RESUMEN
Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth.
Asunto(s)
Quinasas Ciclina-Dependientes/metabolismo , Epidermis/metabolismo , Epidermis/patología , Proteínas Proto-Oncogénicas , Proteínas ras/metabolismo , Animales , Cadherinas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Ciclo Celular/fisiología , Células Cultivadas , Ciclina D1/metabolismo , Ciclina E/metabolismo , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/genética , Factores de Crecimiento Endotelial/metabolismo , Células Epidérmicas , Técnicas de Transferencia de Gen , Genes Reporteros , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Queratinocitos/metabolismo , Pulmón/patología , Linfocinas/metabolismo , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Telómero/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , Proteínas ras/genéticaRESUMEN
OBJECTIVES: This phase 1 study investigated safety/tolerability, pharmacokinetics, and preliminary efficacy of SC-002, a delta-like ligand 3-directed antibody-drug conjugate, in advanced small cell lung cancer and large cell neuroendocrine carcinoma. MATERIALS AND METHODS: Eligible patients received SC-002 at 1 of 7 dose levels during the dose-escalation portion of the study. RESULTS: Thirty-five enrolled patients received ≥1 dose of SC-002. Twenty-three (66%) patients experienced serious adverse events (AEs), 37% considered related to SC-002. Grade 3/4 AEs occurred in 21 (60%) and 2 (6%) patients; the most common were effusion and hypoalbuminemia. One grade 5 AE occurred in 1 patient. Five (14%) patients achieved a partial response and no patients achieved a complete response. CONCLUSION: SC-002 treatment was associated with systemic toxicity and limited efficacy.
Asunto(s)
Carcinoma de Células Grandes , Carcinoma Neuroendocrino , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma Neuroendocrino/tratamiento farmacológico , Cefalosporinas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
RDP58 is the first lead compound in a series of immunomodulating decapeptides discovered through activity-based screening and computer-aided, rational design. RDP58 disrupts cellular responses signaled through the Toll-like and tumor necrosis factor (TNF) receptor families and occludes important signal transduction pathways involved in inflammation, inhibiting the production of tumor necrosis factor alpha (TNFalpha), interferon-gamma, interleukin (IL)-2, IL-6, and IL-12. These pro-inflammatory cytokines are thought to be involved in the pathogenesis of several inflammatory and autoimmune diseases, including atopic dermatitis and psoriasis. The goal of this study was to determine the ability of RDP58 to inhibit skin inflammation following exposure to the well-characterized protein kinase C activator and tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of RDP58 to the epidermis following TPA treatment resulted in the amelioration of the phorbol ester-induced irritant contact dermatitis. Substantial reductions were observed in skin thickness and tissue weight, neutrophil-mediated myeloperoxidase activity, inflammatory cytokine production, and various histopathological indicators. We also found RDP58 to be effective in reducing the compounding inflammatory damage brought on by chronic TPA exposure, and that it is capable of targeting inflammatory mediators specifically in the keratinocyte. These results demonstrate that topically applied RDP58 is an effective anti-inflammatory treatment in the phorbol ester-induced dermatitis model, and suggest that it may have therapeutic potential in a variety of immune-related cutaneous diseases.
Asunto(s)
Dermatitis Irritante/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Péptidos/uso terapéutico , Administración Tópica , Animales , Citocinas/metabolismo , Dermatitis Irritante/patología , Factores Inmunológicos/administración & dosificación , Mediadores de Inflamación/antagonistas & inhibidores , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Activación Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Péptidos/administración & dosificación , Peroxidasa/metabolismo , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
BACKGROUND: RDP58 is a novel anti-inflammatory d-amino acid decapeptide that inhibits synthesis of proinflammatory cytokines by disrupting cell signaling at the pre-MAPK MyD88-IRAK-TRAF6 protein complex. We therefore evaluated its efficacy and safety in parallel multicenter, double-blind, randomized concept studies in ulcerative colitis (UC). METHODS: In the first trial, 34 patients with mild to moderate active UC were randomized (1:2) to placebo (n = 13) or RDP58 100 mg (n = 21). In the second trial, 93 similar patients were randomized (1:1:1) to placebo (n = 30) RDP58 200 mg (n = 31), or RDP 300 mg (n = 32). In both studies, treatment success was defined as a simple clinical colitis activity index score of no more than 3 at 28 days. Sigmoidoscopy and rectal biopsy (at baseline and 28 days) and safety measures (baseline and 28 and 56 days) were other endpoints. RESULTS: Treatment success on RDP 100 mg was 29% versus 46% on placebo (P = 0.46). There were no significant differences in sigmoidoscopy or histology score. In the second study, treatment success on the higher doses of RDP58 (200 and 300 mg) was 71% and 72%, respectively, versus 43% on placebo (P = 0.016). Improvements in sigmoidoscopy scores (41% on 200 mg and 46% on 300 mg versus 32% on placebo) did not reach significance, but histology scores improved significantly (P = 0.002) versus placebo. Overall, adverse events were no different between placebo (3.3 +/- 2.4) and RDP58 (2.7 +/- 1.4, 300-mg group). CONCLUSIONS: RDP58 at a dose of 200 or 300 mg, but not 100 mg, was effective in mild-to-moderate UC. RDP58 was safe and well tolerated, and its novel action makes it an attractive potential therapy.
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Colitis Ulcerosa/tratamiento farmacológico , Péptidos/administración & dosificación , Administración Oral , Adulto , Colitis Ulcerosa/diagnóstico , Colonoscopía , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Probabilidad , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
PURPOSE: In a recent phase II study of onartuzumab (MetMAb), patients whose non-small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. EXPERIMENTAL DESIGN: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA. RESULTS: A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean≥5 copies/cell by FISH); however, benefit was maintained in "MET IHC-positive"/MET FISH-negative patients (HR, 0.37; P=0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P=0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P=0.09) in favor of onartuzumab treatment. CONCLUSIONS: MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/biosíntesis , Quinazolinas/administración & dosificación , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Receptores ErbB/biosíntesis , Clorhidrato de Erlotinib , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , ARN Mensajero/biosíntesisAsunto(s)
Quinasas Ciclina-Dependientes/metabolismo , FN-kappa B/fisiología , Neoplasias/etiología , Proteína Oncogénica p21(ras)/fisiología , Proteínas Proto-Oncogénicas , Diferenciación Celular , División Celular , Quinasa 4 Dependiente de la Ciclina , Fase G1 , Regulación Neoplásica de la Expresión Génica , Humanos , Modelos BiológicosRESUMEN
BACKGROUND: Various growth proteins have been used to encourage periodontal tissue regeneration. The purpose of this pilot study is to evaluate the periodontal regeneration achieved with the use of a synthetic anabolic peptide (AP) combined with either beta-tricalcium phosphate (beta-TCP) or an absorbable collagen sponge (ACS) as the carrier. METHODS: Periodontal defects were created bilaterally adjacent to four mandibular teeth in five baboons. Plaque was allowed to accumulate around wire ligatures placed into the defects. After 2 months, the wire ligatures were removed, and a notch was placed at the base of the defect. The four teeth were randomly treated with one of the following treatments: 1) saline + ACS serving as the control, 2) AP + ACS, 3) saline + beta-TCP serving as another control, or 4) AP + beta-TCP. The baboons were sacrificed 5 months post-treatment, and histomorphometric analyses were performed under masked conditions. RESULTS: At 5 months post-surgery, the mean length of new cementum for sites treated with AP + ACS, AP + beta-TCP, saline + ACS, saline + beta-TCP amounted to 3.32 +/- 1.7 mm, 3.86 +/- 1.0 mm, 2.87 +/- 1.3 mm, and 3.15 +/- 1.9 mm, respectively. The mean width of new cementum for the corresponding values was 52.5 +/- 14.7 microm, 54.5 +/- 24.2 microm, 37.4 +/- 12.7 microm, and 48.9 +/- 12.4 microm, respectively. The mean width of new periodontal ligament for corresponding values was 246 +/- 140 microm, 166 +/- 26 microm, 251 +/- 92 microm, and 240 +/- 91 microm. No statistically significant difference was observed for any of the parameters among groups in this pilot study. CONCLUSIONS: Preclinical studies showed that AP has positive anabolic effects on bone cells. In this study, no adverse tissue reactions were observed in the AP-treated sites, including root resorption, ankylosis, or a foreign body reaction. The cementum length and width were greater in the sites treated with AP versus sites treated with a control; however, these differences were not significant in the small number of animals used. Further research is needed to define the potential of AP as a periodontal therapeutic agent.
Asunto(s)
Implantes Absorbibles , Anabolizantes/uso terapéutico , Materiales Biocompatibles , Fosfatos de Calcio , Colágeno , Proteínas de la Matriz Extracelular/uso terapéutico , Glicoproteínas/uso terapéutico , Regeneración Tisular Guiada Periodontal/métodos , Fragmentos de Péptidos/uso terapéutico , Enfermedades Periodontales/cirugía , Fosfoproteínas/uso terapéutico , Pérdida de Hueso Alveolar/patología , Pérdida de Hueso Alveolar/cirugía , Animales , Regeneración Ósea/efectos de los fármacos , Cementogénesis/efectos de los fármacos , Cemento Dental/efectos de los fármacos , Cemento Dental/patología , Portadores de Fármacos , Femenino , Papio , Pérdida de la Inserción Periodontal/patología , Pérdida de la Inserción Periodontal/cirugía , Enfermedades Periodontales/patología , Ligamento Periodontal/efectos de los fármacos , Ligamento Periodontal/patología , Proyectos Piloto , Distribución Aleatoria , Factores de TiempoRESUMEN
The nuclear factor NF-kappaB and oncogenic Ras can alter proliferation in epidermis, the most common site of human cancer. These proteins are implicated in epidermal squamous cell carcinoma in mice, however, the potential effects of altering their function are uncertain. Whereas inhibition of NF-kappaB enhances apoptosis in certain tumours, blockade of NF-kappaB predisposes murine skin to squamous cell carcinoma. Because therapeutics inhibiting Ras and NF-kappaB pathways are being developed to treat human cancer, it is essential to assess the effects of altering these regulators. The medical relevance of murine studies is limited, however, by differences between mouse and human skin, and by the greater ease of transforming murine cells. Here we show that in normal human epidermal cells both NF-kappaB and oncogenic Ras trigger cell-cycle arrest. Growth arrest triggered by oncogenic Ras can be bypassed by IkappaBalpha-mediated blockade of NF-kappaB, generating malignant human epidermal tissue resembling squamous cell carcinoma. Human cell tumorigenesis is dependent on laminin 5 and alpha6beta4 integrin. Thus, IkappaBalpha circumvents restraints on growth promotion induced by oncogenic Ras and can act with Ras to induce invasive human tissue neoplasia.