RESUMO
Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient-derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Mieloma Múltiplo/terapia , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Citotoxicidade Imunológica/efeitos dos fármacos , Citotoxicidade Imunológica/imunologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Receptores KIR/antagonistas & inibidores , Receptores KIR/imunologia , RecidivaRESUMO
Novel therapies are urgently needed to improve clinical outcomes for patients with acute myeloid leukemia (AML). The investigational drug alisertib (MLN8237) is a novel Aurora A kinase inhibitor being studied in multiple Phase I and II studies. We investigated the preclinical efficacy and pharmacodynamics of alisertib in AML cell lines, primary AML cells and mouse models of AML. Here, we report that alisertib disrupted cell viability, diminished clonogenic survival, induced expression of the FOXO3a targets p27 and BIM and triggered apoptosis. A link between Aurora A expression and sensitivity to ara-C was established, suggesting that Aurora A inhibition may be a promising strategy to increase the efficacy of ara-C. Accordingly, alisertib significantly potentiated the antileukemic activity of ara-C in both AML cell lines and primary blasts. Targeted FOXO3a knockdown significantly blunted the pro-apoptotic effects of the alisertib/ara-C combination, indicating that it is an important regulator of sensitivity to these agents. In vivo studies demonstrated that alisertib significantly augmented the efficacy of ara-C without affecting its pharmacokinetic profile and led to the induction of p27 and BIM. Our collective data indicate that targeting Aurora A with alisertib represents a novel approach to increase the efficacy of ara-C that warrants further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azepinas/farmacologia , Citarabina/farmacologia , Fatores de Transcrição Forkhead/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Aurora Quinase A , Aurora Quinases , Proteína 11 Semelhante a Bcl-2 , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box O3 , Células HL-60 , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS: Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. RESULTS: Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). CONCLUSION: Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.
Assuntos
Depsipeptídeos/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/efeitos adversos , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Resultado do Tratamento , Doenças Vasculares/induzido quimicamente , Vômito/induzido quimicamente , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citarabina/farmacologia , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Piridazinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Citarabina/uso terapêutico , Sinergismo Farmacológico , Humanos , Imidazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêuticoRESUMO
BACKGROUND: The three phases of cancer survivorship include the acute survival phase (ASP), the extended survival phase (ESP), and the permanent survival phase (PSP). This Institutional Review Board-approved retrospective pilot project compared races and leukemia subtypes among patients in the ASP, ESP, and PSP. METHODS: Fifty-five adult patients from our National Cancer Institute-designated cancer center were individually interviewed. Subjects were asked about multiple areas of survivorship including their social support system, distress level, and quality of life. RESULTS: Demographics of the 55 patients are acute lymphocytic leukemia (ALL), 10; acute myelocytic leukemia (AML), 9; chronic lymphocytic leukemia (CLL), 23; and chronic myelocytic leukemia (CML), 13. There were 23 females and 32 males, 30 Hispanics, 20 Caucasians, and 5 African-Americans. Twenty-two patients were in the ASP, 21 in the ESP, and 12 in the PSP. AML patients experienced the most physical, family, emotional, and spiritual problems (78%, 33%, 56%, and 22%, respectively). AML patients also had the highest distress level with a mean score of 5.8 (SD 1.7), compared to ALL (1.8), CLL (3.2), and CML (5.1) (P value < .001). Among all the phases of survivorship, the ASP had the highest distress level (mean, 4.8) and the worst quality of life (mean, 2.3). The ASP patients had the most treatment for depression (38%). When comparing races, African Americans and Hispanics (40% and 37%, respectively) were unable to cope with finances, compared to Caucasians (5%), (P value .016). Fear of recurrence was higher in Hispanics (67%), compared to African Americans (40%) and Caucasians (30%) (P value .031). Hispanics (40%) experienced more problems with housing, insurance, and work, as compared to African Americans (20%) and Caucasians (10%) (P value .047). CONCLUSION: This study addresses the perceptions and beliefs of leukemia survivors and found that AML and minority patients need further investigation on various aspects of quality of life.
Assuntos
Leucemia/etnologia , Leucemia/patologia , Negro ou Afro-Americano , Feminino , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Taxa de Sobrevida , População BrancaRESUMO
Ofatumumab, the human CD20 monoclonal antibody that binds a distinct epitope from rituximab, has demonstrated clinical benefit as monotherapy for patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (FA-ref) and patients refractory to fludarabine with bulky (> 5 cm) lymph nodes (BF-ref). To potentially gain insight into outcomes in patients previously treated with or refractory to rituximab, we performed an ad hoc retrospective analysis in the final 96 FA-ref and 111 BF-ref patients. There were 117 patients previously treated with rituximab (98 rituximab-refractory); 89 patients were rituximab-naive. For rituximab-treated, rituximab-refractory, and rituximab-naive patients, overall response rate was 43%, 44%, and 53%; median progression-free survival was 5.3, 5.5, and 5.6 months; and median overall survival was 15.5, 15.5, and 20.2 months. There were no significant differences in ofatumumab-related infusion reactions, or hematologic or infectious adverse events between subgroups. In summary, ofatumumab monotherapy was effective and well tolerated in patients with fludarabine-refractory chronic lymphocytic leukemia, including in patients with previous rituximab exposure. This trial was registered at www.clinicaltrials.gov as #NCT00349349.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/terapia , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab , Vidarabina/uso terapêuticoRESUMO
The Aurora family of serine/threonine kinases is essential for chromosome alignment, segregation, centrosomal maturation, mitotic spindle formation, and cytokinesis during mitosis. Their fundamental role in cell cycle regulation and aberrant expression in a broad range of malignancies prompted the development of small molecules that selectively inhibit their activity. Recent studies have revealed new insights into the cellular effects of Aurora kinase inhibition. Moreover, early phase clinical studies have shown that these agents have therapeutic efficacy. In this review, we will outline the functions of Aurora kinases in normal cell division and in malignancy. We will focus on recent preclinical and clinical studies that have explored the mechanism of action and clinical effect of Aurora inhibitors in cancer treatment.
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Aurora Quinases , Ciclo Celular , Humanos , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/fisiologiaRESUMO
INTRODUCTION: Bone marrow aspiration and biopsy is an invasive procedure associated with morbidity and mortality risk. We compared a powered bone marrow aspiration and biopsy device to the traditional method by relatively assessing pain scores, procedure times, biopsy capture rates, quality of material retrieved, and safety and operator satisfaction. METHODS: Two large academic medical centres participated in this trial. Patients were randomised to have procedures carried out using the powered system or the manual technique. A visual analogue scale pain score was recorded immediately following skin puncture and once again at the end of the procedure for each patient. Procedure time was measured from skin puncture to core specimen acquisition. Pathologic assessment of 30 randomised samples was carried out. Operator satisfaction with devices was measured on a scale of 0-10, with 10 as the highest rating. RESULTS: Five operators from two sites enrolled 50 patients (powered, n=25; manual, n=25). Groups were evenly matched, with no significant differences in the means for age, weight and height. The powered system was superior to the manual system with respect to patient perceived pain from needle insertion (2.6±2.0 vs 4.1±2.5, p=0.022) and procedural time (100.0±72.8 s vs 224.1±79.0 s, p<0.001). Overall pain scores at the end of both procedures were comparable (3.2±2.2 vs 3.8±3.0, p=0.438). No complications were observed in either arm of the study. Blinded pathologic analysis of the specimens retrieved revealed that cores obtained using the powered system were longer and wider than those obtained using the manual technique (25.4±12.3 mm² vs 11.9±5.6 mm², p=0.001). For marrow aspiration, no difference was seen between groups for clot/particle spicules or smear spicules. Operator assessment favoured the use of the powered device. CONCLUSIONS: Results of this trial suggest that the use of a powered bone marrow biopsy device significantly reduces needle insertion pain and procedural time when compared to a manual technique. The superior size and overall quality of core specimens retrieved by the powered device provides more material for pathologic evaluation, thereby increasing diagnostic yield and reducing the need for repeat procedures.
Assuntos
Biópsia por Agulha/instrumentação , Células da Medula Óssea/patologia , Exame de Medula Óssea/instrumentação , Biópsia por Agulha/efeitos adversos , Biópsia por Agulha/métodos , Exame de Medula Óssea/efeitos adversos , Exame de Medula Óssea/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/etiologia , Estudos ProspectivosRESUMO
The mammalian target of rapamycin (mTOR) regulates protein synthesis in addition to cell growth and cell proliferation. Elucidation of the roles of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway in the regulation of the pathogenesis of hematological neoplasms has led to the development and clinical evaluation of agents targeting this pathway for the treatment of leukemia and lymphomas. Clinical trials conducted to date have shown modest responses to mTOR inhibition in patients with various hematological malignancies. Novel agents that simultaneously target mTOR complex 2 (mTORC2) or AKT in addition to mTOR complex 1 (mTORC1) may offer an opportunity to improve therapeutic efficacy.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/metabolismo , Humanos , Terapia de Alvo Molecular , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismoRESUMO
We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had ß2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, ß2-microglobulin and the number of O-FC courses were significantly correlated (P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at www.clinicaltrials.gov as NCT00410163.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Vidarabina/análogos & derivados , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Ciclofosfamida/efeitos adversos , Feminino , Humanos , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversosRESUMO
BACKGROUND: In patients with chronic lymphocytic leukemia (CLL), treatment with lenalidomide induces a unique, previously uncharacterized, immune response called tumor flare reaction (TFR). The clinical significance of this reaction remains unknown. METHODS: Forty-five patients with CLL who were treated with lenalidomide in a phase 2 clinical trial were evaluated for the clinical features, intensity, and duration of TFR. Correlation was made with tumor response and the immune cellular microenvironment. Steroids for the prophylaxis of TFR was not given to patients in Group A (n = 29) whereas patients in Group B (n = 16) received low-dose prednisone as well as a slow dose escalation of lenalidomide for the prevention of TFR. RESULTS: Thirty (67%) patients experienced a TFR, with a grade 2 or 3 reaction (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) observed in 33% of patients (47% in Group A and 9% in Group B; P = .05). The median time to onset of the TFR was 6 days, and was longer in the patients receiving prophylaxis (4 days vs 9 days, respectively; P = .01). A complete response was observed in 7 of 30 (23%) patients with TFR and 1 of 15 (7%) patients without TFR. The median progression-free survival was 19.9 months and 19.4 months, respectively, for patients with versus those without TFR (P = .92). CONCLUSIONS: TFR is a unique immune-mediated phenomenon noted with lenalidomide treatment only in patients with CLL that correlates with clinical response. It can be effectively managed with anti-inflammatory agents.
Assuntos
Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/imunologia , Talidomida/análogos & derivados , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Talidomida/efeitos adversos , Resultado do TratamentoRESUMO
Novel therapies are urgently needed to prevent and treat tyrosine kinase inhibitor resistance in chronic myeloid leukaemia (CML). MLN8237 is a novel Aurora A kinase inhibitor under investigation in multiple phase I and II studies. Here we report that MLN8237 possessed equipotent activity against Ba/F3 cells and primary CML cells expressing unmutated and mutated forms of breakpoint cluster region-Abelson kinase (BCR-ABL). Notably, this agent retained high activity against the T315I and E255K BCR-ABL mutations, which confer the greatest degree of resistance to standard therapy. MLN8237 treatment disrupted cell cycle kinetics, induced apoptosis, caused a dose-dependent reduction in the expression of the large inhibitor of apoptosis protein Apollon, and produced a morphological phenotype consistent with Aurora A kinase inhibition. In contrast to other Aurora kinase inhibitors, MLN8237 did not significantly affect BCR-ABL activity. Moreover, inhibition of Aurora A with MLN8237 significantly increased the in vitro and in vivo efficacy of nilotinib. Targeted knockdown of Apollon sensitized CML cells to nilotinib-induced apoptosis, indicating that this is an important factor underlying MLN8237's ability to increase the efficacy of nilotinib. Our collective data demonstrate that this combination strategy represents a novel therapeutic approach for refractory CML that has the potential to suppress the emergence of T315I mutated CML clones.
Assuntos
Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aurora Quinases , Benzamidas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Proteínas Inibidoras de Apoptose/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação , Piperazinas/farmacologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismoRESUMO
This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m(2) on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m(2) weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70-98%) with 1 complete response (4%), 1 near-complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Rituximab , Fatores de Tempo , Macroglobulinemia de Waldenstrom/mortalidadeRESUMO
The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1-Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic functions of WT1 by clinically available Hsp90 inhibitors.
Assuntos
Regulação Leucêmica da Expressão Gênica , Proteínas de Choque Térmico HSP90/metabolismo , Leucemia Mieloide/genética , Proteínas WT1/genética , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Linhagem Celular Tumoral , Etoposídeo/farmacologia , Feminino , Inativação Gênica , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Humanos , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , Camundongos , Camundongos SCID , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios e Motivos de Interação entre Proteínas , Estrutura Terciária de Proteína , Triazóis/uso terapêutico , Proteínas WT1/química , Proteínas WT1/metabolismoRESUMO
NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappaB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.
Assuntos
Ciclopentanos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteassoma , Pirimidinas/farmacologia , Ubiquitinas/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Proteínas Culina , Dano ao DNA/efeitos dos fármacos , Imunofluorescência , Humanos , Camundongos , Proteína NEDD8 , NF-kappa B/genética , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
PURPOSE: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM). PATIENTS AND METHODS: Patients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response. RESULTS: Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached. CONCLUSION: The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Farmacológicos/sangue , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacologia , Bortezomib , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Recidiva , Rituximab , Análise de Sobrevida , Macroglobulinemia de Waldenstrom/imunologiaRESUMO
Chronic myeloid leukemia (CML) is the consequence of a single balanced translocation that produces the BCR-ABL fusion oncogene which is detectable in over 90% of patients at presentation. The BCR-ABL inhibitor imatinib mesylate (IM) has improved survival in all phases of CML and is the standard of care for newly diagnosed patients in chronic phase. Despite the very significant therapeutic benefits of IM, a small minority of patients with early stage disease do not benefit optimally while IM therapy in patients with advanced disease is of modest benefit in many. Diverse mechanisms may be responsible for IM failures, with point mutations within the Bcr-Abl kinase domain being amongst the most common resistance mechanisms described in patients with advanced CML. The development of novel agents designed to overcome IM resistance, while still primarily targeted on BCR-ABL, led to the creation of the high affinity aminopyrimidine inhibitor, nilotinib. Nilotinib is much more potent as a BCR-ABL inhibitor than IM and inhibits both wild type and IM-resistant BCR-ABL with significant clinical activity across the entire spectrum of BCR-ABL mutants with the exception of T315I. The selection of a second generation tyrosine kinase inhibitor to rescue patients with imatinib failure will be based on several factors including age, co-morbid medical problems and ABL kinase mutational profile. It should be noted that while the use of targeted BCR-ABL kinase inhibitors in CML represents a paradigm shift in CML management these agents are not likely to have activity against the quiescent CML stem cell pool. The purpose of this review is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior therapy with IM or dasatinib.
RESUMO
Novel agents have demonstrated enhanced efficacy when combined with other antimyeloma agents especially dexamethasone. The steroid doses employed in myeloma regimens are often poorly tolerated. Therefore, in a phase II clinical trial we investigated the efficacy of a steroid-free combination including bortezomib, pegylated liposomal doxorubicin and thalidomide (VDT regimen). Twenty-three patients with relapsed or refractory myeloma or other plasma cell cancers were treated with the VDT regimen. Patient had a median of five prior therapies and 65.2% were refractory to their last regimen. The overall response rates were 55.5% and 22%, respectively. The median progression free survival was 10.9 months (95% CI: 7.3-15.8) and the median overall survival was 15.7 months (95% CI: 9.1-not reached). Fatigue and sensory neuropathy were the most common side effects noted. We observe that VDT is an effective steroid-free regimen with ability to induce durable remission even in patients with refractory myeloma.
Assuntos
Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Doxorrubicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pirazinas/administração & dosagem , Talidomida/administração & dosagem , Adulto , Idoso , Bortezomib , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Terapia de Salvação/métodos , Esteroides/uso terapêutico , Resultado do TratamentoRESUMO
Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukemia (CML) and are increasingly used in other malignancies. Despite the apparent selectivity of these agents significant side effects can occur mainly due to off target kinase inhibition. Clinical consequences of serosal inflammation, including pleural and pericardial effusions, have emerged as a frequent adverse event associated with dasatinib while occurring much less frequently during imatinib and nilotinib therapy. The pathogenesis is uncertain but may involve inhibition of platelet derived growth factor or expansion of cytotoxic T and natural killer cells. The development of serosal inflammation with dasatinib poses a significant challenge to physicians, as it cannot be predicted, the time of onset is variable, and management frequently requires repeat invasive procedures.