RESUMO
BACKGROUND: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. METHODS: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. RESULTS: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. CONCLUSIONS: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva , Linfoma de Célula do Manto/terapia , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Linfócitos T/transplante , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.
Assuntos
Agonistas GABAérgicos/farmacologia , Ácidos Picolínicos/farmacologia , Receptor de Glutamato Metabotrópico 5/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Agonistas GABAérgicos/farmacocinética , Células HEK293 , Humanos , Fosfatos de Inositol/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Picolínicos/farmacocinética , Piridinas/metabolismo , Ensaio Radioligante , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
INTRODUCTION: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. METHODS: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. CONCLUSIONS: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Linfoma de Célula do Manto , Pirimidinas , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Pirimidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piperidinas/uso terapêutico , Imunoterapia Adotiva/métodos , Adulto , Idoso de 80 Anos ou maisRESUMO
To quantify the clinical unmet need of r/r MCL patients who progress on a covalent Bruton tyrosine kinase inhibitor (BTKi), we conducted a systematic review to identify studies that reported overall survival (OS), progression-free survival (PFS), or response outcomes of patients who received a chemo(immunotherapy) ± targeted agent standard therapy (STx) or brexucabtagene autoleucel (brexu-cel) in the post-BTKi setting. Twenty-six studies (23 observational; three trials) reporting outcomes from 2005 to 2022 were included. Using two-stage frequentist meta-analyses, the estimated median PFS/OS for patients treated with an STx was 7.6 months (95% CI: 3.9-14.6) and 9.1 months (95% CI: 7.3-11.3), respectively. The estimated objective response rate (ORR) was 45% (95% CI: 34-57%). For patients treated with brexu-cel, the estimated median PFS/OS was 14.9 months (95% CI: 10.5-21.0) and 32.1 months (95% CI: 25.2-41.2), with a pooled ORR of 89% (95% CI: 86-91%). Our findings highlight a significant unmet need for patients whose disease progresses on a covalent BTKi.
RESUMO
PURPOSE: Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor [BTKi]) or high-risk characteristics. METHODS: Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 106 CAR T cells/kg). RESULTS: After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse. CONCLUSION: These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.
Assuntos
Linfoma de Célula do Manto , Receptores de Antígenos Quiméricos , Adulto , Humanos , Receptores de Antígenos Quiméricos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Imunoterapia Adotiva/efeitos adversos , Seguimentos , Cloridrato de Bendamustina/uso terapêutico , Recidiva Local de Neoplasia/etiologiaRESUMO
AIMS: The objective of this study is to estimate the cost-effectiveness of KTE-X19 versus standard of care (SoC) in the treatment of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) post-Bruton tyrosine kinase inhibitor (BTKi) treatment from a UK healthcare perspective. MATERIALS AND METHODS: A three-state partitioned survival model (pre-progression, post-progression and death) with a cycle length of one month was used to extrapolate progression-free and overall survival over a lifetime horizon. Population inputs along with KTE-X19 (brexucabtagene autoleucel) efficacy and safety data were derived from the single-arm trial ZUMA-2 (NCT02601313). The composition of SoC was informed by a literature-based meta-analysis, SoC efficacy data were obtained from the SCHOLAR-2 real-world study. Survival was modelled using standard parametric curves for SoC and a mixture-cure methodology for KTE-X19. It was assumed that patients whose disease had not progressed after five years experienced long-term remission. Costs, resource use and utility, and adverse event disutility inputs were obtained from published literature and publicly available data sources. An annual discount rate of 3.5% was applied to costs and health outcomes. Modelled outcomes for KTE-X19 and SoC included expected life years (LY), quality-adjusted life years (QALY) and total costs. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Estimated median survival was 5.96 years for KTE-X19 and 1.38 for SoC. Discounted LYs, QALYs and lifetime costs were 8.27, 5.99 and £385,765 for KTE-X19 versus 1.98, 1.48 and £79,742 for SoC, respectively. The KTE-X19 versus SoC cost per QALY was £67,713 and the cost per LY was £48,645. Influential scenario analyses use alternative KTE-X19 survival curves and discount rates, and shorter time horizons. CONCLUSION: Considering the survival and quality of life benefits compared to SoC, KTE-X19 for R/R MCL appears as a cost-effective treatment in the real-world UK setting.
Assuntos
Imunoterapia Adotiva , Linfoma de Célula do Manto , Recidiva Local de Neoplasia , Receptores de Antígenos Quiméricos , Adulto , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/economia , Linfoma de Célula do Manto/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Receptores de Antígenos Quiméricos/uso terapêutico , Padrão de CuidadoRESUMO
Integrating the battery behavior and supercapacitor behavior in a single electrode to obtain better electrochemical performance has been widely researched. However, there is still a lack of research studies on an integrated battery-capacitor supercapacitor electrode (BatCap electrode). In this work, an integrated BatCap electrode porous carbon-coated Mn-Ni-layered double oxide (Mn-Ni LDO-C) was fabricated successfully using controllable heat treatment of polypyrrole-precoated Mn-Ni-layered double hydroxide (Mn-Ni LDH@PPy). This Mn-Ni LDO-C electrode was grown on Ni foam directly and possessed a hierarchical structure that consisted of a pyridinic N (N-6)-doped porous carbon shell and a Mn-Ni LDO core within abundant oxygen vacancies. Benefiting from the synergistic effect of N-6-doped porous carbon and increased oxygen vacancies, Mn-Ni LDO-C exhibited excellent electrochemical performance. The capacity of Mn-Ni LDO-C reached 2.36 C cm-2 (1478.1 C g-1) at 1 mA cm-2 and remained at 92.1% of the initial capacity after 5000 cycles at a current density of 20 mA cm-2. The aqueous battery-supercapacitor hybrid device Mn-Ni LDO-C//active carbon (Mn-Ni LDO-C//AC) also presented superior cycle stability: it retained 85.3% of the original capacity after 5000 cycles at 2 A g-1. Meanwhile, Mn-Ni LDO-C//AC could work normally under a wider potential window (2.0 V), so that the device held the highest energy density of 78.2 Wh kg-1 at a power density of 499.7 W kg-1 and retained 39.1 Wh kg-1 at the highest power density of 31.3 kW kg-1. Two Mn-Ni LDO-C//AC devices connected in series could light a light-emitting diode (LED) bulb easily and keep the LED brightly illuminated for more than 10 min. In general, this work synthesized an integrated BatCap electrode Mn-Ni LDO-C; the integrated electrode exhibited high electrochemical performance, thus has a promising application prospect in the field of energy storage.
RESUMO
With the battery-type anode and capacitor-type cathode, lithium-ion capacitors (LICs) are expected to exhibit both high energy and high power density but suffer from the mismatch of the electrode reaction kinetics and capacity. Herein, to alleviate the mismatch between the two electrodes and synergistically enhance the energy/power density, we design a method of microwave irradiation reduction to prepare graphene-based electrode material (MRPG/CNT) with fast ion/electron pathway. The three-dimensional structure of CNT intercalation to graphene inhibits the restacking of graphene sheets and improves the conductivity of the electrode material, resulting a rapid ion and electron diffusion channel. Due to its specific properties, MRPG/CNT materials can be used as both anode and cathode electrodes of LICs at the same time. As anode, MRPG/CNT shows a high capacity of 1200 mAh g-1 as well as high rate performance. As cathode, MRPG/CNT displays a high capacity of 108 mAh g-1 and the capacity retention of 100% after 8000 cycles. Coupling the prelithiated MRPG/CNT anode with MRPG/CNT cathode gives a full-graphene-based symmetric LIC, which achieves a high energy density of 232.6 Wh kg-1 at 226.0 W kg-1, 111.2 Wh kg-1 at the ultrahigh power density of 45.2 kW kg-1, and superior capacity retention of 86% after 5000 cycles. The structure design of this electrode provides a new strategy for alleviating the mismatch of LIC electrodes and constructing high-performance symmetrical LICs.
RESUMO
As a tradeoff between supercapacitors and batteries, lithium-ion capacitors (LICs) are designed to deliver high energy density, high power density, and long cycling stability. Owing to the different energy storage mechanisms of capacitor-type cathodes and battery-type anodes, engineering and fabricating LICs with excellent energy density and power density remains a challenge. Herein, to alleviate the mismatch between the anode and cathode, we ingeniously designed a graphene with oxidized-polydopamine coating (LG@DA1) and N,P codoped porous foam structure activated carbon (CPC750) as the battery-type anode and capacitor-type cathode, respectively. Using oxidized-polydopamine to stabilize the structure of graphene, increase layer spacing, and modify the surface chemical property, the LG@DA1 anode delivers a maximum capacity of 1100 mAh g-1 as well as good cycling stability. With N,P codoping and a porous foam structure, the CPC750 cathode exhibits a large effective specific surface area and a high specific capacity of 87.5 mAh g-1. In specific, the present LG@DA1//CPC750 LIC showcases a high energy density of 170.6 Wh kg-1 and superior capacity retention of 93.5% after 2000 cycles. The success of the present LIC can be attributed to the structural stability design, surface chemistry regulation, and enhanced utilization of effective active sites of the anode and cathode; thus, this strategy can be applied to improve the performance of LICs.
RESUMO
Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of nonselective antimuscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here, we utilize genetic mAChR knockout animals in combination with nonselective mAChR antagonists to confirm that the M4 receptor activation is required for the locomotor-stimulating and antiparkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have antiparkinsonian and antidystonic efficacy in pharmacological and genetic models of movement disorders.
RESUMO
Histone acetylation levels are regulated through the opposing activities of histone acetyltransferases (HATs) and deacetylases (HDACs). While much is known about gene-specific control of histone acetylation, little is understood about how total or cellular levels of histone acetylation are regulated. To identify regulators of cellular levels of histone acetylation, we developed an immunofluorescence-based approach to screen the single-gene deletion library of Saccharomyces cerevisiae for strains with significant reductions in cellular histone acetylation levels. Of the 4848 mutants screened, we identified 63 strains with considerable cellular hypoacetylation of N-terminal lysines in histones H3 and H4. The cellular hypoacetylation was validated for subsets of the identified strains through secondary screens including mass spectrometric analysis of individual lysines and chromatin immunoprecipitation of specific genomic loci. Among the identified mutants were several members of the Ccr4-Not complex, V-type ATPases, and vacuolar protein-sorting complexes as well as genes with unknown functions. We show that Gcn5, a major HAT in yeast, has diminished histone acetyltransferase activity in particular mutants, providing a plausible explanation for reduction of cellular acetylation levels in vivo. Our findings have revealed unexpected and novel links between histone acetylation, Gcn5 HAT activity, and diverse processes such as transcription, cellular ion homeostasis, and protein transport.
Assuntos
Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Saccharomyces cerevisiae/genética , Acetilação , Western Blotting , Imunoprecipitação da Cromatina , Imunofluorescência , Genômica , Histona Acetiltransferases/genética , Espectrometria de Massas , Mutação/genética , Saccharomyces cerevisiae/metabolismoRESUMO
Optimal therapeutic strategy remains an unmet need in localised high-risk prostate cancer (LHRPC). Androgen biosynthesis inhibition in the preoperative setting may improve outcomes. In this single-centre randomised trial, we looked at therapy outcomes of preoperative treatment with abiraterone acetate+prednisone (AAP)+luteinising hormone-releasing hormone agonist (LHRHa) or LHRHa alone followed by radical prostatectomy in 65 men. We did not see a significant difference of organ-confined carcinoma (p=0.27). However, tumour volume measures were significantly lower for AAP+LHRHa treatment (p≤0.001). Of note, lower tumour epithelium volume correlated with improved biochemical recurrence-free survival at ≥4-yr follow-up (p=0.0014). Tumours pretreated with AAP+LHRHa had lower proliferation and androgen signalling expression than LHRHa. On multivariate analysis, glucocorticoid receptor (GR) overexpression correlated with persistent tumours in AAP+LHRHa (p=0.018). The presence of nuclear androgen receptor splice variant (nARV7) correlated with persistent tumours in both arms. No new safety signals were observed. This is the first study investigating the role of preoperative AAP+LHRHa versus LHRHa alone in LHRPC. We report significant cytoreduction by tumour volume measures inversely correlating with biochemical relapse. Validation of these proposed tumour volume measures is planned. A potential role of GR in resistance to androgen biosynthesis inhibition warrants further study. PATIENT SUMMARY: This is the first study of abiraterone acetate plus leuprolide versus leuprolide alone in high-risk localised prostate cancer followed by prostatectomy. Patients in the combination arm had a significantly smaller tumour size.
Assuntos
Acetato de Abiraterona/administração & dosagem , Antineoplásicos/administração & dosagem , Hormônio Liberador de Gonadotropina/análogos & derivados , Prednisona/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Idoso , Combinação de Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Medição de RiscoRESUMO
The ansamycin antibiotics contain metacyclophanic macrolactams, many of which possess potent antitumor activity. Only a few total syntheses of this family of natural products have been reported, and modifications to increase potency have not been described. Therefore, a method was developed to prepare the trienomycin A core via resin-bound triphenylphosphonium salts, which serve as both a reagent and a traceless linker to afford olefinic products that undergo ring-closing metathesis (RCM) to give macrocyclic scaffolds of varying ring sizes.
Assuntos
Antibacterianos/síntese química , Iminas/química , Lactamas Macrocíclicas/síntese química , Rifabutina/síntese química , Antibacterianos/química , Catálise , Lactamas Macrocíclicas/química , Estrutura Molecular , Compostos Organometálicos/química , Ródio/química , Rifabutina/química , EstereoisomerismoRESUMO
Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75mg/m2 + AA 1000mg + P 10mg was deemed the RP2D, with DLT in one of six patients. PSA declines from baseline of ≥50% and ≥90% were observed for 85.7% and 66.7% of patients, respectively. During median follow-up of 14.5 mo, eight patients had PSA progression and six had radiographic progression or died. Systemic exposure was comparable for docetaxel and abiraterone when given alone or in combination. Studies are ongoing to confirm the efficacy of potent androgen receptor-targeted therapy plus taxane in early mCRPC. PATIENT SUMMARY: The combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.
Assuntos
Acetato de Abiraterona , Prednisona , Neoplasias de Próstata Resistentes à Castração , Taxoides , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/efeitos adversos , Acetato de Abiraterona/farmacocinética , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/farmacocinética , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Taxoides/farmacocinética , Resultado do TratamentoRESUMO
PURPOSE: Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure. PATIENTS AND METHODS: Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level. RESULTS: A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively. CONCLUSION: A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.
Assuntos
Androstenos/uso terapêutico , Biomarcadores Tumorais/análise , Células Neoplásicas Circulantes/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Acetato de Abiraterona , Adulto , Idoso , Idoso de 80 Anos ou mais , Determinação de Ponto Final , Humanos , L-Lactato Desidrogenase/análise , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
The neuropeptide immunohistochemistry and neural connectivity of areas surrounding the thalamic auditory nucleus (the nucleus ovoidalis [Ov]), as well as the areas to which it is connected, were investigated in a songbird, the Bengalese finch. The results showed that met-enkephalin was present in the Ov shell and most of the areas connected to it, but not in the Ov core. Anterograde and retrograde tracing studies showed that the Ov shell was more widely connected than the Ov core. The Ov shell was mainly connected to: 1). areas flanking the primary telencephalic auditory field (i.e., fields L2b, L1, and L3) and areas surrounding the robust nucleus of the archistriatum (RA); 2). several hypothalamic areas such as the nucleus ventromedialis hypothalami (VMN) and the nucleus anterior medialis hypothalami (AM). Some of these areas connected to the Ov shell are thought to be involved in auditory mediated neurosecretory activities. These results, which are similar to those reported previously in non-songbirds, suggest that the Ov shell and other surrounding areas of auditory and song-control nuclei are conserved in birds. These findings are discussed in terms of the evolution of the core-and-surround organization of auditory and song-control nuclei.
Assuntos
Vias Auditivas/química , Evolução Biológica , Aves Canoras/fisiologia , Núcleos Talâmicos/química , Animais , Vias Auditivas/fisiologia , Feminino , Imunoquímica , Masculino , Vias Neurais/química , Vias Neurais/fisiologia , Núcleos Talâmicos/fisiologiaRESUMO
The contribution of the factor Va C1 domain (fVa-C1) to assembly of the prothrombinase complex has not been previously investigated. The homologous fVa-C2 domain contains a binding site for phosphatidylserine (PS) that includes the indole moieties of Trp(2063)/Trp(2064) at the apex of spike-1. In order to investigate the structure and function of fVa-C1 a molecular model was constructed based on the structure of fVa-C2. The aromatic and hydrophobic side chains of Tyr (1956) /Leu (1957) in fVa-C1 are located at the predicted apex of spike-3. Exposed charged and hydrophobic residues in fVa-C1 were changed to alanine in clusters of 1-3 mutations per construct. The resultant 20 mutants were expressed in COS cells and screened for binding to immobilized PS and prothrombinase activity on phospholipid vesicles containing either 25% or 5% PS. Two mutants, (Y1956,L1957)A, and (R2023,R2027)A showed both decreased binding to immobilized PS and a selective decrease in prothrombinase activity on membranes containing 5% PS. The interaction of purified (Y1956,L1957)A with phospholipid vesicles was studied using fluorescence resonance energy transfer and prothrombinase assays. The affinity of (Y1956,L1957)A binding to 25% PS membranes was reduced 12-fold compared to rHFVa. Prothrombin activation in the presence of (Y1956,L1957)A was markedly impaired on phos-pholipid vesicles containing 10% or less PS. We conclude that solvent exposed hydrophobic and aromatic amino acids in both fVa-C1 and fVa-C2 contribute to the interaction of factor V with PS membranes.
Assuntos
Membrana Celular/metabolismo , Fator V/química , Alanina/química , Sequência de Aminoácidos , Animais , Células COS , Meios de Cultivo Condicionados/farmacologia , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Transferência Ressonante de Energia de Fluorescência , Humanos , Cinética , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Mutação , Fosfatidilserinas/química , Fosfolipídeos/química , Ligação Proteica , Estrutura Terciária de Proteína , Tromboplastina/química , Tromboplastina/metabolismoRESUMO
PURPOSE: Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. PATIENTS AND METHODS: A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. RESULTS: The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority. CONCLUSION: LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante , Neoplasias da Próstata/tratamento farmacológico , Acetato de Abiraterona , Idoso , Androstadienos/administração & dosagem , Humanos , Leuprolida/administração & dosagem , Leuprolida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Receptores Androgênicos/análise , Testosterona/sangueRESUMO
[reaction: see text] Reactions of enamines, preformed from beta-dicarbonyl and monocarbonyl compounds, with Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) under mild conditions (triethylamine (TEA) or molecular sieves) easily led to the corresponding difluorinated carbonyl compounds in high yields.
RESUMO
Interactions between factor Va and membrane phosphatidylserine (PS) regulate activity of the prothrombinase complex. Two solvent-exposed hydrophobic residues located in the C2 domain, Trp(2063) and Trp(2064), have been proposed to contribute to factor Va membrane interactions by insertion into the hydrophobic membrane bilayer. However, the prothrombinase activity of rHFVa W(2063, 2064)A was found to be significantly impaired only at low concentrations of PS (5 mol %). In this study, we find that 10-fold higher concentrations of mutant factor Va are required for half-maximal prothrombinase activity on membranes containing 25% PS. The ability of the mutant factor Va to interact with factor Xa on a membrane was also impaired since 4-fold higher concentrations of factor Xa were required for half-maximal prothrombinase activity. The interaction of factor Va with 25% PS membranes was also characterized using fluorescence energy transfer and surface plasmon resonance. We found that the affinity of mutant factor Va for membranes containing 25% PS was reduced at least 400-fold with a K(d) > 10(-7) M. The binding of mutant factor Va to 25% PS membranes was markedly enhanced in the presence of factor Xa, indicating stabilization of the factor Va-factor Xa-membrane complex. Our findings indicate that Trp(2063) and Trp(2064) play a critical role in the high-affinity binding of factor Va to PS membranes. It remains to be determined whether occupancy of this PS binding site in factor Va is also required for high-affinity binding to factor Xa.