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1.
J Transl Med ; 15(1): 210, 2017 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-29047383

RESUMEN

BACKGROUND: The mitochondrial protein p32 is a validated therapeutic target of cancer overexpressed in glioma. Therapeutic targeting of p32 with monoclonal antibody or p32-binding LyP-1 tumor-homing peptide can limit tumor growth. However, these agents do not specifically target mitochondrial-localized p32 and would not readily cross the blood-brain barrier to target p32-overexpressing gliomas. Identifying small molecule inhibitors of p32 overexpressed in cancer is a more rational therapeutic strategy. Thus, in this study we employed a pharmacophore modeling strategy to identify small molecules that could bind and inhibit mitochondrial p32. METHODS: A pharmacophore model of C1q and LyP-1 peptide association with p32 was used to screen a virtual compound library. A primary screening assay for inhibitors of p32 was developed to identify compounds that could rescue p32-dependent glutamine-addicted glioma cells from glutamine withdrawal. Inhibitors from this screen were analyzed for direct binding to p32 by fluorescence polarization assay and protein thermal shift. Affect of the p32 inhibitor on glioma cell proliferation was assessed by Alamar Blue assay, and affect on metabolism was examined by measuring lactate secretion. RESULTS: Identification of a hit compound (M36) validates the pharmacophore model. M36 binds directly to p32 and inhibits LyP-1 tumor homing peptide association with p32 in vitro. M36 effectively inhibits the growth of p32 overexpressing glioma cells, and sensitizes the cells to glucose depletion. CONCLUSIONS: This study demonstrates a novel screening strategy to identify potential inhibitors of mitochondrial p32 protein overexpressed in glioma. High throughput screening employing this strategy has potential to identify highly selective, potent, brain-penetrant small molecules amenable for further drug development.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas Mitocondriales/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Secuencia de Aminoácidos , Neoplasias Encefálicas/patología , Proteínas Portadoras , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Polarización de Fluorescencia , Glioma/patología , Glucosa/farmacología , Humanos , Ácido Láctico/metabolismo , Proteínas Mitocondriales/química , Modelos Moleculares , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequeñas/química
2.
PLoS Genet ; 9(2): e1003253, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23459592

RESUMEN

Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.


Asunto(s)
Transformación Celular Neoplásica , Glioblastoma , Complejos Multiproteicos , Proteína Oncogénica v-akt , Fosfatidilinositol 3-Quinasas , Serina-Treonina Quinasas TOR , Animales , Apoptosis/genética , Astrocitos/citología , Astrocitos/metabolismo , Proliferación Celular , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulación Neoplásica de la Expresión Génica , Genoma de los Insectos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Neuroglía/metabolismo , Proteína Oncogénica v-akt/genética , Proteína Oncogénica v-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo
3.
bioRxiv ; 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38328254

RESUMEN

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with activated RAS from upstream mutations were equally sensitive. Conversely, cells from normal tissues or RAS WT cancer cells harboring downstream BRAF mutations were insensitive. Insensitivity to ADT-007 was attributed to low activated RAS levels and metabolic deactivation by UDP-glucuronosyltransferases expressed in normal cells but repressed in RAS mutant cancer cells. Cellular, biochemical, and biophysical experiments show ADT-007 binds nucleotide-free RAS to block GTP activation of RAS and MAPK/AKT signaling. Local administration of ADT-007 strongly inhibited tumor growth in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer while activating innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for treating RAS-driven cancers. SIGNIFICANCE: ADT-007 is a 1 st -in-class pan-RAS inhibitor with ultra-high potency and unique selectivity for cancer cells with mutant or activated RAS capable of circumventing resistance and activating antitumor immunity. Further development of ADT-007 analogs or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy is warranted.

4.
J Neurooncol ; 113(3): 365-73, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23640138

RESUMEN

Frozen tissue, a gold standard biospecimen, can yield well preserved nucleic acids and proteins after over a decade but is vulnerable to thawing and has substantial fiscal, spatial, and environmental costs. A long-term room temperature biospecimen storage alternative that preserves broad analytical utility can potentially empower tissue-based research. As there is scant data on the analytical utility of lyophilized brain tumor biospecimens, we evaluated lyophilized (freeze-dried) samples stored for 1 year at room temperature. Lyophilized tumor tissue processed into paraffin sections produced good histology. Yields of extracted DNA, RNA, and protein approximated those of frozen tissue. After 1 year, lyophilized samples yielded high molecular weight DNA that permitted copy number variation analysis, IDH 1 mutation detection, and MGMT promoter methylation PCR. A 27 % decrease in RIN scores over the 1 year suggests that RNA degradation was inhibited though incompletely. Nevertheless, RT-PCR studies on lyophilized tissue performed similarly to frozen tissue. In contrast to FFPE tissues where protein bands were absent or shifted to a lower molecular weight, lyophilized samples showed similar protein bands as frozen tissue on SDS-PAGE analysis. Lyophilized tissue performed similarly to frozen tissue for Western blots and enzyme activity assays. Immunohistochemistry of lyophilized tissue that were processed into FFPE blocks often required longer incubation times for staining than standard FFPE samples but generally provided robust antigen detection. This preliminary study suggests that lyophilization has promise for long-term room temperature storage while permitting varied tests; however, further work is required to better stabilize nucleic acids particularly RNA.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , ADN de Neoplasias/análisis , Liofilización , Proteínas de Neoplasias/análisis , ARN Neoplásico/análisis , Western Blotting , Neoplasias Encefálicas/genética , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Humanos , Técnicas para Inmunoenzimas , Isocitrato Deshidrogenasa/genética , Mutación/genética , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Temperatura , Factores de Tiempo , Fijación del Tejido , Proteínas Supresoras de Tumor/genética
5.
Biomed Pharmacother ; 166: 115349, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37634476

RESUMEN

BACKGROUND: DNA methylation, histone modifications, and miRNAs affect ovarian cancer (OC) progression and therapy response. PURPOSE: Identification of epigenetically downregulated miRNAs in drug-resistant OC cell lines with a possible role in drug resistance and/or drug-induced mesenchymal-like phenotype. METHODS: MiRNA profiling was performed on parental and carboplatin-resistant OC cells, MES-OV and MES-OV CBP. RT-qPCR validation, epigenetic modulation and other CBP-resistant OC cell lines were used to select miRNAs of interest. The integration of miRNA-predicted target genes and differentially expressed genes (DEGs), pathway and functional analysis were used for forecasting their biological role. Data mining was performed to determine their possible prognostic and predictive values. RESULTS: MiRNA profiling revealed 48 downregulated miRNAs in OC cells whose drug sensitivity and metastatic potential were impacted by epigenetic modulators. Of the fourteen selected, nine were validated as changed, and seven of these restored their expression upon treatment with epigenetic inhibitors. Only three had similar expression patterns in other OC cell lines. MiRNA-mRNA integrative analysis resulted in 56 target DEGs. Pathway analysis revealed that these genes are involved in cell adhesion, migration, and invasion. The functional analysis confirmed the role of miR-103a-3p, miR-17-5p and miR-107 in cell invasion, while data mining showed their prognostic and predictive values. Only miR-103a-3p was epigenetically regulated at the constitutive level. CONCLUSION: High throughput miRNA and cDNA profiling coupled with pathway analysis and data mining delivered evidence for miRNAs which can be epigenetically regulated in drug-resistant, mesenchymal-like OC cells as possible markers to combat therapy-induced short overall survival and tumor metastatic potential.


Asunto(s)
Neoplasias Ováricas , Femenino , Humanos , Carboplatino/farmacología , Pronóstico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Fenotipo
6.
Coll Antropol ; 36(3): 1041-3, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23213969

RESUMEN

Tumors that grow within the adrenal medulla are called pheochromocytoma; when located extra-adrenal, they are called paraganglioma. Paraganglioma of the bladder are very rare, with only 180 reported cases. Less than 30 were malignant. We report a case of a 72-years old man with bladder paraganglioma who presented with painless hematuria. Urgent transurethral resection (TUR) was performed. Definitive pathohistological diagnosis was confirmed to imunohistochemical and electron microscopy. Clinical diagnostic showed normal value of epinephrine and norepinehrine in the urine. Scintigraphy of entire body and targeted pictures of pelvis where taken 24, 48 and 72 hours after administration of RI. No loci of pathologic accumulation of 131-I MIBG where found. Computer tomography (CT) of pelvis and abdomen were normal. Considering staging and pathohistological analysis, we treated our patient with TUR and longtime follow-up afterworth.


Asunto(s)
Paraganglioma/patología , Paraganglioma/orina , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/orina , Anciano , Epinefrina/orina , Humanos , Inmunohistoquímica , Masculino , Microscopía Electrónica , Norepinefrina/orina , Paraganglioma/diagnóstico por imagen , Ultrasonografía , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen
7.
Biotechniques ; 68(4): 180-184, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32040335

RESUMEN

CRISPR-Cas9 has proven to be a versatile tool for the discovery of essential genetic elements involved in various disease states. CRISPR-assisted dense mutagenesis focused on therapeutically challenging protein complexes allows us to systematically perturb protein-coding sequences in situ and correlate them with functional readouts. Such perturbations can mimic targeting by therapeutics and serve as a foundation for the discovery of highly specific modulators. However, translation of such genomics data has been challenging due to the missing link for proteomics under the physiological state of the cell. We present a method based on cellular thermal shift assays to easily interrogate proteomic shifts generated by CRISPR-assisted dense mutagenesis, as well as a case focused on NuRD epigenetic complex.


Asunto(s)
Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Mutagénesis Insercional/genética , Proteoma/genética , Proteómica/métodos , Línea Celular , Humanos , Proteoma/análisis
8.
Rev Bras Ginecol Obstet ; 42(5): 297-302, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32483810

RESUMEN

OBJECTIVE: Desmoplastic small round cell tumor (DSRCT) is a rare intraabdominal neoplasm that grows along serosal surfaces and is primarily found in young men. To date, only 16 cases of ovarian DSRCT have been previously reported in women in the English literature, and no large population-based studies on this topic exist. CASE REPORT: We report the case of a 19-year-old virgo with unremarkable past medical history, initially presented with abdominal fullness. After being treated with the optimal treatment modality (primary and secondary surgical debulking, unique chemotherapy, protocol and adjuvant radiotherapy), the patient has remained without tumor disease for 40 months. CONCLUSION: Although the best therapy for patients with DSRCT has yet to be determined, combining complete surgical resection, adjuvant chemotherapy, and radiotherapy is required to prolong survival and to achieve proper quality of life.


Asunto(s)
Tumor Desmoplásico de Células Pequeñas Redondas/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias Ováricas/diagnóstico , Adolescente , Terapia Combinada , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Tumor Desmoplásico de Células Pequeñas Redondas/terapia , Diagnóstico Diferencial , Femenino , Humanos , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia
9.
Sci Rep ; 10(1): 8348, 2020 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-32433555

RESUMEN

To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into "responder" and "non-responder". By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular ERN1 (IRE1) and ATF4. We also identified two additional genes selectively overexpressed among non-responders, IGFBP3 and IGFBP5. CRISPR-mediated deletion of the ERN1, IGFBP3, IGFBP5 signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably, >65% of GBM cases in The Cancer Genome Atlas express the non-responder (ERN1, IGFBP3, IGFBP5) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Endorribonucleasas/metabolismo , Glioblastoma/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/antagonistas & inhibidores , Tapsigargina/farmacología , Adulto , Apoptosis/efectos de los fármacos , Encéfalo/patología , Encéfalo/cirugía , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/cirugía , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Estrés del Retículo Endoplásmico/efectos de los fármacos , Endorribonucleasas/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/cirugía , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Cultivo Primario de Células , Supervivencia sin Progresión , Proteínas Serina-Treonina Quinasas/genética , RNA-Seq , Transducción de Señal/genética , Esferoides Celulares , Tapsigargina/análogos & derivados , Tapsigargina/uso terapéutico , Células Tumorales Cultivadas , Respuesta de Proteína Desplegada/efectos de los fármacos
10.
Sci Rep ; 10(1): 8096, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32415084

RESUMEN

Abnormal regulation of ß-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, ß-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel ß-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of ß-catenin. C2 selectively inhibits ß-catenin, lowers its cellular load and significantly reduces viability of ß-catenin-driven cancer cells. Through direct binding to ß-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of ß-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of ß-catenin.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/antagonistas & inhibidores , Regulación Alostérica , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Apoptosis , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/aislamiento & purificación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Coll Antropol ; 33(1): 201-4, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19408626

RESUMEN

The aim of this study was to determine the efficacy and operative complications of the suprapubic arc (SPARC) procedure in stress incontinent women with and without previous anti-incontinence surgery. One-hundred and twenty-one patients with stress urinary incontinence (SUI) were treated with SPARC for correction of urethral hypermobility (N = 65) and intrinsic sphincter deficiency (N = 56) between August 2002 and February 2007. The long-term surgical results, operative complications (bladder injury, retropubic hematoma, de novo urgency and urinary infection) and patients' satisfaction were assessed. The overall complication rate was 9.9% (12/121). The perioperative complication rate was 1.7% including 2 urinary bladder injuries. Significant difference in the overall complications rate was detected between women with and without previous surgery (23/45, 51.1% vs. 6/108, 5.5%, chi2 = 49.89, P < 0.001). The overall postoperative complication rate was 8.3% (10/121) including 4 de novo urgencies, 4 urinary infections and 2 retropubic hematomas. There were 3 patients with postoperative urinary retention managed conservatively, without voiding difficulties on control visits. The objective cure rate after the follow-up was 86.8% (105/121). In patients with SUI and without preceding vaginal operations SPARC is a good method with low incidence of perioperative complications, promising long-term results and high patient satisfaction.


Asunto(s)
Complicaciones Posoperatorias/etiología , Incontinencia Urinaria de Esfuerzo/cirugía , Procedimientos Quirúrgicos Urológicos/métodos , Adulto , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos
12.
Methods Mol Biol ; 1904: 401-415, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30539482

RESUMEN

Pritumumab, a natural human IgG1kappa mAb, was isolated from the regional lymph node of a patient with cervical cancer. This antibody has been reported to bind the cytoskeletal protein vimentin, and to cell surface expressed vimentin referred to as ecto-domain vimentin (EDV). Here, we report details of the development of a potency of binding assay for pritumumab as a prerequisite before pursuing clinical trials. The enzyme linked immunosorbent assay (ELISA) to detect antibody-binding antigen can serve as a potency assay for release of manufactured samples to be used in clinical studies. Several layers of controls for this assay along with suitability testing for reagents and components of the assay must be developed before the assay can be incorporated for stability testing and release of manufatured samples.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Vimentina/inmunología , Animales , Anticuerpos Monoclonales/metabolismo , Afinidad de Anticuerpos , Ensayo de Inmunoadsorción Enzimática , Humanos , Cinética , Unión Proteica/inmunología , Conejos , Vimentina/metabolismo
13.
Hum Antibodies ; 27(1): 53-62, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30223393

RESUMEN

Antibody drug conjugates (ADCs) represent a promising and an efficient strategy for targeted cancer therapy. Comprised of a monoclonal antibody, a cytotoxic drug, and a linker, ADCs offer tumor selectively, reduced toxicity, and improved stability in systemic circulation. Recent approvals of two ADCs have led to a resurgence in ADC research, with more than 60 ADCs under various stages of clinical development. The therapeutic success of future ADCs is dependent on adherence to key requirements of their design and careful selection of the target antigen on cancer cells. Here we review the main components in the design of antibody drug conjugates, improvements made, and lessons learned over two decades of research, as well as the future of third generation ADCs.


Asunto(s)
Quimioterapia/tendencias , Inmunoconjugados/uso terapéutico , Terapia Molecular Dirigida/tendencias , Neoplasias/inmunología , Neoplasias/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Antineoplásicos , Humanos
14.
Hum Antibodies ; 26(2): 95-101, 2018 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-29036806

RESUMEN

Immunotherapy is now at the forefront of cancer therapeutic development. Gliomas are a particularly aggressive form of brain cancer for which immunotherapy may hold promise. Pritumumab (also known in the literature as CLNH11, CLN-IgG, and ACA-11) was the first monoclonal antibody tested in cancer patients. Pritumumab is a natural human monoclonal antibody developed from a B lymphocyte isolated from a regional draining lymph node of a patient with cervical carcinoma. The antibody binds ecto-domain vimentin on the surface of cancer cells. Pritumumab was originally tested in clinical trials with brain cancer patients in Japan where it demonstrated therapeutic benefit. It was reported to be a safe and effective therapy for brain cancer patients at doses 5-10 fold less than currently approved antibodies. Phase I dose escalation clinical trials are now being planned with pritumumab for the near future. Here we review data on the development and characterization of pritumumab, and review clinical trails data assessing immunotherapeutic effects of pritumumab for glioma patients.


Asunto(s)
Anticuerpos Monoclonales/aislamiento & purificación , Antineoplásicos Inmunológicos/aislamiento & purificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Inmunoglobulina G/aislamiento & purificación , Vimentina/inmunología , Animales , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/metabolismo , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos B/química , Linfocitos B/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Ensayos Clínicos como Asunto , Expresión Génica , Glioma/genética , Glioma/inmunología , Glioma/mortalidad , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/uso terapéutico , Inmunoterapia/métodos , Ratones , Análisis de Supervivencia , Vimentina/antagonistas & inhibidores , Vimentina/genética , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Immunotherapy ; 9(7): 589-606, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28595516

RESUMEN

The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.


Asunto(s)
Células Dendríticas/trasplante , Inmunoterapia Adoptiva/métodos , Linfocitos Infiltrantes de Tumor/trasplante , Neoplasias/terapia , Receptores de Esteroides/genética , Linfocitos T/trasplante , Animales , Células Dendríticas/inmunología , Terapia Genética , Humanos , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Interferencia de ARN , Proteínas Represoras , Linfocitos T/inmunología , Microambiente Tumoral
16.
Oncotarget ; 8(14): 22370-22384, 2017 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-26517684

RESUMEN

Transcription factors (TFs) are a major class of protein signaling molecules that play key cellular roles in cancers such as the highly lethal brain cancer-glioblastoma (GBM). However, the development of specific TF inhibitors has proved difficult owing to expansive protein-protein interfaces and the absence of hydrophobic pockets. We uniquely defined the dimerization surface as an expansive parental pharmacophore comprised of several regional daughter pharmacophores. We targeted the OLIG2 TF which is essential for GBM survival and growth, we hypothesized that small molecules able to fit each subpharmacophore would inhibit OLIG2 activation. The most active compound was OLIG2 selective, it entered the brain, and it exhibited potent anti-GBM activity in cell-based assays and in pre-clinical mouse orthotopic models. These data suggest that (1) our multiple pharmacophore approach warrants further investigation, and (2) our most potent compounds merit detailed pharmacodynamic, biophysical, and mechanistic characterization for potential preclinical development as GBM therapeutics.


Asunto(s)
Antineoplásicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Neoplasias Encefálicas/tratamiento farmacológico , Diseño de Fármacos , Glioblastoma/tratamiento farmacológico , Guanidinas/uso terapéutico , Terapia Molecular Dirigida , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Procesos de Crecimiento Celular , Supervivencia Celular/genética , Simulación por Computador , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Proteínas del Tejido Nervioso/química , Factor de Transcripción 2 de los Oligodendrocitos , Unión Proteica , Conformación Proteica , Bibliotecas de Moléculas Pequeñas , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Oncogene ; 23(21): 3781-9, 2004 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-15021911

RESUMEN

Sam68 (Src-associated in mitosis; 68 kDa) is a member of the STAR (signal transduction and activation of RNA) family of KH domain-containing RNA binding proteins. Accumulating evidence suggests that it plays an important role in cell cycle control. Tyrosine phosphorylation by Src family kinases and breast tumor kinase can negatively regulate its RNA binding activity. To date, there are no reports of a factor, such as a phosphatase, which can positively regulate Sam68 association with RNA. Acetylation is a reversible post-translational modification known to influence the activity of DNA binding proteins. However, acetylation of a cellular RNA binding protein as a mechanism for regulating its activity has not yet been reported. Here we demonstrate Sam68 to be acetylated in vivo. A screen of several human mammary epithelial cell lines revealed variations in Sam68 acetylation. Interestingly, the highest level of acetylation was found in tumorigenic breast cancer cell lines. The screen also showed a positive correlation between Sam68 acetylation and its ability to bind RNA. The acetyltransferase CBP was shown to acetylate Sam68 and enhance its binding to poly(U) RNA. These results suggest that Sam68 association with RNA substrates may be positively regulated by acetylation, and that enhanced acetylation and RNA binding activity of Sam68 may play a role in tumor cell proliferation.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Unión al ARN/metabolismo , ARN/metabolismo , Acetilación , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteína de Unión a CREB , Línea Celular Tumoral , Histona Desacetilasas/fisiología , Humanos , Ratones , Células 3T3 NIH , Proteínas Nucleares/fisiología , Transactivadores/fisiología
18.
Oncotarget ; 6(2): 1157-70, 2015 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-25528767

RESUMEN

Metabolic reprogramming is a key feature of tumorigenesis that is controlled by oncogenes. Enhanced utilization of glucose and glutamine are the best-established hallmarks of tumor metabolism. The oncogene c-Myc is one of the major players responsible for this metabolic alteration. However, the molecular mechanisms involved in Myc-induced metabolic reprogramming are not well defined. Here we identify p32, a mitochondrial protein known to play a role in the expression of mitochondrial respiratory chain complexes, as a critical player in Myc-induced glutamine addiction. We show that p32 is a direct transcriptional target of Myc and that high level of Myc in malignant brain cancers correlates with high expression of p32. Attenuation of p32 expression reduced growth rate of glioma cells expressing Myc and impaired tumor formation in vivo. Loss of p32 in glutamine addicted glioma cells induced resistance to glutamine deprivation and imparted sensitivity to glucose withdrawal. Finally, we provide evidence that p32 expression contributes to Myc-induced glutamine addiction of cancer cells. Our findings suggest that Myc promotes the expression of p32, which is required to maintain sufficient respiratory capacity to sustain glutamine metabolism in Myc transformed cells.


Asunto(s)
Neoplasias Encefálicas/genética , Proteínas Portadoras/genética , Glioma/genética , Glutamina/metabolismo , Proteínas Mitocondriales/genética , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proteínas Portadoras/metabolismo , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Glioma/patología , Humanos , Immunoblotting , Inmunohistoquímica , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Proteínas Mitocondriales/metabolismo , Modelos Genéticos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Int J Gynaecol Obstet ; 125(3): 237-40, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24680842

RESUMEN

OBJECTIVE: To determine the incidence of fetal brain injury by fetal brain magnetic resonance imaging (MRI) in pregnancies complicated with preterm labor (PL), preterm premature rupture of the membranes (PPROM), and intrauterine growth restriction (IUGR), and to compare fetal brain MRI with prenatal surveillance methods, and with immediate and long-term neurodevelopmental outcome. METHODS: Between February 2007 and January 2009, high-risk pregnancies were analyzed by MRI at 1.5 Tesla after 24 weeks of gestation at the Clinical Hospital Center Zagreb, Croatia. Long-term outcome was defined as neurodevelopmental outcome at 24 months. RESULTS: Among 70 pregnancies analyzed, 40.0% had abnormal fetal brain MRI. The highest incidence occurred in the PL group. There was no correlation between abnormal MRI and fetal surveillance methods (ultrasound, Doppler blood flow analysis, cardiotocography, biophysical profile) or immediate neonatal outcome (1-minute Apgar score, umbilical cord pH). Via MRI, fetal brain injury would have been diagnosed for 45.7% of fetuses with a long-term neurodevelopmental handicap. Binary logistic regression showed that, as compared with other surveillance methods, fetal brain MRI was the best predictor of long-term neurodevelopmental disability. CONCLUSION: PL, IUGR, and PPROM were associated with an early intrauterine CNS insult that was not accurately detected by existing prenatal testing options.


Asunto(s)
Lesiones Encefálicas/fisiopatología , Discapacidades del Desarrollo/diagnóstico , Imagen por Resonancia Magnética/métodos , Diagnóstico Prenatal/métodos , Lesiones Encefálicas/diagnóstico , Lesiones Encefálicas/epidemiología , Preescolar , Croacia , Discapacidades del Desarrollo/epidemiología , Femenino , Retardo del Crecimiento Fetal/fisiopatología , Rotura Prematura de Membranas Fetales/fisiopatología , Feto/fisiopatología , Humanos , Incidencia , Lactante , Recién Nacido , Modelos Logísticos , Trabajo de Parto Prematuro/fisiopatología , Embarazo , Embarazo de Alto Riesgo , Factores de Tiempo
20.
J Clin Invest ; 123(2): 548-51, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23298839

RESUMEN

RNA sequencing facilitates the discovery of novel gene fusions in cancer. In this issue of the JCI, Parker et al. identify an FGFR3-TACC3 fusion oncogene in glioblastoma and demonstrate a novel mechanism of pathogenicity. A miR-99a binding site within the 3'-untranslated region (3'-UTR) of FGFR3 is lost, releasing FGFR3 signaling from miR-99a-dependent inhibition and greatly enhancing tumor progression relative to WT FGFR3. These results provide compelling insight into the pathogenicity of a novel fusion oncogene and suggest new therapeutic approaches for a subset of glioblastomas.


Asunto(s)
Neoplasias Encefálicas/genética , Fusión Génica , Glioblastoma/genética , MicroARNs/genética , Proteínas Asociadas a Microtúbulos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Animales , Humanos , Masculino
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