RESUMEN
Neuroblastoma is the most common extracranial malignant tumor of childhood, accounting for 15% of all pediatric cancer deaths. Despite significant advances in our understanding of neuroblastoma biology, five-year survival rates for high-risk disease remain less than 50%, highlighting the importance of identifying novel therapeutic targets to combat the disease. MYCN amplification is the most frequent and predictive molecular aberration correlating with poor outcome in neuroblastoma. N-Myc is a short-lived protein primarily due to its rapid proteasomal degradation, a potentially exploitable vulnerability in neuroblastoma. AF1q is an oncoprotein with established roles in leukemia and solid tumor progression. It is normally expressed in brain and sympathetic neurons and has been postulated to play a part in neural differentiation. However, no role for AF1q in tumors of neural origin has been reported. In this study, we found AF1q to be a universal marker of neuroblastoma tumors. Silencing AF1q in neuroblastoma cells caused proteasomal degradation of N-Myc through Ras/ERK and AKT/GSK3ß pathways, activated p53 and blocked cell cycle progression, culminating in cell death via the intrinsic apoptotic pathway. Moreover, silencing AF1q attenuated neuroblastoma tumorigenicity in vivo signifying AF1q's importance in neuroblastoma oncogenesis. Our findings reveal AF1q to be a novel regulator of N-Myc and potential therapeutic target in neuroblastoma.
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Neuroblastoma , Niño , Humanos , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/patología , Proteínas Oncogénicas/metabolismo , Transformación Celular Neoplásica , Factores de Transcripción/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
Pediatric patients should have access to medicines that have been appropriately evaluated for safety and efficacy through revised labelling. Given this goal, the adequacy of the pediatric clinical development plan and resulting safety database are critical factors to inform a favorable benefit-risk assessment for the intended use of the medicinal product. While extrapolation from adults can be used to support efficacy of drugs in children, there may be a reluctance to use the same approach in safety assessments, wiping out potential gains in trial efficiency through a reduction of sample size. To address this issue, we explore safety review in pediatric trials, including specific types of safety assessments and precision on the estimation of event rates for specific adverse events (AEs) that can be achieved. In addition, we discuss the assessments which can provide a benchmark for the use of extrapolation of safety that focuses on on-target effects. Finally, we explore a unified approach for understanding precision using Bayesian approaches as the most appropriate methodology to describe or ascertain risk in probabilistic terms for the estimate of the event rate of specific AEs.
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Teorema de Bayes , Adulto , Humanos , Niño , Tamaño de la Muestra , Bases de Datos Factuales , Medición de RiesgoRESUMEN
With the development of novel treatment therapies as well as evolving and innovative approaches to conduct clinical trials, the landscape of pediatric oncology drug development has dramatically changed in recent years. Despite this change, approvals for new drugs and labeling updates to ensure availability of proper treatment for pediatric patients with cancer remain slow. The context of drug development in pediatric tumors has also changed with regulatory initiatives in the US and Europe, creating a great need for faster development of novel drugs. Today, conventional study designs have been replaced or complemented by novel clinical trial designs, such as master protocols and platform trials, to optimize cancer drug development and enable faster regulatory approval. The iMATRIX platform is a mechanism-of-action (MOA)-based phase 1/2 trial framework for concurrently studying multiple molecules across a range of relevant pediatric tumor types, taking into account the biology of each pediatric tumor type. Six studies have been conducted, ongoing, or planned on the iMATRIX platform - investigating atezolizumab, cobimetinib, entrectinib, idasanutlin, alectinib, and glofitamab. A brief overview of study designs and characteristics are shared in this article, along with learnings from them.
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Oncología Médica , Neoplasias , Humanos , Niño , Oncología Médica/métodos , Neoplasias/tratamiento farmacológico , Desarrollo de Medicamentos , BiologíaRESUMEN
The ongoing contamination of groundwater with per- and polyfluoroalkyl substances (PFAS) has resulted in a global and rapidly growing interest in PFAS groundwater remediation. Preferred technologies that lead to PFAS destruction are often limited by not addressing all PFAS, being energy-intensive or not being suited for in-situ application. We developed nNiFe-activated carbon (AC) nanocomposites and demonstrated varying degrees of PFAS reduction and fluoride generation with these nanocomposites in batch reactors for several PFAS. Here we explore nNiFe-AC's effectiveness to transform perfluoroalkyl acid acids (PFAAs) under steady-state flow (0.0044 to 0.15 mL/min) in nNiFe-AC:sand packed columns. Column experiments included, two perfluorooctane sulfonate (PFOS) in deionized water and two PFAA mixtures in deionized water or bicarbonate buffer containing five perfluoroalkyl carboxylates (PFCAs, C5-C9) and three perfluoroalkyl sulfonates (PFSAs, C4, C6 and C8) at temperatures of 50 or 60°C were evaluated. PFOS transformation was similar in PFOS-only and PFAA mixture column experiments. Overall, % PFAA transformation under flow conditions exceeded what we observed previously in batch reactors with up to 53% transformation of a PFAA mixture with â¼ 8% defluorination. Longer chain PFAS dominated the PFAAs transformed and a bicarbonate matrix appeared to reduce overall transformation. PFAA breakthrough was slower than predicted from only sorption due to transformation; some longer chain PFAS like PFOS did not breakthrough. Here, nNiFe-AC technology with both in-situ and ex-situ potential application was shown to be a plausible part of a treatment train needed to address the ongoing challenge for cleaning up PFAS-contaminated waters.
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Fluorocarburos , Nanocompuestos , Contaminantes Químicos del Agua , Carbón Orgánico , Contaminantes Químicos del Agua/análisis , Bicarbonatos , Fluorocarburos/análisis , AguaRESUMEN
Pediatric drug development has many unique challenges, one of which is the evaluation of growth and development changes in children that are expected and are not due to the study intervention. Children grow and mature at different pace. The potential impact of the drug could vary with the developmental age of the participants receiving the treatment. For example, sexual maturation is a critical consideration in children of age 10 and above, but not in younger age groups. How the investigational drug impacts children is ultimately a risk-benefit consideration. In this paper, practical considerations and recommendations are provided on how to assess growth and development based on data collected from clinical trials in pediatric patients. The endpoints and measures related to growth, sexual maturation and neurocognitive development are discussed. Basic analysis approaches are recommended.
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Drogas en Investigación , Crecimiento y Desarrollo , Niño , HumanosRESUMEN
The widespread use of aqueous film-forming foam (AFFF) for firefighting activities (e.g., fire training to extinguish fuel-based fires at aircraft facilities) has led to extensive groundwater and soil contamination by per- and polyfluoroalkyl substances (PFASs) that are highly recalcitrant to destruction using conventional treatment technologies. This study reports on the hydrothermal alkaline treatment of diverse PFASs present in AFFFs. Quantitative and semiquantitative high-resolution mass spectrometry analyses of PFASs demonstrate a rapid degradation of all 109 PFASs identified in two AFFFs (sulfonate- and fluorotelomer-based formulations) in water amended with an alkali (e.g., 1-5 M NaOH) at near-critical temperature and pressure (350 °C, 16.5 MPa). This includes per- and polyfluoroalkyl acids and a range of acid precursors. Most PFASs were degraded to nondetectable levels within 15 min, and the most recalcitrant perfluoroalkyl sulfonates were degraded within 30 min when treated with 5 M NaOH. 19F NMR spectroscopic analysis and fluoride ion analysis confirm the near-complete defluorination of PFASs in both dilute and concentrated AFFF mixtures, and no stable volatile organofluorine species were detected in reactor headspace gases by the gas chromatography-mass spectrometry analysis. These findings indicate a significant potential for application of hydrothermal treatment technologies to manage PFAS waste streams, including on-site treatment of unused AFFF chemical stockpiles, investigation-derived wastes, and concentrated source zone materials.
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Fluorocarburos , Agua Subterránea , Contaminantes Químicos del Agua , Fluorocarburos/análisis , Suelo , Agua , Contaminantes Químicos del Agua/análisisRESUMEN
OBJECTIVE: This study investigated the safety and tolerability of lifastuzumab vedotin (DNIB0600A) (LIFA), an antibody-drug conjugate, in patients with recurrent platinum-sensitive ovarian cancer (PSOC). METHODS: In this open-label, multicenter phase 1b study, LIFA was administered intravenously once every 3 weeks (Q3W) with starting dose 1.2 mg/kg in a 3 + 3 dose-escalation scheme. All patients received carboplatin at dose AUC 6 mg/mL·min (AUC6) Q3W for up to 6 cycles. Dose expansion cohorts were enrolled ± bevacizumab 15 mg/kg Q3W. RESULTS: Patients received LIFA at 1.2, 1.8, and 2.4 mg (n = 4, 5, and 20, respectively) with carboplatin. The maximum tolerated dose was not reached. The recommended phase 2 dose (RP2D) was LIFA 2.4 mg/kg + carboplatin AUC6 (cycles 1-6), with or without bevacizumab 15 mg/kg. Twelve patients received RP2D with bevacizumab. All patients experienced ≥1 adverse event (AE). The most common treatment-related AEs were neutropenia, peripheral neuropathy, thrombocytopenia, nausea, fatigue, anemia, diarrhea, vomiting, hypomagnesaemia, aspartate aminotransferase increased, alanine aminotransferase increased, and alopecia. Thirty-four (83%) patients experienced grade ≥ 3 AEs, the most frequent of which were neutropenia and thrombocytopenia. Nine (22%) patients experienced serious AEs. Pulmonary toxicities (34%), considered a potential risk of LIFA, included one patient who discontinued study treatment due to grade 2 pneumonitis. The median duration of progression-free survival was 10.71 months (95% CI: 8.54, 13.86) with confirmed complete/partial responses in 24 (59%) patients. Pharmacokinetics of mono-therapy LIFA was similar in combination therapy. CONCLUSION: LIFA in combination with carboplatin ± bevacizumab demonstrated acceptable safety and encouraging activity in PSOC patients.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma Epitelial de Ovario/metabolismo , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Neoplasias Ováricas/metabolismo , Supervivencia sin ProgresiónRESUMEN
PURPOSE: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). PATIENTS AND METHODS: LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). RESULTS: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). CONCLUSIONS: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacocinética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma Epitelial de Ovario/patología , Femenino , Humanos , Inmunoconjugados/farmacocinética , Inmunoconjugados/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Seguridad del Paciente , Distribución Tisular , Resultado del TratamientoRESUMEN
Sphingosine-1-phosphate lyase (SPL) is an intracellular enzyme that controls the final step in the sphingolipid degradative pathway, the only biochemical pathway for removal of sphingolipids. Specifically, SPL catalyzes the cleavage of sphingosine 1-phosphate (S1P) at the C2-3 carbon bond, resulting in its irreversible degradation to phosphoethanolamine (PE) and hexadecenal. The substrate of the reaction, S1P, is a bioactive sphingolipid metabolite that signals through a family of five G protein-coupled S1P receptors (S1PRs) to mediate biological activities including cell migration, cell survival/death/proliferation and cell extrusion, thereby contributing to development, physiological functions and - when improperly regulated - the pathophysiology of disease. In 2017, several groups including ours reported a novel childhood syndrome that featured a wide range of presentations including fetal hydrops, steroid-resistant nephrotic syndrome (SRNS), primary adrenal insufficiency (PAI), rapid or insidious neurological deterioration, immunodeficiency, acanthosis and endocrine abnormalities. In all cases, the disease was attributed to recessive mutations in the human SPL gene, SGPL1. We now refer to this condition as SPL Insufficiency Syndrome, or SPLIS. Some features of this new sphingolipidosis were predicted by the reported phenotypes of Sgpl1 homozygous null mice that serve as vertebrate SPLIS disease models. However, other SPLIS features reveal previously unrecognized roles for SPL in human physiology. In this review, we briefly summarize the biochemistry, functions and regulation of SPL, the main clinical and biochemical features of SPLIS and what is known about the pathophysiology of this condition from murine and cell models. Lastly, we consider potential therapeutic strategies for the treatment of SPLIS patients.
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Aldehído-Liasas/deficiencia , Movimiento Celular , Errores Innatos del Metabolismo Lipídico , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Animales , Modelos Animales de Enfermedad , Humanos , Errores Innatos del Metabolismo Lipídico/enzimología , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/patología , Lisofosfolípidos/genética , Ratones , Ratones Mutantes , Esfingosina/genética , Esfingosina/metabolismo , SíndromeRESUMEN
BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.
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Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/tratamiento farmacológico , Vemurafenib/uso terapéutico , Adolescente , Antineoplásicos/farmacocinética , Niño , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Melanoma/genética , Melanoma/patología , Pronóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Distribución Tisular , Vemurafenib/farmacocinéticaRESUMEN
Circulating tumor DNA (ctDNA) has potential to serve as a biomarker for noninvasive monitoring of treatment response and disease progression. However, broad clinical applicability of ctDNA has been limited by the low sensitivity, throughput, and patient coverage offered by existing ctDNA detection methods. Herein, we report the adaptation and characterization of the microfluidics multiplex PCR sequencing technology for high-throughput and sensitive quantitation of ctDNA. A multiplex PCR preamplification step was developed and incorporated into the microfluidics multiplex PCR sequencing work flow to enable low-input ctDNA analysis with enhanced sensitivity. An empirical bayesian model was developed to characterize both position and substitution-associated system errors specific to this platform and provided a tailored approach to greatly enhance the confidence and accuracy of variant calling for ctDNA analysis. Clinical validation of this platform for ctDNA mutation detection demonstrated an overall sensitivity of 92% and specificity of 100% when using mutation calls in the matched tumor tissues as a benchmark. Finally, we established an early proof of concept of clinical utility of this ctDNA work flow for monitoring disease progression using clinical trial samples. Our novel ctDNA work flow provides a high-throughput and sensitive platform that can be implemented in clinical trials for mutation detection and disease monitoring from plasma ctDNA.
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Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/sangre , Humanos , Microfluídica/métodos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Mutación , Neoplasias/genética , Neoplasias/patologíaRESUMEN
In the age of personalized medicine stratifying tumors into molecularly defined subtypes associated with distinctive clinical behaviors and predictable responses to therapies holds tremendous value. Towards this end, we developed a custom microfluidics-based bladder cancer gene expression panel for characterization of archival clinical samples. In silico analysis indicated that the content of our panel was capable of accurately segregating bladder cancers from several public datasets into the clinically relevant basal and luminal subtypes. On a technical level, our bladder cancer panel yielded robust and reproducible results when analyzing formalin-fixed, paraffin-embedded (FFPE) tissues. We applied our panel in the analysis of a novel set of 204 FFPE samples that included non-muscle invasive bladder cancers (NMIBCs), muscle invasive disease (MIBCs), and bladder cancer metastases (METs). We found NMIBCs to be mostly luminal-like, MIBCs to include both luminal- and basal-like types, and METs to be predominantly of a basal-like transcriptional profile. Mutational analysis confirmed the expected enrichment of FGFR3 mutations in luminal samples, and, consistently, FGFR3 IHC showed high protein expression levels of the receptor in these tumors. Our bladder cancer panel enables basal/luminal characterization of FFPE tissues and with further development could be used for stratification of bladder cancer samples in the clinic.
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Bancos de Muestras Biológicas , Regulación Neoplásica de la Expresión Génica , Microfluídica/métodos , Transcripción Genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Simulación por Computador , Femenino , Formaldehído , Genes Relacionados con las Neoplasias , Humanos , Masculino , Persona de Mediana Edad , Adhesión en Parafina , Reproducibilidad de los Resultados , Fijación del Tejido , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND/AIMS: The aim of this study was to evaluate the prevalence of colorectal neoplasia in subjects with fundic gland polyps (FGPs) and the relationship between FGPs and colorectal neoplasia in Korea. METHODS: We analyzed 128 consecutive patients with FPGs who underwent colonoscopy between January 2009 and December 2013. For each case, age- (±5 years) and sex-matched controls were identified from among patients with hyperplastic polyps, gastric neoplasms, and healthy controls. Clinical characteristics were reviewed from medical records, colonoscopic findings, pathologic findings, and computed tomography images. The outcome was evaluated by comparison of advanced colonic neoplasia detection rates. RESULTS: Of the 128 patients, seven (5.1%) had colon cancers and seven (5.1%) had advanced adenomas. A case-control study revealed that the odds of detecting a colorectal cancer was 3.8 times greater in patients with FGPs than in the age- and sex-matched healthy controls (odds ratio [OR], 3.80; 95% confidence interval [CI], 1.09-13.24; P =0.04) and 4.1 times greater in patients with FGPs than in healthy controls over 50 years of age (OR, 4.10; 95% CI, 1.16-14.45; P =0.04). Among patients with FGPs over 50 years old, male sex (OR, 4.83; 95% CI, 1.23-18.94; P =0.02), and age (OR, 9.90; 95% CI, 1.21-81.08; P =0.03) were associated with an increased prevalence of advanced colorectal neoplasms. CONCLUSIONS: The yield of colonoscopy in colorectal cancer patients with FGPs was substantially higher than that in average-risk subjects. Colonoscopy verification is warranted in patients with FGPs, especially in those 50 years of age or older.
RESUMEN
Periostin is a matricellular protein that interacts with various integrin molecules on the cell surface. Although periostin is expressed in inflamed colonic mucosa, its role in the regulation of intestinal inflammation remains unclear. We investigated the role of periostin in intestinal inflammation using Postn-deficient (Postn-/-) mice. Intestinal epithelial cells (IECs) were transfected by Postn small interfering RNAs. Periostin expression was determined in colon tissue samples from ulcerative colitis (UC) patients. Oral administration of dextran sulfate sodium (DSS) or rectal administration of trinitrobenzene sulfonic acid, induced severe colitis in wild-type mice, but not in Postn-/- mice. Administration of recombinant periostin induced colitis in Postn-/- mice. The periostin neutralizing-antibody ameliorated the severity of colitis in DSS-treated wild-type mice. Silencing of Postn inhibited inteleukin (IL)-8 mRNA expression and NF-κB DNA-binding activity in IECs. Tumor necrosis factor (TNF)-α upregulated mRNA expression of Postn in IECs, and recombinant periostin strongly enhanced IL-8 expression in combination with TNF-α, which was suppressed by an antibody against integrin αv (CD51). Periostin and CD51 were expressed at significantly higher levels in UC patients than in controls. Periostin mediates intestinal inflammation through the activation of NF-κB signaling, which suggests that periostin is a potential therapeutic target for inflammatory bowel disease.
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Moléculas de Adhesión Celular/metabolismo , Inflamación/metabolismo , Intestinos/patología , FN-kappa B/metabolismo , Transducción de Señal , Enfermedad Aguda , Animales , Anticuerpos Neutralizantes/farmacología , Línea Celular , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Colon/metabolismo , Colon/patología , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Enterocitos/patología , Silenciador del Gen/efectos de los fármacos , Humanos , Inflamación/patología , Integrina alfaV/metabolismo , Interleucina-8/metabolismo , Masculino , Ratones Endogámicos C57BL , Unión Proteica/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Transducción de Señal/efectos de los fármacosRESUMEN
DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2-2.8 mg/kg; q3w) or weekly (0.8-1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer.
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Proteínas Ligadas a GPI/antagonistas & inhibidores , Inmunoconjugados/uso terapéutico , Terapia Molecular Dirigida , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Adulto , Anciano , Antineoplásicos/farmacología , Biomarcadores , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Inmunoconjugados/farmacología , Inmunohistoquímica , Mesotelina , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Platino (Metal)/uso terapéutico , Retratamiento , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Roxithromycin is known to have anti-inflammatory and immunoregulatory activity. However, little information is available on the effect of roxithromycin in intestinal inflammation. The aim of this study was to investigate the effect of roxithromycin on NF- κB signaling and ER stress in intestinal epithelial cells (IECs) and the effect of roxithromycin on dextran sulfate sodium (DSS)-induced acute colitis in a murine model. HCT116 cells and COLO205 cells were pretreated with roxithromycin and then stimulated with tumor necrosis factor-α (TNF-α). Interleukin (IL)-8 expression was determined by real-time reverse transcription-polymerase chain reaction. Nuclear factor kappaB (NF-κB) DNA-binding activity and IκB phosphorylation/degradation were evaluated by electrophoretic mobility shift assay and Western blot analysis. The molecular markers of endoplasmic reticulum stress, including p-JNK, phosphorylated eukaryotic initiation factor 2 (p-eIF2α), C/EBP homologous protein (CHOP), and X-box binding protein 1 (XBP1) were evaluated using western blotting and PCR. Mice were given 4% DSS for five days with or without roxithromycin. Primary IECs were isolated from mice with DSS-induced colitis. Roxithromycin significantly inhibited the upregulated expression of IL-8. Pretreatment with roxithromycin markedly attenuated NF-κB DNA-binding activity and IκB phosphorylation/degradation. CHOP and XBP1 mRNA expression were enhanced in the presence of TNF-α, and it was dampened by pretreatment of roxithromycin. c-Jun-N-terminal kinase (JNK) phosphorylation and the level of p-eIF2α were also downregulated by the pretreatment of roxithromycin. Roxithromycin significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histology. In addition, the DSS-induced phospho-IκB kinase activation was significantly decreased in roxithromycin-pretreated mice. Finally, IκB degradation was reduced in primary IECs from mice treated with roxithromycin. These results suggest that roxithromycin may have potential usefulness in the treatment of inflammatory bowel disease.
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Antiinflamatorios/farmacología , Colitis/tratamiento farmacológico , Retículo Endoplásmico/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Roxitromicina/farmacología , Animales , Antiinflamatorios/uso terapéutico , Colitis/fisiopatología , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Retículo Endoplásmico/fisiología , Células HCT116/efectos de los fármacos , Células HCT116/fisiología , Humanos , Interleucina-8/fisiología , Mucosa Intestinal/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Roxitromicina/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
PURPOSE: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. EXPERIMENTAL DESIGN: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial. RESULTS: We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy. CONCLUSIONS: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.
Asunto(s)
Antineoplásicos/farmacología , Moléculas de Adhesión Celular/metabolismo , Resistencia a Antineoplásicos , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Adulto , Anciano , Carboplatino/farmacología , Carcinoma Epitelial de Ovario , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Fibroblastos/metabolismo , Humanos , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Paclitaxel/farmacología , Transcriptoma , Resultado del Tratamiento , Microambiente Tumoral , Regulación hacia ArribaRESUMEN
OBJECTIVE: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are used to control blood cholesterol levels and reduce cardiovascular disease. It has been repeatedly reported that statins may cause new-onset diabetes mellitus (DM). However, limited evidence exists from direct head to head comparisons of statins on whether the risk of DM differs among statins. We investigated the risk of development of new-onset diabetes in subjects treated with different statins. METHODS: We retrospectively enrolled consecutive 3680 patients without DM or impaired fasting glucose who started receiving statin treatment for cholesterol control. We evaluated the incidence of new-onset diabetes according to the type of statin. RESULTS: The mean duration of follow-up was 62.6±15.3 months. The incidence of DM was significantly higher in the pitavastatin group (49 of 628; 7.8%) compared to that in the other statin groups [atorvastatin (68 of 1327; 5.1%), rosuvastatin (77 of 1191; 6.5%), simvastatin (11 of 326; 3.4%), and pravastatin (12 of 298; 5.8%); p=0.041]. The risk of diabetes was the highest in the pitavastatin group compared with that in the simvastatin group [hazard ratio (HR)=2.68, p=0.011]. Other statins showed no significant risk differences compared to that for simvastatin. Fasting blood glucose (FBG) level at baseline and body-mass index (BMI) were associated with the development of diabetes [FBG, HR=1.11, p<0.001; BMI, HR=1.02, p=0.005]. CONCLUSIONS: Among the five statins, pitavastatin showed the strongest effect on the development of new-onset diabetes.
Asunto(s)
Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/epidemiología , Anciano , Atorvastatina , Femenino , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Humanos , Hipercolesterolemia/complicaciones , Masculino , Persona de Mediana Edad , Pravastatina/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Quinolinas/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Rosuvastatina Cálcica , Simvastatina/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
Members of the mammalian tristetraprolin family of CCCH tandem zinc finger proteins can bind to certain AU-rich elements (AREs) in mRNAs, leading to their deadenylation and destabilization. Mammals express three or four members of this family, but Drosophila melanogaster and other insects appear to contain a single gene, Tis11. We found that recombinant Drosophila Tis11 protein could bind to ARE-containing RNA oligonucleotides with low nanomolar affinity. Remarkably, co-expression in mammalian cells with "target" RNAs demonstrated that Tis11 could promote destabilization of ARE-containing mRNAs and that this was partially dependent on a conserved C-terminal sequence resembling the mammalian NOT1 binding domain. Drosophila Tis11 promoted both deadenylation and decay of a target transcript in this heterologous cell system. We used chromosome deletion/duplication and P element insertion to produce two types of Tis11 deficiency in adult flies, both of which were viable and fertile. To address the hypothesis that Tis11 deficiency would lead to the abnormal accumulation of potential target transcripts, we analyzed gene expression in adult flies by deep mRNA sequencing. We identified 69 transcripts from 56 genes that were significantly up-regulated more than 1.5-fold in both types of Tis11-deficient flies. Ten of the up-regulated transcripts encoded probable proteases, but many other functional classes of proteins were represented. Many of the up-regulated transcripts contained potential binding sites for tristetraprolin family member proteins that were conserved in other Drosophila species. Tis11 is thus an ARE-binding, mRNA-destabilizing protein that may play a role in post-transcriptional gene expression in Drosophila and other insects.