for WM. International treatment guidelines for WM suggest suitable regimens in the newly diagnosed and relapsed/refractory settings, in accordance with patient age, disease presentation, and efficacy and safety profiles of particular drugs. These factors must be considered when choosing appropriate therapy for individual patients with WM, to maximize response and prolong survival, while minimizing the risk of adverse events. This review article provides a clinical perspective of the modern management of patients with WM, in the context of available trial data for novel regimens and recently updated treatment guidelines.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Imunoterapia/métodos , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.
Assuntos
Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Quimioterapia Combinada , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fator 88 de Diferenciação Mieloide/genética , Receptores CXCR4/genética , Recidiva , Rituximab/administração & dosagem , Rituximab/efeitos adversosAssuntos
Mieloma Múltiplo/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Sobrevivência Celular , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Isoenzimas , Camundongos , Camundongos SCID , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Indeed, the BM niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM niche is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a noncellular compartment including the extracellular matrix (ECM) and the liquid milieu (cytokines, growth factors, and chemokines). In this paper we discuss how the interaction between the malignant plasma cell and the BM microenvironment allowed myeloma progression through cell homing and the new concept of premetastatic niche.
Assuntos
Medula Óssea/imunologia , Citocinas/imunologia , Modelos Imunológicos , Mieloma Múltiplo/imunologia , Animais , HumanosRESUMO
Drug resistance is a growing area of concern. It has been shown that a small, residual pool of leukemic CD34+ progenitor cells can survive in the marrow microenvironment of chronic myeloid leukemia (CML) patients after years of kinase inhibitor treatment. Bone marrow (BM) stroma has been implicated in the long-term survival of leukemic cells, and contributes to the expansion and proliferation of both transformed and normal hematopoietic cells. Mechanistically, we found that CML cells expressed CXCR4, and that plerixafor diminished BCR-ABL-positive cell migration and reduced adhesion of these cells to extra cellular-matrix components and to BM stromal cells in vitro. Moreover, plerixafor decreased the drug resistance of CML cells induced by co-culture with BM stromal cells in vitro. Using a functional mouse model of progressive and residual disease, we demonstrated the ability of the CXCR4 inhibitor, plerixafor, to mobilize leukemic cells in vivo, such that a plerixafor-nilotinib combination reduced the leukemia burden in mice significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib as single agent. These results support the idea of using CXCR4 inhibition in conjunction with targeted tyrosine kinase inhibition to override drug resistance in CML and suppress or eradicate residual disease.
Assuntos
Antineoplásicos/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas/uso terapêutico , Receptores CXCR4/antagonistas & inibidores , Células Estromais/efeitos dos fármacos , Animais , Benzilaminas , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Adesão Celular , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Ciclamos , Resistencia a Medicamentos Antineoplásicos , Citometria de Fluxo , Compostos Heterocíclicos/farmacologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
Bone marrow microenvironment has been shown to play a crucial role in supporting the pathogenesis and the progression of several B-cell malignancies, including Waldenstrom's Macroglobulinemia (WM). Among the different cell types within the bone marrow milieu, endothelial cells have been proven to support WM cells growth. Based on the understanding of bone marrow neo-angiogenesis in plasma cell dyscrasias, a number of anti-angiogenic molecules are now available for the treatment of these diseases. Indeed, anti-angiogenic drugs, such as proteasome-, proteins kinase-C (PKC)-, phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR)-, and histone deacetylase (HDAC)- inhibitors are now available, playing a key role in the treatment of WM both in the preclinical settings and as part of clinical trials.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/patologia , Inibidores da Angiogênese/farmacologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Ácidos Borônicos/uso terapêutico , Bortezomib , Células Endoteliais/patologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Panobinostat , Inibidores de Proteases , Inibidores de Proteassoma , Proteína Quinase C/antagonistas & inibidores , Pirazinas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Microambiente TumoralRESUMO
The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique ß-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.
Assuntos
Antineoplásicos/uso terapêutico , Lactonas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Inibidores de Proteassoma , Pirróis/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20-41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant.
Assuntos
Linfoma não Hodgkin/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Salvação/métodos , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Everolimo , Feminino , Humanos , Linfoma não Hodgkin/complicações , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Sirolimo/administração & dosagem , Resultado do TratamentoRESUMO
Although outcomes for patients with multiple myeloma (MM) have improved over the past decade, the disease remains incurable and even patients who respond well to induction therapy ultimately relapse and require additional treatment. Conventional chemotherapy and high-dose therapy with stem cell transplantation (SCT) have historically been utilized in the management of relapsed MM, but in recent years the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, have assumed a primary role in this setting. This review focuses on the role of thalidomide, lenalidomide and bortezomib in relapsed and refractory MM, with additional discussion dedicated to emerging drugs in relapsed MM that may prove beneficial to patients with this disease.
Assuntos
Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Terapia de Salvação/métodos , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib , Humanos , Imunossupressores/uso terapêutico , Lenalidomida , Pirazinas/uso terapêutico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
The purpose of this study was to determine the effect of thalidomide on stem cell collection and engraftment in patients with multiple myeloma. We performed a retrospective review of 67 patients newly diagnosed with multiple myeloma at Mayo Clinic and treated with a single regimen prior to stem cell transplantation between January of 2000 and September of 2001. Stem cells were collected from 24 patients who received thalidomide, 200 mg/day, with dexamethasone as initial therapy before stem cell collection. These patients were compared with 43 control patients seen during the same period who had received only one previous regimen before stem cell collection and transplantation. The cumulative thalidomide dose before stem cell collection was 17 000 mg over a median of four cycles (range, 2-7 cycles). The thalidomide and control groups were not significantly different in their baseline characteristics, number of stem cells collected, time to collection, or time to engraftment of neutrophils or platelet count of 50 000/microl. Time to platelet count of 20 000/microl was delayed by a median of 4 days (P=0.008), but platelet transfusion requirements did not differ (P=0.95). We concluded that thalidomide does not substantially affect peripheral cell mobilization or engraftment.