RESUMO
Pevonedistat (TAK924) is a Nedd8-activating enzyme inhibitor with preclinical activity in non-Hodgkin lymphoma (NHL). This open-label, Phase I, multicenter, investigator-sponsored study enrolled patients with relapsed/refractory (R/R) NHL and chronic lymphocytic leukemia (CLL). The primary objective was safety. Pevonedistat was given intravenously on days 1, 3, 5 of a 21-day cycle for 8 cycles at five dose levels (15 to 50 mg/m2); ibrutinib was administered at 420 or 560 mg orally daily continuously. Eighteen patients with NHL were enrolled, including 8 patients with mantle cell lymphoma (MCL) and 4 patients with CLL. One dose-limiting toxicity (mediastinal hemorrhage) occurred at 50 mg/m2 of pevonedistat which is the estimated maximum tolerated dose. Bruising and diarrhea were the most common adverse events (56% and 44%). Atrial fibrillation occurred in 3 patients (17%). Grade ≥3 toxicities included arthralgia, atrial fibrillation, bone pain, diarrhea, hypertension, and mediastinal hemorrhage (one patient each). The overall response rate (ORR) was 65% (100% ORR in MCL). Pevonedistat disposition was not modified by ibrutinib. scRNA-Seq analysis showed that pevonedistat downregulated NFκB signaling in malignant B-cells in vivo. Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB signaling in vivo.
Assuntos
Inibidores Enzimáticos , Leucemia Linfocítica Crônica de Células B , Linfoma de Célula do Manto , Linfoma não Hodgkin , Proteína NEDD8 , Adulto , Humanos , Fibrilação Atrial , Inibidores Enzimáticos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Proteína NEDD8/antagonistas & inibidoresRESUMO
Although small molecule inhibitors of B-cell receptor-associated kinases have revolutionized therapy in chronic lymphocytic leukemia (CLL), responses are incomplete. Pro-survival signaling emanating from the microenvironment may foster therapeutic resistance of the malignant B cells resident in the protective lymphoid niches. B-cell activating factor (BAFF) is critical to the survival of both healthy and neoplastic B cells. However, the pro-survival pathways triggered by BAFF have not been fully characterized. Here we show that BAFF elicited resistance to spontaneous and drug-induced apoptosis in stromal co-cultures, induced activation of both canonical and non-canonical NFκB signaling pathways, and triggered B-cell receptor signaling in CLL cells, independently of IGHV mutational status. SYK, a proximal kinase in the B-cell receptor signaling cascade, acted via STAT3 to bolster transcription of the anti-apoptotic protein Mcl-1, thereby contributing to apoptosis resistance in BAFF-stimulated cells. SYK inhibitor entospletinib downregulated Mcl-1, abrogating BAFF-mediated cell survival. BAFF-B-cell receptor crosstalk in neoplastic B cells was mediated by SYK interaction with TRAF2/TRAF3 complex. Thus, SYK inhibition is a promising therapeutic strategy uniquely poised to antagonize crosstalk between BAFF and B-cell receptor, thereby disrupting the pro-survival microenvironment signaling in chronic lymphocytic leukemia.
Assuntos
Fator Ativador de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Quinase Syk/antagonistas & inibidores , Animais , Células CHO , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Análise por Conglomerados , Cricetulus , Perfilação da Expressão Gênica , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Modelos Biológicos , NF-kappa B/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNFAssuntos
Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Piperidinas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: Prostate-specific antigen (PSA) kinetics have failed to predict for the presence of prostate cancer in screening populations in which many patients harbor subclinical disease. We hypothesized that the prebiopsy PSA doubling time (PSADT) and PSA velocity (PSAV) could predict for cancer detection in a referral population with a suspicion of prostate cancer. METHODS: Data were collected from 1699 consecutive veterans with a PSA level of 10 ng/mL or less who underwent prostate biopsy. Logistic regression analysis was performed on the following: age, race, family history, digital rectal examination findings, PSA, PSA density, PSADT, PSAV, prostate volume, and ultrasound lesions. Model building was accomplished with 70% of the data, and validation was done using the remaining 30%. These data were also analyzed using classification and regression tree analysis. RESULTS: Using logistic regression analysis (P <0.05) on the model building set, prostate cancer was associated with age (older than 70 years), PSA level (greater than 2.9 ng/mL), PSA density (more than 0.12 ng/mL/cm3), digital rectal examination findings, and the presence of a lesion on ultrasonography. A PSADT of 2 to 5 years was marginally associated with prostate cancer detection (odds ratio 1.6, 95% confidence interval 1.1 to 2.3), and a PSADT of less than 2 years or longer than 5 years and PSAV were not predictive. On classification and regression tree analysis, PSADT was not selected as a predictive factor. Furthermore, neither PSADT nor PSAV was predictive of Gleason score 7 or worse cancer. CONCLUSIONS: In contrast to its prognostic value after the diagnosis of prostate cancer has been established, PSA kinetics offer little to clinical decision making as predictors of cancer or high-grade cancer in men with a PSA level of 10 ng/mL or less.
Assuntos
Biópsia por Agulha , Antígeno Prostático Específico/análise , Neoplasias da Próstata/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Intervalos de Confiança , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Valor Preditivo dos Testes , Probabilidade , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Ultrassonografia , Ultrassom Focalizado Transretal de Alta IntensidadeRESUMO
PURPOSE: Prostate cancer screening allows early cancer detection but not all patients benefit from subsequent therapy. Thus, identifying patients who are likely to harbor aggressive cancer could significantly decrease the number of prostate biopsies performed. MATERIALS AND METHODS: Data were collected on 1,563 consecutive referred men with serum PSA 10 ng/ml or less who underwent an initial prostate biopsy. Predictors of aggressive cancer (Gleason sum 7 or greater) were identified using CART analysis. Model building was done in a randomly selected training set (70% of the data) and validation was completed using the remaining data. RESULTS: Cancer was detected in 406 men (26.1%). Gleason 7 or greater cancer was found in 130 men (8.3%). CART created a decision tree that identified certain groups at risk for aggressive cancer, namely 1) PSAD greater than 0.165 ng/ml/cc, and 2) PSAD greater than 0.058 to 0.165 ng/ml/cc or less, age greater than 57.5 years and prostate volume greater than 22.7 cc. The incidence of aggressive prostate cancer was 1.1% when PSAD was 0.058 ng/ml/cc or less in the validation set. The sensitivity and specificity of CART for identifying men with aggressive cancer were 100% and 31.8% for model building data, and 91.5% and 33.5% for the validation data set, respectively. CONCLUSIONS: CART identified groups at risk for aggressive prostate cancer. Application of this CART could decrease unnecessary biopsies by 33.5% when only a diagnosis of high grade prostate cancer would lead to subsequent therapy.