RESUMO
BTK (Bruton's tyrosine kinase) inhibitors are highly effective front-line therapy for CLL (chronic lymphocytic leukemia) due to high response rates and prolonged progression-free survival, even in patients with high-risk disease features. They are also generally well tolerated, with the newer BTK inhibitors demonstrating better tolerability than ibrutinib while maintaining efficacy. Adverse effects such as bleeding or infections are usually manageable with supportive care or dose adjustments. Orally administered BTK inhibitors do not require intensive or inpatient monitoring and improve quality-of-life outcomes. Moreover, the established activity of venetoclax in the setting of BTK inhibitor failure is also reassuring as a salvage option. Nevertheless, the advantage of venetoclax as a time-limited treatment option is substantial, despite its inferior progression-free survival, since these patients can get another challenge with a reasonable chance of success. BTK inhibitors after venetoclax may be effective, but long-term data is limited. Given these reasons, BTK inhibitors remain the preferred treatment option as initial therapy for patients with CLL, especially those with del17p or TP53 mutations.
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Tirosina Quinase da Agamaglobulinemia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
OBJECTIVE: Malignant pleural mesothelioma (MPM) is a deadly disease with varying treatment options. This study retrospectively describes treatment practices at the University of Washington Medical System from 1980 to 2011, and evaluates the impact of trimodality therapy and radiation (photon and neutron) on survival. METHODS: A retrospective study was conducted on patients treated for MPM. Univariate and multivariate methods were utilized to evaluate potential factors associated with survival. Treatments received and baseline characteristics were included. Survival analysis of trimodality therapy was performed using a propensity score method to control for baseline characteristics. RESULTS: Among 78 eligible patients, the median age at diagnosis was 59 years and the median survival was 13.7 months. On multivariate analysis, the significant predictors of improved survival were age, smoking history, location, and receipt of radiation therapy or chemotherapy. In the 48 patients receiving radiation therapy, the difference in survival between neutron therapy and non-neutron therapy patients was not statistically significant: hazard ratio, 1.20 (95% confidence interval, 0.68-2.13), P=0.52. Patients receiving trimodality therapy were more likely to have early-stage disease (60% vs. 30%) and epithelioid histology (86% vs. 58%). In a propensity score-weighted Cox proportional hazards model, trimodality therapy patients had improved overall survival, hazard ratio 0.45, P=0.004, median 14.6 versus 8.6 months. CONCLUSIONS: Trimodality therapy was significantly associated with prolonged survival in patients with MPM, even when adjusting for baseline patient factors. Radiation therapy was associated with improved survival, but the modality of radiation therapy used was not associated with outcome.
Assuntos
Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Mesotelioma/mortalidade , Mesotelioma/terapia , Pleura/cirurgia , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/terapia , Adulto , Fatores Etários , Idoso , Análise de Variância , Quimioterapia Adjuvante , Estudos de Coortes , Terapia Combinada/métodos , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Pleurais/patologia , Prognóstico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Análise de SobrevidaRESUMO
BACKGROUND/AIM: Developments in imaging have improved cancer diagnosis, but identification of malignant cells during surgical resection remains a challenge. The aim of this study was to investigate the pacifastin family of peptides for novel activity targeting tumor cells and the delivery of either imaging or therapeutic agents. MATERIALS AND METHODS: Variants of pacifastin family peptides were generated, chemically modified and tested in human tumor xenografts. RESULTS: A tumor-homing peptide-dye conjugate (THP1) accumulated in tumors in vivo and was internalized into cells. Examination of related peptides revealed residues critical for accumulation and allowed the engineering of improved tumor-targeting variants. A THP1-drug conjugate carrying the microtubule inhibitor, MMAE, showed limited activity in vitro and no difference compared to vehicle control in vivo. CONCLUSION: Although there are some obstacles to developing pacifastin-derived peptides for therapeutic activity, these optimized peptides have great promise for cancer imaging.
Assuntos
Neoplasias/diagnóstico por imagem , Peptídeos/uso terapêutico , Proteínas , Animais , Autorradiografia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos Nus , Microscopia Confocal , Neoplasias/tratamento farmacológico , Peptídeos/farmacologia , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêuticoRESUMO
Histone deacetylase (HDAC) inhibitors can radiosensitize cancer cells. Radiation is critical in high-risk neuroblastoma treatment, and combinations of HDAC inhibitor vorinostat and radiation are proposed for neuroblastoma trials. Therefore, we investigated radiosensitizing effects of vorinostat in neuroblastoma. Treatment of neuroblastoma cell lines decreased cell viability and resulted in additive effects with radiation. In a murine metastatic neuroblastoma in vivo model vorinostat and radiation combinations decreased tumor volumes compared to single modality. DNA repair enzyme Ku-86 was reduced in several neuroblastoma cells treated with vorinostat. Thus, vorinostat potentiates anti-neoplastic effects of radiation in neuroblastoma possibly due to down-regulation of DNA repair enzyme Ku-86.
Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/radioterapia , Radiossensibilizantes/uso terapêutico , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Western Blotting , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Terapia Combinada , Enzimas Reparadoras do DNA/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/fisiologia , Raios gama , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Nus , Neuroblastoma/secundário , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco , VorinostatRESUMO
Due to its molecular heterogeneity and infiltrative nature, glioblastoma multiforme (GBM) is notoriously resistant to traditional and experimental therapeutics. To overcome these hurdles, targeted agents have been combined with conventional therapy. We evaluated the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor (XL765) in in vitro and in vivo studies. In vivo serially passaged human GBM xenografts that are more genetically stable than GBM cell lines in culture were used for all experiments. Biochemical downstream changes were evaluated by immunoblot and cytotoxicity by colorimetric ATP-based assay. For in vivo experiments, human xenograft GBM 39 grown intracranially in nude mice was altered to express luciferase to monitor tumor burden by optical imaging. XL765 resulted in concentration-dependent decreases in cell viability in vitro. Cytotoxic doses resulted in specific inhibition of PI3K signaling. Combining XL765 with temozolomide (TMZ) resulted in additive toxicity in 4 of 5 xenografts. In vivo, XL765 administered by oral gavage resulted in greater than 12-fold reduction in median tumor bioluminescence compared with control (Mann-Whitney test p = 0.001) and improvement in median survival (logrank p = 0.05). TMZ alone showed a 30-fold decrease in median bioluminescence, but the combination XL765 + TMZ yielded a 140-fold reduction in median bioluminescence (Mann-Whitney test p = 0.05) with a trend toward improvement in median survival (logrank p = 0.09) compared with TMZ alone. XL765 shows activity as monotherapy and in combination with conventional therapeutics in a range of genetically diverse GBM xenografts.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos Alquilantes/uso terapêutico , Western Blotting , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Glioblastoma/metabolismo , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Temozolomida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Skeletal muscle differentiation requires a cascade of transcriptional events to control the spatial and temporal expression of muscle-specific genes. Until recently, muscle-specific transcription was primarily attributed to prototypic enhancer-binding factors, while the role of core promoter recognition complexes in directing myogenesis remained unknown. Here, we report the development of a purified reconstituted system to analyze the properties of a TAF3/TRF3 complex in directing transcription initiation at the Myogenin promoter. Importantly, this new complex is required to replace the canonical TFIID to recapitulate MyoD-dependent activation of Myogenin. In vitro and cell-based assays identify a domain of TAF3 that mediates coactivator functions targeted by MyoD. Our findings also suggest changes to CRSP/Mediator in terminally differentiated myotubes. This switching of the core promoter recognition complex during myogenesis allows a more balanced division of labor between activators and TAF coactivators, thus providing another strategy to accommodate cell-specific regulation during metazoan development.