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1.
Invest New Drugs ; 38(1): 120-130, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-30887250

RESUMEN

Background PF-06650808 is a novel anti-Notch3 antibody-drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT). PF-06650808 was administered intravenously every 3 weeks at a starting dose of 0.2 mg/kg, escalated up to 6.4 mg/kg following the modified continual reassessment method. An additional dose level, 2.0 mg/kg, was evaluated in patients with advanced, estrogen receptor-positive (ER+) BC. Results The majority of patients had advanced BC (60%) and almost all (90%) had received ≥3 prior lines of anticancer therapy. Treatment with PF-06650808 was generally well tolerated at dose levels ≤2.0 mg/kg with no DLTs. The maximum tolerated dose (MTD) was estimated to be 2.4 mg/kg. The most common treatment-related AEs in all patients were fatigue (40.0%), decreased appetite (37.5%), nausea (35.0%), alopecia (32.5%), abdominal pain (25.0%), pruritus (25.0%), and vomiting (25.0%). Five patients achieved a partial response (PR), including 2 unconfirmed PRs; 4 of the responders had ER+/PR+/HER2- BC. Sixteen (51.6%) patients achieved stable disease, including 8 (57.1%) of 14 patients with ER+ BC. Tumor samples from all responders tested positive for NOTCH3 expression in a retrospective, exploratory analysis. Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inmunoconjugados/química , Neoplasias/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Receptor Notch3/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/farmacocinética , Neoplasias de la Mama/secundario , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Oligopéptidos/farmacocinética , Pronóstico , Receptor Notch3/inmunología , Estudios Retrospectivos , Distribución Tisular , Adulto Joven
2.
Int J Cancer ; 145(7): 1798-1808, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30680712

RESUMEN

PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.


Asunto(s)
Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Aminoglicósidos/efectos adversos , Animales , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Esquema de Medicación , Efrina-A4/metabolismo , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Ratones , Persona de Mediana Edad , Neoplasias/metabolismo , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo
3.
Cancer Cell Int ; 19: 209, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31406485

RESUMEN

The recent advent of immunomodulatory therapies into the clinic has demanded the identification of innovative predictive biomarkers to identify patients most likely to respond to immunotherapy and support the design of tailored clinical trials. Current molecular testing for selection of patients with gastrointestinal or pulmonary carcinomas relies on the prevalence of PD-L1 expression in tumor as well as immune cells by immunohistochemistry and/or on the evaluation of the microsatellite status. Tumor Mutational Burden (TMB) has emerged as a promising novel biomarker in this setting to further aid in patient selection. This has been facilitated by the increasing implementation of molecular pathology laboratories with comprehensive next generation sequencing (NGS) technologies. However, the significant overall costs and expertise required for the interpretation of NGS data has limited TMB evaluation in routine diagnostics, so far. This review focuses on the current use of TMB analysis in the clinical setting in the context of immune checkpoint inhibitor therapies.

4.
J Biol Chem ; 289(8): 4952-68, 2014 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-24403067

RESUMEN

Tumor cell mitochondria are key biosynthetic hubs that provide macromolecules for cancer progression and angiogenesis. Soluble decorin protein core, hereafter referred to as decorin, potently attenuated mitochondrial respiratory complexes and mitochondrial DNA (mtDNA) in MDA-MB-231 breast carcinoma cells. We found a rapid and dynamic interplay between peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the decorin-induced tumor suppressor gene, mitostatin. This interaction stabilized mitostatin mRNA with concurrent accumulation of mitostatin protein. In contrast, siRNA-mediated abrogation of PGC-1α-blocked decorin-evoked stabilization of mitostatin. Mechanistically, PGC-1α bound MITOSTATIN mRNA to achieve rapid stabilization. These processes were orchestrated by the decorin/Met axis, as blocking the Met-tyrosine kinase or knockdown of Met abrogated these responses. Furthermore, depletion of mitostatin blocked decorin- or rapamycin-evoked mitophagy, increased vascular endothelial growth factor A (VEGFA) production, and compromised decorin-evoked VEGFA suppression. Collectively, our findings underscore the complexity of PGC-1α-mediated mitochondrial homeostasis and establish mitostatin as a key regulator of tumor cell mitophagy and angiostasis.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Decorina/farmacología , Mitofagia/efectos de los fármacos , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Portadoras , Línea Celular Tumoral , ADN Mitocondrial/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Mitofagia/genética , Modelos Biológicos , Fosforilación Oxidativa/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Unión Proteica/efectos de los fármacos , Unión Proteica/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Estabilidad del ARN/efectos de los fármacos , Estabilidad del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
5.
Cancer Cell ; 11(3): 275-89, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17349584

RESUMEN

The FEZ1/LZTS1 (LZTS1) protein is frequently downregulated in human cancers of different histotypes. LZTS1 is expressed in normal tissues, and its introduction in cancer cells inhibits cell growth and suppresses tumorigenicity, owing to an accumulation of cells in G2/M. Here, we define its role in cell cycle regulation and tumor progression by generating Lzts1 knockout mice. In Lzts1(-/-) mouse embryo fibroblasts (MEFs), Cdc25C degradation was increased during M phase, resulting in decreased Cdk1 activity. As a consequence, Lzts1(-/-) MEFs showed accelerated mitotic progression, resistance to taxol- and nocodazole-induced M phase arrest, and improper chromosome segregation. Accordingly, Lzts1 deficiency was associated with an increased incidence of both spontaneous and carcinogen-induced cancers in mice.


Asunto(s)
Proteína Quinasa CDC2/fisiología , Proteínas de Ciclo Celular/fisiología , Transformación Celular Neoplásica , Mitosis , Neoplasias Gástricas/patología , Proteínas Supresoras de Tumor/fisiología , Fosfatasas cdc25/fisiología , Animales , Antineoplásicos/farmacología , Carcinógenos , División Celular , Células Cultivadas , Segregación Cromosómica , Dimetilnitrosamina/análogos & derivados , Fibroblastos/metabolismo , Fibroblastos/patología , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Nocodazol/farmacología , Paclitaxel/farmacología , Neoplasias Gástricas/inducido químicamente , Neoplasias Gástricas/genética , Proteínas Supresoras de Tumor/genética
6.
J Clin Oncol ; 42(21): 2565-2577, 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-38788174

RESUMEN

PURPOSE: CT041 is a chimeric antigen receptor (CAR)-modified T-cell therapy that specifically targets claudin18.2 in solid tumors. Here, we report the pooled analysis results of two exploratory clinical trials to evaluate CT041 in patients with previously treated pancreatic cancer (PC). PATIENTS AND METHODS: These two multicenter, open-label phase I/Ib trials (CT041-CG4006, CT041-ST-01) have a similar target population and evaluation schedule. The primary objective was to assess the safety and tolerability of CT041, whereas secondary objectives included efficacy, pharmacokinetics, and immunogenicity. RESULTS: The combined cohort comprised 24 patients with advanced PC. Among them, five patients (20.8%) had previously received one line of therapy, whereas 19 (79.2%) received ≥2 lines of therapy. The most common treatment-emergent adverse events of grade 3 or more were preconditioning-related hematologic toxicities. Cytokine release syndrome (CRS) and GI disorders were most reported grade 1 or 2 adverse events. The overall response rate and disease control rate were 16.7% and 70.8%. The median progression-free survival (mPFS) after infusion was 3.3 months (95% CI, 1.8 to 6.2), and the median overall survival (mOS) was 10.0 months (95% CI, 5.5 to 17.6). The median duration of response (mDoR)was 9.5 months (95% CI, 2.6 to Not reached), with a DoR rate at 12 months of 50% (95% CI, 5.8 to 84.5). The mPFS (6.0 v 1.0 months, P < .001) and mOS (17.6 v 4.0 months, P < .001) were prolonged in patients achieving partial response/stable disease than the progressive disease group. CA19-9 levels had reduced by at least 30% in 17 (70.8%) patients. CONCLUSION: In patients with metastatic PC after progression on previous therapy, CT041 demonstrated a tolerable safety profile and encouraging anticancer efficacy signals. Response benefit observed here needs to be ascertained in the future.


Asunto(s)
Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Adulto , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Claudinas
7.
Genome Res ; 20(5): 589-99, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20439436

RESUMEN

We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Nonmalignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs. hsa-miR-103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150 kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR-204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network.


Asunto(s)
Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Leucemia , MicroARNs/genética , Neoplasias , Adenocarcinoma/metabolismo , Animales , Línea Celular Tumoral , Dosificación de Gen , Humanos , Leucemia/genética , Leucemia/metabolismo , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Ratones , MicroARNs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
8.
EMBO Rep ; 11(11): 854-60, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20930847

RESUMEN

Trichoplein/mitostatin (TpMs) is a keratin-binding protein that partly colocalizes with mitochondria and is often downregulated in epithelial cancers, but its function remains unclear. In this study, we report that TpMs regulates the tethering between mitochondria and endoplasmic reticulum (ER) in a Mitofusin 2 (Mfn2)-dependent manner. Subcellular fractionation and immunostaining show that TpMs is present at the interface between mitochondria and ER. The expression of TpMs leads to mitochondrial fragmentation and loosens tethering with ER, whereas its silencing has opposite effects. Functionally, the reduced tethering by TpMs inhibits apoptosis by Ca(2+)-dependent stimuli that require ER-mitochondria juxtaposition. Biochemical and genetic evidence support a model in which TpMs requires Mfn2 to modulate mitochondrial shape and tethering. Thus, TpMs is a new regulator of mitochondria-ER juxtaposition.


Asunto(s)
Proteínas Portadoras/metabolismo , Retículo Endoplásmico/metabolismo , Mitocondrias/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Calcio/farmacología , Muerte Celular/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , GTP Fosfohidrolasas/metabolismo , Células HeLa , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Forma de los Orgánulos/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos
9.
Int J Cancer ; 129(7): 1661-70, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21128279

RESUMEN

Barrett's esophagus (BE) is characterized by the native stratified squamous epithelium (N) lining the esophagus being replaced by a columnar epithelium with intestinal differentiation (Barrett's mucosa; BM). BM is considered as the main risk factor for esophageal adenocarcinoma (Barrett's adenocarcinoma; BAc). MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting messenger RNAs and they are reportedly dysregulated in BM. To test the hypothesis that a specific miRNA expression signature characterizes BM development and progression, we performed miRNA microarray analysis comparing native esophageal mucosa with all the phenotypic lesions seen in the Barrett's carcinogenic process. Specimens were collected from 14 BE patients who had undergone esophagectomy, including: 14 with N, 14 with BM, 7 with low-grade intraepithelial neoplasia, 5 with high-grade intra-epithelial neoplasia and 11 with BAc. Microarray findings were further validated by quantitive real-time polymerase chain reaction and in situ hybridization analyses using a different series of consecutive cases (162 biopsy samples and 5 esophagectomies) of histologically proven, long-segment BE. We identified a miRNA signature of Barrett's carcinogenesis consisting of an increased expression of 6 miRNAs and a reduced expression of 7 miRNAs. To further support these results, we investigated target gene expression using the Oncomine database and/or immunohistochemical analysis. We found that target gene expression correlated significantly with miRNA dysregulation. Specific miRNAs are directly involved in BE progression to cancer. miRNA profiling significantly expands current knowledge on the molecular history of Barrett's carcinogenesis, also identifying molecular markers of cancer progression.


Asunto(s)
Esófago de Barrett/genética , MicroARNs , Progresión de la Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Humanos , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Estudios de Validación como Asunto
10.
Am J Pathol ; 176(6): 2997-3006, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20395438

RESUMEN

The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. Aberrant IGF-IR signaling is implicated in several types of tumors, including carcinomas of the lung, breast, prostate, pancreas, liver, and colon. However, the contribution of the IGF-IR to the development of the transformed phenotype in urothelial cells has not been clearly established. In this study we demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues compared with nonmalignant controls. We have investigated the role of the IGF-IR in bladder cancer by using urothelial carcinoma-derived 5637 and T24 cells. Although activation of the IGF-IR did not appreciably affect their growth, it did promote migration and stimulate in vitro wound closure and invasion. These effects required the activation of the Akt and Mitogen-activated protein kinase (MAPK) pathways as well as IGF-I-induced Akt- and MAPK-dependent phosphorylation of paxillin, which relocated at dynamic focal adhesions and was necessary for promoting motility in bladder cancer cells. Our results provide the first evidence for a role of the IGF-IR in motility and invasion of bladder cancer cells and support the hypothesis that the IGF-IR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. Thus, the IGF-IR may also serve as a novel biomarker for bladder cancer.


Asunto(s)
Movimiento Celular/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Paxillin/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Línea Celular Tumoral , Transformación Celular Neoplásica , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/genética , Invasividad Neoplásica , Paxillin/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptor IGF Tipo 1/genética , Transducción de Señal/fisiología
11.
Am J Pathol ; 174(3): 1037-47, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19179604

RESUMEN

The growth factor proepithelin has recently emerged as an important regulator of transformation in several physiological and pathological systems. In this study, we determined the biological roles of proepithelin in prostate cancer cells using purified human recombinant proepithelin as well as proepithelin-depletion strategies. Proepithelin promoted the migration of androgen-dependent and -independent human prostate cancer cells; androgen-independent DU145 cells were the more responsive. In these cells, proepithelin additionally stimulated wound closure, invasion, and promotion of cell growth in vitro. These effects required the activation of both the Akt and mitogen-activated protein kinase pathways. We have analyzed proepithelin expression levels in different available prostate cancer microarray studies using the Oncomine database and found a statistically significant increase in proepithelin mRNA expression levels in prostate cancers compared with nonneoplastic controls. Notably, depletion of endogenous proepithelin by siRNA and antisense strategies impaired the ability of DU145 cells to grow and migrate after serum withdrawal and inhibited anchorage-independent growth. Our results provide the first evidence for a role of proepithelin in stimulating the migration, invasion, proliferation, and anchorage-independent growth of prostate cancer cells. This study supports the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and initial progression of prostate cancer. Furthermore, proepithelin may prove to be a useful clinical marker for the diagnosis of prostate tumors.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/fisiología , Neoplasias de la Próstata/patología , División Celular , Línea Celular Tumoral , Movimiento Celular , Silenciador del Gen , Granulinas , Homeostasis , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Invasividad Neoplásica , Progranulinas , Neoplasias de la Próstata/genética , Precursores de Proteínas/genética , Precursores de Proteínas/fisiología , Transducción de Señal , Cicatrización de Heridas
12.
J Pathol ; 219(2): 214-21, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19593777

RESUMEN

Small non-coding microRNAs (miRNAs) contribute to cancer development and progression, and are differentially expressed in normal tissues and cancers. However, the specific role of miRNAs in the metastatic process is still unknown. To seek a specific miRNA expression signature characterizing the metastatic phenotype of solid tumours, we performed a miRNA microarray analysis on 43 paired primary tumours (ten colon, ten bladder, 13 breast, and ten lung cancers) and one of their related metastatic lymph nodes. We identified a metastatic cancer miRNA signature comprising 15 overexpressed and 17 underexpressed miRNAs. Our results were confirmed by qRT-PCR analysis. Among the miRNAs identified, some have a well-characterized association with cancer progression, eg miR-10b, miR-21, miR-30a, miR-30e, miR-125b, miR-141, miR-200b, miR-200c, and miR-205. To further support our data, we performed an immunohistochemical analysis for three well-defined miRNA gene targets (PDCD4, DHFR, and HOXD10 genes) on a small series of paired colon, breast, and bladder cancers, and one of their metastatic lymph nodes. We found that the immunohistochemical expression of these targets significantly follows the corresponding miRNA deregulation. Our results suggest that specific miRNAs may be directly involved in cancer metastasis and that they may represent a novel diagnostic tool in the characterization of metastatic cancer gene targets.


Asunto(s)
Metástasis Linfática/genética , MicroARNs/genética , ARN Neoplásico/genética , Neoplasias de la Mama/genética , Neoplasias del Colon/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Humanos , Neoplasias Pulmonares/genética , Metástasis Linfática/diagnóstico , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Neoplasias de la Vejiga Urinaria/genética
13.
Mol Cancer Ther ; 19(8): 1660-1669, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32451330

RESUMEN

Glycosylation is a complex multienzyme-related process that is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface-specific glycotopes that can be targeted by antibodies. Murine DS6 mAb (muDS6) was generated from serous ovary adenocarcinoma immunization. It recognizes CA6, a Mucin-1 (MUC1)-associated sialoglycotope that is highly detected in breast, ovarian, lung, and bladder carcinomas. SAR566658 antibody-drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative drug, DM4. SAR566658 binds to tumor cells with subnanomolar affinity, allowing good ADC internalization and intracellular delivery of DM4, resulting in tumor cell death (IC50 from 1 to 7.3 nmol/L). SAR566658 showed in vivo antitumor efficacy against CA6-positive human pancreas, cervix, bladder, and ovary tumor xenografts and against three breast patient-derived xenografts. Tumor regression was observed in all tumor models with minimal effective dose correlating with CA6 expression. SAR566658 displayed better efficacy than standard-of-care nontargeted tubulin binders. These data support the development of SAR566658 in patients with CA6-expressing tumors.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carbohidratos/química , Inmunoconjugados/uso terapéutico , Mucina-1/química , Neoplasias/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales Humanizados/química , Antígenos de Neoplasias/química , Antígenos de Neoplasias/inmunología , Antineoplásicos/química , Apoptosis , Proliferación Celular , Femenino , Humanos , Inmunoconjugados/química , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mucina-1/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Carcinogenesis ; 30(5): 861-8, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19237611

RESUMEN

The growth factor proepithelin functions as an important regulator of proliferation and motility. Proepithelin is overexpressed in a great variety of cancer cell lines and clinical specimens of breast, ovarian and renal cancer, as well as glioblastomas. Using recombinant proepithelin on 5637 transitional cell carcinoma-derived cells, we have shown previously that proepithelin plays a critical role in bladder cancer by promoting motility of bladder cancer cells. In this study, we used the ONCOMINE database and gene microarray analysis tool to analyze proepithelin expression in several bladder cancer microarray studies. We found a statistically significant increase in proepithelin messenger RNA expression in bladder cancers vis-à-vis non-neoplastic tissues, and this was associated with pathologic and prognostic parameters. Targeted downregulation of proepithelin in T24 transitional carcinoma cells with small hairpin RNA inhibited both Akt and mitogen-activated protein kinase pathways, severely reduced the ability of T24 cells to proliferate in the absence of serum and inhibited migration, invasion and wound healing. In support of these in vitro results, we discovered that proepithelin expression was significantly upregulated in invasive bladder cancer tissues compared with normal urothelium. In addition, proepithelin was secreted in the urine, where it was detectable by immunoblotting and enzyme-linked immunosorbent assay. Collectively, these results support the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and progression of bladder cancer and suggest that proepithelin may prove a novel biomarker for the diagnosis and prognosis of bladder neoplasms.


Asunto(s)
Sustancias de Crecimiento/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/genética , Línea Celular Tumoral , Movimiento Celular , Progresión de la Enfermedad , Regulación hacia Abajo , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Análisis por Micromatrices , Pronóstico , Progranulinas , ARN Mensajero/genética , Proteínas Recombinantes/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/fisiopatología
15.
Breast Cancer Res ; 11(4): R58, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19664288

RESUMEN

INTRODUCTION: MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. To test the hypothesis that there is a specific miRNA expression signature which characterizes male breast cancers, we performed miRNA microarray analysis in a series of male breast cancers and compared them with cases of male gynecomastia and female breast cancers. METHODS: Paraffin blocks were obtained at the Department of Pathology of Thomas Jefferson University from 28 male patients including 23 breast cancers and five cases of male gynecomastia, and from 10 female ductal breast carcinomas. The RNA harvested was hybridized to miRNA microarrays (~1,100 miRNA probes, including 326 human and 249 mouse miRNA genes, spotted in duplicate). To further support the microarray data, an immunohistochemical analysis for two specific miRNA gene targets (HOXD10 and VEGF) was performed in a small series of male breast carcinoma and gynecomastia samples. RESULTS: We identified a male breast cancer miRNA signature composed of a large portion of underexpressed miRNAs. In particular, 17 miRNAs with increased expression and 26 miRNAs with decreased expression were identified in male breast cancer compared with gynecomastia. Among these miRNAs, some had well-characterized cancer development association and some showed a deregulation in cancer specimens similar to the one previously observed in the published signatures of female breast cancer. Comparing male with female breast cancer miRNA expression signatures, 17 significantly deregulated miRNAs were observed (four overexpressed and 13 underexpressed in male breast cancers). The HOXD10 and VEGF gene immunohistochemical expression significantly follows the corresponding miRNA deregulation. CONCLUSIONS: Our results suggest that specific miRNAs may be directly involved in male breast cancer development and that they may represent a novel diagnostic tool in the characterization of specific cancer gene targets.


Asunto(s)
Adenocarcinoma/genética , Neoplasias de la Mama Masculina/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Estudio de Asociación del Genoma Completo , MicroARNs/genética , ARN Neoplásico/genética , Adenocarcinoma/química , Adenocarcinoma/diagnóstico , Neoplasias de la Mama/química , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama Masculina/química , Neoplasias de la Mama Masculina/diagnóstico , Transformación Celular Neoplásica/genética , Diagnóstico Diferencial , Femenino , Estudios de Asociación Genética , Ginecomastia/diagnóstico , Ginecomastia/genética , Ginecomastia/metabolismo , Proteínas de Homeodominio/genética , Humanos , Masculino , MicroARNs/biosíntesis , MicroARNs/fisiología , Proteínas de Neoplasias/genética , ARN Neoplásico/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Caracteres Sexuales , Factores de Transcripción/genética , Factor A de Crecimiento Endotelial Vascular/genética
16.
Am J Pathol ; 173(3): 844-55, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18688028

RESUMEN

Decorin, a member of the small leucine-rich proteoglycan gene family, down-regulates members of the ErbB receptor tyrosine kinase family and attenuates their signaling, leading to growth inhibition. We investigated the effects of decorin on the growth of ErbB2-overexpressing mammary carcinoma cells in comparison with AG879, an established ErbB2 kinase inhibitor. Cell proliferation and anchorage-independent growth assays showed that decorin was a potent inhibitor of breast cancer cell growth and a pro-apoptotic agent. When decorin and AG879 were used in combination, the inhibitory effect was synergistic in proliferation assays but only additive in both colony formation and apoptosis assays. Active recombinant human decorin protein core, AG879, or a combination of both was administered systemically to mice bearing orthotopic mammary carcinoma xenografts. Primary tumor growth and metabolism were reduced by approximately 50% by both decorin and AG879. However, no synergism was observed in vivo. Decorin specifically targeted the tumor cells and caused a significant reduction of ErbB2 levels in the tumor xenografts. Most importantly, systemic delivery of decorin prevented metastatic spreading to the lungs, as detected by novel species-specific DNA detection and quantitative assays. In contrast, AG879 failed to have any effect. Our data support a role for decorin as a powerful and effective therapeutic agent against breast cancer due to its inhibition of both primary tumor growth and metastatic spreading.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteínas de la Matriz Extracelular/farmacología , Proteoglicanos/farmacología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular , Decorina , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Glicoproteínas/efectos de los fármacos , Glicoproteínas/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Ratones , Reacción en Cadena de la Polimerasa , Tomografía de Emisión de Positrones , Ratas , Receptor ErbB-2
17.
Carcinogenesis ; 29(4): 846-8, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18192690

RESUMEN

FEZ1/LZTS1 is a tumor suppressor gene that is frequently altered in human cancers of different histotypes. We have reported previously that LZTS1 is downregulated in high-grade bladder cancer and that its restoration suppresses tumorigenicity in urothelial carcinoma cells. To further investigate the role of LZTS1 in the development of bladder cancer, we utilized heterozygous and nullizygous Lzts1 mice in a chemically induced carcinogenesis model. Fifty-eight mice consisting of 25 Lzts1(+/+), 17 Lzts1(+/-) and 16 Lzts1(-/-) were treated with N-butyl-N-(4-hydroxybutil) nitrosamine (BBN). Results showed that there was a significant increase in neoplastic lesions in the Lzts1(+/-) (82.3%) and Lzts1(-/-) (93.8%) versus Lzts1(+/+) (8.0%) mice after BBN treatment. No difference in cancer incidence between Lzts1(+/-) and Lzts1(-/-) was observed. Collectively, these findings indicate that loss of one or both LZTS1 alleles hampers the normal defenses of urothelial cells against carcinogens, favoring bladder cancer development. Therefore, LZTS1 may become an excellent target for gene therapy in advanced bladder carcinoma.


Asunto(s)
Butilhidroxibutilnitrosamina/toxicidad , Carcinógenos/toxicidad , Proteínas de Unión al ADN/deficiencia , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/deficiencia , Neoplasias de la Vejiga Urinaria/genética , Animales , Cartilla de ADN , Proteínas de Unión al ADN/genética , Femenino , Genes Supresores de Tumor , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/patología
18.
N Engl J Med ; 352(16): 1667-76, 2005 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-15843669

RESUMEN

BACKGROUND: The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene. METHODS: We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant. RESULTS: We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles. CONCLUSIONS: A genetic variant of ARLTS1 predisposes patients to familial cancer.


Asunto(s)
Factores de Ribosilacion-ADP/genética , Cromosomas Humanos Par 13 , Genes Supresores de Tumor , Mutación de Línea Germinal , Neoplasias/genética , Polimorfismo Genético , Factores de Ribosilacion-ADP/metabolismo , Animales , Deleción Cromosómica , Codón sin Sentido , Metilación de ADN , Análisis Mutacional de ADN , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Análisis de Secuencia por Matrices de Oligonucleótidos , Pancitopenia/genética , Linaje , ARN Mensajero/metabolismo , Proteínas Supresoras de Tumor/genética
19.
Cancer Res ; 66(14): 7103-10, 2006 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-16849556

RESUMEN

The growth factor proepithelin (also known as progranulin, acrogranin, PC-derived growth factor, or granulin-epithelin precursor) is a secreted glycoprotein that functions as an important regulator of cell growth, migration, and transformation. Proepithelin is overexpressed in a great variety of cancer cell lines and clinical specimens of breast, ovarian, and renal cancer as well as glioblastomas. In this study, we have investigated the effects of proepithelin on bladder cancer cells using human recombinant proepithelin purified to homogeneity from 293-EBNA cells. Although proepithelin did not appreciably affect cell growth, it did promote migration of 5637 bladder cancer cells and stimulate in vitro wound closure and invasion. These effects required the activation of the mitogen-activated protein kinase pathway and paxillin, which upon proepithelin stimulation formed a complex with focal adhesion kinase and active extracellular signal-regulated kinase. Our results provide the first evidence for a role of proepithelin in stimulating migration and invasion of bladder cancer cells, and support the hypothesis that this growth factor may play a critical role in the establishment of the invasive phenotype.


Asunto(s)
Carcinoma de Células Transicionales/patología , Movimiento Celular/fisiología , Quinasa 1 de Adhesión Focal/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Paxillin/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/enzimología , Activación Enzimática , Humanos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Sistema de Señalización de MAP Quinasas , Invasividad Neoplásica , Progranulinas , Precursores de Proteínas/metabolismo , Precursores de Proteínas/farmacología , Proteínas Recombinantes/farmacología , Neoplasias de la Vejiga Urinaria/enzimología
20.
Front Biosci ; 12: 826-38, 2007 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-17127340

RESUMEN

Bladder cancer is one of the most common cancers in the world, leading to approximately 145,000 deaths annually. Bladder cancer is typically managed by surgical removal of the tumor; however, the recurrence rate is disappointingly very high, often requiring systemic chemotherapy. Improvement in the diagnosis and prognosis of bladder cancer will only come from a comprehensive understanding of the genetic factors that lead to its development. In this review, we focus on the chromosomal deletions that contribute to the downregulation of tumor suppressor pathways in bladder cancer. Chromosomal deletions are not a random event, since bladder cancer progression has been associated with specific chromosomal deletions and this progression correlates with specific stages of tumor development. The most commonly found chromosomal deletion in all stages of bladder cancer involves deletions in chromosome 9, resulting in the loss of three genes encoding proteins that activate the Rb and p53 tumor suppressors. Additionally, chromosome 9 harbors the TSC1 tumor suppressor which downregulates the well-known anti-apoptotic Akt/mTOR pathway. Hence, deletions on one chromosome may have a crucial influence on the initial steps in tumor development. Other deletions targeting the tumor suppressors Rb, p53, FHIT and LZTS1 occur at later stages of tumor development. Considering the central importance of these tumor suppressor pathways in the formation and evolution of tumors, the time has come to evaluate available drugs in bladder cancer that target the positive regulators of these pathways.


Asunto(s)
Deleción Cromosómica , Neoplasias de la Vejiga Urinaria/genética , Humanos , Hibridación Fluorescente in Situ , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Transducción de Señal/genética , Neoplasias de la Vejiga Urinaria/metabolismo
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