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2.
Can J Neurol Sci ; 46(4): 403-414, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31293232

RESUMEN

INTRODUCTION: Children diagnosed with medulloblastoma (MB) who are refractory to upfront therapy or experience recurrence have very poor prognoses. Although phase I and phase II trials exist, these treatments bear significant treatment-related morbidity and mortality. METHODS: A retrospective review of children diagnosed with a recurrence of MB from 2002 to 2015 at McMaster University was undertaken. RESULTS: Recurrent disease in 10 patients involved leptomeningeal dissemination, with 3 experiencing local recurrence. In three recurrent patients the disease significantly progressed, and the children were palliated. The remaining 10 children underwent some form of salvage therapy, including surgical re-resection, radiation, and chemotherapy, either in isolation or in varying combinations. Of the 13 children experiencing treatment-refractory or recurrent disease, 4 are currently alive with a median follow-up of 38.5 months (75.5 months). Of the eight patients with molecular subgrouping data, none of the Wnt MB experienced recurrence. CONCLUSION: Recurrent MB carried a poor prognosis with a 5-year overall survival (OS) of 18.2% despite the administration of salvage therapy. The upfront therapy received, available treatment, and tolerability of the proposed salvage therapy resulted in significant heterogeneity in the treatment of our recurrent cohort.

3.
J Neurooncol ; 143(3): 417-428, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31115870

RESUMEN

PURPOSE: Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BMI1 in our patient-derived GBM BTICs and its relationship with CD133, a well-established marker of BTICs. METHODS: Using gain and loss-of-function studies for Bmi1 in neural stem cells (NSCs) and patient-derived GBM BTICs respectively, we assessed in vitro self-renewal and in vivo tumor formation in these two cell populations. We further explored the BMI1 transcriptional regulatory network through RNA sequencing of different GBM BTIC populations that were knocked down for Bmi1. RESULTS: There is a differential role of BMI1 in CD133-positive cells, notably involving cell metabolism. In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties. CONCLUSIONS: Our work sheds light on the association of three genes with CD133-BMI1 circuitry, their importance as downstream effectors of the BMI1 signalling pathway, and their potential as future targets for tackling GBM treatment-resistant cell populations.


Asunto(s)
Antígeno AC133/metabolismo , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Glioblastoma/patología , Células Madre Neoplásicas/patología , Complejo Represivo Polycomb 1/metabolismo , Antígeno AC133/genética , Animales , Apoptosis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferación Celular , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Med Chem ; 62(5): 2651-2665, 2019 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-30776234

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing.

5.
Oncogene ; 38(10): 1702-1716, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30348991

RESUMEN

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.


Asunto(s)
Neoplasias Cerebelosas/tratamiento farmacológico , Meduloblastoma/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Complejo Represivo Polycomb 1/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Niño , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Resultado del Tratamiento , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Methods Mol Biol ; 1869: 1-9, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30324509

RESUMEN

From stem cells, to the cancer stem cell hypothesis and intratumoral heterogeneity, the following introductory chapter on brain tumor stem cells explores the history of normal and cancerous stem cells, and their implication in the current model of brain tumor development. The origins of stem cells date back to the 1960s, when they were first described as cells capable of self-renewal, extensive proliferation, and differentiation. Since then, many advances have been made and adult stem cells are now known to be present in a very wide variety of tissues. Neural stem cells were subsequently discovered 30 years later, which was shortly followed by the discovery of cancer stem cells in leukemia and in brain tumors over the next decade, effectively enabling a new understanding of cancer. Since then, many markers including CD133, brain cancer stem cells have been implicated in a variety of phenomena including intratumoral heterogeneity on the genomic, cellular, and functional levels, tumor initiation, chemotherapy-resistance, radiation-resistance, and are believed to be ultimately responsible for tumor relapse. Understanding this small and rare population of cells could be the key to solving the great enigma that is cancer.


Asunto(s)
Neoplasias Encefálicas/patología , Células Madre Neoplásicas/patología , Animales , Humanos , Células-Madre Neurales/patología
7.
Methods Mol Biol ; 1869: 79-84, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30324515

RESUMEN

Early development of human organisms relies on stem cells, a population of non-specialized cells that can divide symmetrically to give rise to two identical daughter cells, or divide asymmetrically to produce one identical daughter cell and another more specialized cell. The capacity to undergo cellular divisions while maintaining an undifferentiated state is termed self-renewal and is responsible for the maintenance of stem cell populations during development. In addition, self-renewal plays a crucial role in the homeostasis of developed organism through replacement of defective cells.Similar to their non-malignant counterparts, it has been postulated that tumor cells follow a differentiation hierarchy, with the least differentiated cells termed cancer stem cells (CSCs) at the apex. These tumor stem cells possess the ability to self-renew, have a higher capacity to initiate tumor growth when xenografted into an animal model, and can recapitulate the cell heterogeneity of the tumor they originate from. Hence, further investigation of mechanisms governing the self-renewal in cancer can lead to development of novel therapies targeting CSCs.In this chapter, we described the soft agar assay and the limiting dilution assay (LDA) as two easy-to-implement and inexpensive assays to measure the stemness properties of brain tumor stem cells (BTSCs). These techniques constitute useful tools for the preclinical evaluation of therapeutic strategies targeting BTSCs clonogenicity.


Asunto(s)
Bioensayo/métodos , Neoplasias Encefálicas/patología , Autorrenovación de las Células , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Humanos , Análisis de Regresión
8.
Methods Mol Biol ; 1869: 189-196, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30324524

RESUMEN

Traditionally anti-cancer therapeutics have been designed to target rapidly proliferating cells causing DNA damage and inducing apoptosis. However, with the development of the cancer stem cell (CSC) hypothesis, it has been postulated that a rare, slow dividing tumor cell population is able to escape therapy and contribute to tumor relapse and metastasis. The advances in characterization of CSCs across multiple cancer subtypes have allowed for development of targeted therapies using small molecule inhibitors. In this chapter, we describe two in vitro assays measuring proliferation and secondary sphere formation, which have become gold-standard assays to evaluate the effects of targeted therapies against CSCs. Together these assays constitute a rapid, inexpensive, and highly reproducible pipeline for testing small molecule inhibitors prior to more resource demanding in vivo studies.


Asunto(s)
Bioensayo/métodos , Bibliotecas de Moléculas Pequeñas/análisis , Línea Celular , Proliferación Celular , Autorrenovación de las Células , Humanos , Concentración 50 Inhibidora , Suspensiones
9.
Cancer Res ; 78(17): 5124-5134, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-29986997

RESUMEN

Brain metastases (BM) result from the spread of primary tumors to the brain and are a leading cause of cancer mortality in adults. Secondary tissue colonization remains the main bottleneck in metastatic development, yet this "premetastatic" stage of the metastatic cascade, when primary tumor cells cross the blood-brain barrier and seed the brain before initiating a secondary tumor, remains poorly characterized. Current studies rely on specimens from fully developed macrometastases to identify therapeutic options in cancer treatment, overlooking the potentially more treatable "premetastatic" phase when colonizing cancer cells could be targeted before they initiate the secondary brain tumor. Here we use our established brain metastasis initiating cell (BMIC) models and gene expression analyses to characterize premetastasis in human lung-to-BM. Premetastatic BMIC engaged invasive and epithelial developmental mechanisms while simultaneously impeding proliferation and apoptosis. We identified the dopamine agonist apomorphine to be a potential premetastasis-targeting drug. In vivo treatment with apomorphine prevented BM formation, potentially by targeting premetastasis-associated genes KIF16B, SEPW1, and TESK2 Low expression of these genes was associated with poor survival of patients with lung adenocarcinoma. These results illuminate the cellular and molecular dynamics of premetastasis, which is subclinical and currently impossible to identify or interrogate in human patients with BM. These data present several novel therapeutic targets and associated pathways to prevent BM initiation.Significance: These findings unveil molecular features of the premetastatic stage of lung-to-brain metastases and offer a potential therapeutic strategy to prevent brain metastases. Cancer Res; 78(17); 5124-34. ©2018 AACR.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Metástasis de la Neoplasia/tratamiento farmacológico , Apomorfina/farmacología , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Cinesina/genética , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Proteínas Serina-Treonina Quinasas/genética , Selenoproteína W/genética
10.
Oncoimmunology ; 7(7): e1445459, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29900060

RESUMEN

Prostate cancer (PCa) was estimated to have the second highest global incidence rate for male non-skin tumors and is the fifth most deadly in men thus mandating the need for novel treatment options. MG1-Maraba is a potent and versatile oncolytic virus capable of lethally infecting a variety of prostatic tumor cell lines alongside primary PCa biopsies and exerts direct oncolytic effects against large TRAMP-C2 tumors in vivo. An oncolytic immunotherapeutic strategy utilizing a priming vaccine and intravenously administered MG1-Maraba both expressing the human six-transmembrane antigen of the prostate (STEAP) protein generated specific CD8+ T-cell responses against multiple STEAP epitopes and resulted in functional breach of tolerance. Treatment of mice with bulky TRAMP-C2 tumors using oncolytic STEAP immunotherapy induced an overt delay in tumor progression, marked intratumoral lymphocytic infiltration with an active transcriptional profile and up-regulation of MHC class I. The preclinical data generated here offers clear rationale for clinically evaluating this approach for men with advanced PCa.

11.
Methods Mol Biol ; 1692: 1-16, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-28986882

RESUMEN

The Cancer Stem Cell (CSC) hypothesis postulates the existence of a small population of cancer cells with intrinsic properties allowing for resistance to conventional radiochemotherapy regiments and increased metastatic potential. Clinically, the aggressive nature of CSCs has been shown to correlate with increased tumor recurrence, metastatic spread, and overall poor patient outcome across multiple cancer subtypes. Traditionally, isolation of CSCs has been achieved through utilization of cell surface markers, while the functional differences between CSCs and remaining tumor cells have been described through proliferation, differentiation, and limiting dilution assays. The generated insights into CSC biology have further highlighted the importance of studying intratumoral heterogeneity through advanced functional assays, including CRISPR-Cas9 screens in the search of novel targeted therapies. In this chapter, we review the discovery and characterization of cancer stem cells populations within several major cancer subtypes, recent developments of novel assays used in studying therapy resistant tumor cells, as well as recent developments in therapies targeted at cancer stem cells.


Asunto(s)
Células Madre Neoplásicas/metabolismo , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Humanos , Inmunoterapia/métodos , Leucemia/terapia
13.
Front Oncol ; 7: 220, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28971065

RESUMEN

Metastasis is the dissemination of cells from the primary tumor to other locations within the body, and continues to be the predominant cause of death among cancer patients. Metastatic progression within the adult central nervous system is 10 times more frequent than primary brain tumors. Metastases affecting the brain parenchyma and leptomeninges are associated with grave prognosis, and even after successful control of the primary tumor the median survival is a dismal 2-3 months with treatment options typically limited to palliative care. Current treatment options for brain metastases (BM) and disseminated brain tumors are scarce, and the improvement of novel targeted therapies requires a broader understanding of the biological complexity that characterizes metastatic progression. In this review, we provide insight into patterns of BM progression and leptomeningeal spread, outlining the development of clinically relevant in vivo models and their contribution to the discovery of innovative cancer therapies. In vivo models paired with manipulation of in vitro methods have expanded the tools available for investigators to develop agents that can be used to prevent or treat metastatic disease. The knowledge gained from the use of such models can ultimately lead to the prevention of metastatic dissemination and can extend patient survival by transforming a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

14.
Acta Neuropathol ; 134(6): 923-940, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28766011

RESUMEN

Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-ß ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias Encefálicas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Estudios Prospectivos , Proteoglicanos/genética , Proteoglicanos/metabolismo , Interferencia de ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo
15.
Virology ; 486: 54-62, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26402375

RESUMEN

Tobacco necrosis virus (TNV-D) has a plus-strand RNA genome that is neither 5' capped nor 3' poly-adenylated. Instead, it utilizes a 3' cap-independent translational enhancer (3'CITE) located in its 3' untranslated region (UTR) for translation of its proteins. We have examined the protein expression strategies used by TNV-D and our results indicate that: (i) a base pairing interaction between conserved ACCA and UGGU motifs in the genomic 5'UTR and 3'CITE, respectively, is not required for efficient plant cell infection, (ii) similar potential 5'UTR-3'CITE interactions in the two viral subgenomic mRNAs are not needed for efficient translation of viral proteins in vitro, (iii) a small amount of capsid protein is translated from the viral genome by a largely 3'CITE-independent mechanism, (iv) the larger of two possible forms of capsid protein is efficiently translated, and (v) p7b is translated from subgenomic mRNA1 by a leaky scanning mechanism.


Asunto(s)
Regulación Viral de la Expresión Génica , Tombusviridae/genética , Proteínas Virales/genética , Regiones no Traducidas 5' , Secuencia de Bases , Cucumis sativus/virología , Genoma Viral , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Enfermedades de las Plantas/virología , Biosíntesis de Proteínas , ARN Viral/química , ARN Viral/genética , ARN Viral/metabolismo , Tombusviridae/química , Tombusviridae/metabolismo , Proteínas Virales/química , Proteínas Virales/metabolismo
16.
Oncotarget ; 6(29): 27461-77, 2015 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-26314961

RESUMEN

Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases.


Asunto(s)
Neoplasias Encefálicas/secundario , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Genes Reguladores , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Trasplante de Neoplasias , Mapeo de Interacción de Proteínas , Proteómica , ARN Interferente Pequeño/metabolismo , Células Madre/citología
17.
Clin Cancer Res ; 21(23): 5324-37, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26152745

RESUMEN

PURPOSE: Clonal evolution of cancer may be regulated by determinants of stemness, specifically self-renewal, and current therapies have not considered how genetic perturbations or properties of stemness affect such functional processes. Glioblastoma-initiating cells (GICs), identified by expression of the cell surface marker CD133, are shown to be chemoradioresistant. In the current study, we sought to elucidate the functional role of CD133 in self-renewal and identify compounds that can specifically target this CD133(+) treatment-refractory population. EXPERIMENTAL DESIGN: Using gain/loss-of-function studies for CD133 we assessed the in vitro self-renewal and in vivo tumor formation capabilities of patient-derived glioblastoma cells. We generated a CD133 signature combined with an in silico screen to find compounds that target GICs. Self-renewal and proliferation assays on CD133-sorted samples were performed to identify the preferential action of hit compounds. In vivo efficacy of the lead compound pyrvinium was assessed in intracranial GIC xenografts and survival studies. Lastly, microarray analysis was performed on pyrvinium-treated GICs to discover core signaling events involved. RESULTS: We discovered pyrvinium, a small-molecule inhibitor of GIC self-renewal in vitro and in vivo, in part through inhibition of Wnt/ß-catenin signaling and other essential stem cell regulatory pathways. We provide a therapeutically tractable strategy to target self-renewing, chemoradioresistant, and functionally important CD133(+) stem cells that drive glioblastoma relapse and mortality. CONCLUSIONS: Our study provides an integrated approach for the eradication of clonal populations responsible for cancer progression, and may apply to other aggressive and heterogeneous cancers.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Glicoproteínas/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Péptidos/antagonistas & inhibidores , Compuestos de Pirvinio/farmacología , Antígeno AC133 , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Proliferación Celular , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/genética , Modelos Animales de Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Redes Reguladoras de Genes , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/mortalidad , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Péptidos/genética , Péptidos/metabolismo , Pronóstico , Transducción de Señal/efectos de los fármacos , Esferoides Celulares , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Stem Cells Int ; 2015: 141793, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26064134

RESUMEN

CNS tumours occur in both pediatric and adult patients and many of these tumours are associated with poor clinical outcome. Due to a paradigm shift in thinking for the last several years, these tumours are now considered to originate from a small population of stem-like cells within the bulk tumour tissue. These cells, termed as brain tumour initiating cells (BTICs), are perceived to be regulated by microRNAs at the posttranscriptional/translational levels. Proliferation, stemness, differentiation, invasion, angiogenesis, metastasis, apoptosis, and cell cycle constitute some of the significant processes modulated by microRNAs in cancer initiation and progression. Characterization and functional studies on oncogenic or tumour suppressive microRNAs are made possible because of developments in sequencing and microarray techniques. In the current review, we bring recent knowledge of the role of microRNAs in BTIC formation and therapy. Special attention is paid to two highly aggressive and well-characterized brain tumours: gliomas and medulloblastoma. As microRNA seems to be altered in the pathogenesis of many human diseases, "microRNA therapy" may now have potential to improve outcomes for brain tumour patients. In this rapidly evolving field, further understanding of miRNA biology and its contribution towards cancer can be mined for new therapeutic tools.

19.
Adv Exp Med Biol ; 853: 49-68, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25895707

RESUMEN

Representing the leading cause of childhood cancer mortality, pediatric brain tumors are comprised of diverse histological features, genetic perturbations, cellular populations, treatment protocols, and clinical outcomes. In this chapter we discuss recent and emerging data that implicate cancer stem cells (also known as brain tumor-initiating cells) in initiating and maintaining the growth of a number of pediatric brain tumors including: medulloblastoma, supratentorial primitive neuroectodermal tumor, atypical teratoid/rhabdoid tumor, ependymoma, low-grade glioma, glioblastoma, diffuse intrinsic pontine glioma, germ cell tumor, and craniopharyngioma. The development of a stem cell framework for the study and treatment of these tumors will enable future clinical approaches to harness the heterogeneous cellular and genomic landscape of these solid tumors as an avenue for developing targeted patient-oriented therapies, thereby improving the overall survivorship for the most lethal childhood cancer.


Asunto(s)
Neoplasias del Sistema Nervioso Central/patología , Células Madre Neoplásicas/fisiología , Células-Madre Neurales/fisiología , Neoplasias del Sistema Nervioso Central/clasificación , Niño , Ependimoma/patología , Glioblastoma/patología , Glioma/patología , Humanos , Meduloblastoma/patología , Tumores Neuroectodérmicos/patología , Tumor Rabdoide/patología , Teratoma/patología
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