Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Nat Cancer ; 5(6): 844-865, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38937652

RESUMEN

Epigenetic dysregulation is increasingly appreciated as a hallmark of cancer, including disease initiation, maintenance and therapy resistance. As a result, there have been advances in the development and evaluation of epigenetic therapies for cancer, revealing substantial promise but also challenges. Three epigenetic inhibitor classes are approved in the USA, and many more are currently undergoing clinical investigation. In this Review, we discuss recent developments for each epigenetic drug class and their implications for therapy, as well as highlight new insights into the role of epigenetics in cancer.


Asunto(s)
Epigénesis Genética , Epigenoma , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Epigénesis Genética/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Metilación de ADN/efectos de los fármacos , Inhibidores de Histona Desacetilasas/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Terapia Molecular Dirigida/métodos , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos
2.
Sci Adv ; 10(22): eadm9449, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38820154

RESUMEN

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional genomic screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We characterized the DNA recruitment sites of the SAGA complex in neuroblastoma and the consequences of loss of SAGA complex lysine acetyltransferase (KAT) activity on histone acetylation and gene expression. We demonstrate that loss of SAGA complex KAT activity is associated with reduced MYCN binding on chromatin, suppression of MYC/MYCN gene expression programs, and impaired cell cycle progression. Further, we showed that the SAGA complex is pharmacologically targetable in vitro and in vivo with a KAT2A/KAT2B proteolysis targeting chimeric. Our findings expand our understanding of the histone-modifying complexes that maintain the oncogenic transcriptional state in this disease and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Lisina Acetiltransferasas , Proteína Proto-Oncogénica N-Myc , Neuroblastoma , Transactivadores , Animales , Humanos , Ratones , Acetilación , Línea Celular Tumoral , Cromatina/metabolismo , Cromatina/genética , Amplificación de Genes , Histona Acetiltransferasas/metabolismo , Histona Acetiltransferasas/genética , Histonas/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología , Lisina Acetiltransferasas/genética , Lisina Acetiltransferasas/metabolismo , Transactivadores/genética , Transactivadores/metabolismo
3.
Cancer Res ; 83(2): 285-300, 2023 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-36398965

RESUMEN

Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single-agent MEK inhibitors is common, however, and combination therapies are typically required to achieve significant clinical benefit in advanced cancers. Here we focused on identifying MEK inhibitor-based combination therapies in neuroblastoma with mutations that activate the RAS/MAPK signaling pathway, which are rare at diagnosis but frequent in relapsed neuroblastoma. A genome-scale CRISPR-Cas9 functional genomic screen was deployed to identify genes that when knocked out sensitize RAS-mutant neuroblastoma to MEK inhibition. Loss of either CCNC or CDK8, two members of the mediator kinase module, sensitized neuroblastoma to MEK inhibition. Furthermore, small-molecule kinase inhibitors of CDK8 improved response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors. Transcriptional profiling revealed that loss of CDK8 or CCNC antagonized the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevented the compensatory upregulation of progrowth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies. SIGNIFICANCE: Transcriptional adaptation to MEK inhibition is mediated by CDK8 and can be blocked by the addition of CDK8 inhibitors to improve response to MEK inhibitors in RAS-mutant neuroblastoma, a clinically challenging disease.


Asunto(s)
Recurrencia Local de Neoplasia , Neuroblastoma , Adulto , Humanos , Línea Celular Tumoral , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Neuroblastoma/patología , Mutación , Quinasas de Proteína Quinasa Activadas por Mitógenos , Quinasa 8 Dependiente de Ciclina/genética
4.
Nat Cell Biol ; 25(2): 285-297, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36658220

RESUMEN

Transcription factors (TFs) are frequently mutated in cancer. Paediatric cancers exhibit few mutations genome-wide but frequently harbour sentinel mutations that affect TFs, which provides a context to precisely study the transcriptional circuits that support mutant TF-driven oncogenesis. A broadly relevant mechanism that has garnered intense focus involves the ability of mutant TFs to hijack wild-type lineage-specific TFs in self-reinforcing transcriptional circuits. However, it is not known whether this specific type of circuitry is equally crucial in all mutant TF-driven cancers. Here we describe an alternative yet central transcriptional mechanism that promotes Ewing sarcoma, wherein constraint, rather than reinforcement, of the activity of the fusion TF EWS-FLI supports cancer growth. We discover that ETV6 is a crucial TF dependency that is specific to this disease because it, counter-intuitively, represses the transcriptional output of EWS-FLI. This work discovers a previously undescribed transcriptional mechanism that promotes cancer.


Asunto(s)
Sarcoma de Ewing , Niño , Humanos , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , Sarcoma de Ewing/genética
5.
Mol Pharm ; 9(8): 2237-47, 2012 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-22738427

RESUMEN

Polyvinylpyrrolidone is widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant, whereas the cross-linked form is a superdisintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties that have then been polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in the most common solvents and in water, properties that suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly water-soluble drug. The results show that the novel PVPs induce the drug to become "X-ray amorphous", which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks of storage.


Asunto(s)
Portadores de Fármacos/química , Povidona/química , Agua/química , Enlace de Hidrógeno , Ibuprofeno/química , Solubilidad
6.
J Peripher Nerv Syst ; 17(1): 76-89, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22462669

RESUMEN

Peripheral neuropathy is a common side effect of a number of pharmaceutical compounds, including several chemotherapy drugs. Among these are vincristine sulfate, a mitotic inhibitor used to treat a variety of leukemias, lymphomas, and other cancers, and bortezomib, a 26S proteasome inhibitor used primarily to treat relapsed multiple myeloma and mantle cell lymphoma. To gain insight into the mechanisms by which these compounds act, we tested their effects in zebrafish. Vincristine or bortezomib given during late embryonic development caused significant defects at both behavioral and cellular levels. Intriguingly, the effects of the two drugs appear to be distinct. Vincristine causes uncoordinated swimming behavior, which is coupled with a reduction in the density of sensory innervation and overall size of motor axon arbors. Bortezomib, in contrast, increases the duration and amplitude of muscle contractions associated with escape swimming, which is coupled with a preferential reduction in fine processes and branches of sensory and motor axons. These results demonstrate that zebrafish is a convenient in vivo assay system for screening potential pharmaceutical compounds for neurotoxic side effects, and they provide an important step toward understanding how vincristine and bortezomib cause peripheral neuropathy.


Asunto(s)
Antineoplásicos/efectos adversos , Axones/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Ácidos Borónicos/efectos adversos , Pirazinas/efectos adversos , Vincristina/efectos adversos , Animales , Axones/patología , Bortezomib , Inmunohistoquímica , Larva/efectos de los fármacos , Pez Cebra
7.
Cancer Discov ; 11(9): 2282-2299, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33883167

RESUMEN

Cancer dependency maps, which use CRISPR/Cas9 depletion screens to profile the landscape of genetic dependencies in hundreds of cancer cell lines, have identified context-specific dependencies that could be therapeutically exploited. An ideal therapy is both lethal and precise, but these depletion screens cannot readily distinguish between gene effects that are cytostatic or cytotoxic. Here, we use a diverse panel of functional genomic screening assays to identify NXT1 as a selective and rapidly lethal in vivo relevant genetic dependency in MYCN-amplified neuroblastoma. NXT1 heterodimerizes with NXF1, and together they form the principal mRNA nuclear export machinery. We describe a previously unrecognized mechanism of synthetic lethality between NXT1 and its paralog NXT2: their common essential binding partner NXF1 is lost only in the absence of both. We propose a potential therapeutic strategy for tumor-selective elimination of a protein that, if targeted directly, is expected to cause widespread toxicity. SIGNIFICANCE: We provide a framework for identifying new therapeutic targets from functional genomic screens. We nominate NXT1 as a selective lethal target in neuroblastoma and propose a therapeutic approach where the essential protein NXF1 can be selectively eliminated in tumor cells by exploiting the NXT1-NXT2 paralog relationship.See related commentary by Wang and Abdel-Wahab, p. 2129.This article is highlighted in the In This Issue feature, p. 2113.


Asunto(s)
Neoplasias/tratamiento farmacológico , Proteínas de Transporte Nucleocitoplasmático/genética , Línea Celular Tumoral , Humanos , Neoplasias/genética
8.
Nat Genet ; 53(4): 529-538, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33753930

RESUMEN

Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR-Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.


Asunto(s)
Mapeo Cromosómico/métodos , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Mutación , Proteínas de Neoplasias/genética , Neoplasias/genética , Adulto , Proteína 9 Asociada a CRISPR/genética , Proteína 9 Asociada a CRISPR/metabolismo , Sistemas CRISPR-Cas , Línea Celular Tumoral , Niño , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Edición Génica , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Proteínas de Neoplasias/clasificación , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , ARN Guía de Kinetoplastida/genética , ARN Guía de Kinetoplastida/metabolismo
9.
Cancer Cell ; 32(3): 271-273, 2017 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-28898689

RESUMEN

In this issue of Cancer Cell, Bosse et al. report GPC2 as a therapeutic target in neuroblastoma. They show that GPC2 is selectively expressed on the cell surface of neuroblastoma and is a dependency in this disease. Moreover, they demonstrate the therapeutic potential of an antibody-drug conjugate targeting GPC2.


Asunto(s)
Línea Celular Tumoral , Neuroblastoma , Humanos
10.
Cancer Discov ; 7(12): 1450-1463, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28963352

RESUMEN

Although agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here, we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin antioxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating apoptosis signal-regulating kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non-small cell lung cancers. Together, these studies identify a promising therapeutic combination for several currently untreatable malignancies and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.Significance: There are no effective therapies for NF1- or RAS-mutant cancers. We show that combined mTOR/HDAC inhibitors kill these RAS-driven tumors by causing catastrophic oxidative stress. This study identifies a promising therapeutic combination and demonstrates that selective enhancement of oxidative stress may be more broadly exploited for developing cancer therapies. Cancer Discov; 7(12); 1450-63. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.


Asunto(s)
Proteínas Portadoras/genética , Inhibidores de Histona Desacetilasas/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Portadoras/metabolismo , Humanos , Estrés Oxidativo , Transducción de Señal
11.
Cancer Discov ; 4(9): 1062-73, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24913553

RESUMEN

UNLABELLED: NF1 encodes a RAS GTPase-activating protein. Accordingly, aberrant RAS activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which RAS pathway components represent optimal therapeutic targets. Here, we identify mTORC1 as the key PI3K effector in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. However, we find that tumor regression requires sustained inhibition of both mTORC1 and MEK. Transcriptional profiling studies were therefore used to establish a signature of effective mTORC1-MEK inhibition in vivo. We unexpectedly found that the glucose transporter GLUT1 was potently suppressed, but only when both pathways were inhibited. Moreover, unlike VHL- and LKB1-mutant cancers, reduction of (18)F-FDG uptake required the suppression of both mTORC1 and MEK. Together, these studies identify optimal and suboptimal therapeutic targets in NF1-mutant malignancies and define a noninvasive means of measuring combined mTORC1-MEK inhibition in vivo, which can be readily incorporated into clinical trials. SIGNIFICANCE: This work demonstrates that mTORC1 and MEK are key therapeutic targets in NF1-mutant cancers and establishes a noninvasive biomarker of effective, combined target inhibition that can be evaluated in clinical trials.


Asunto(s)
Neoplasias/genética , Neoplasias/metabolismo , Neurofibromina 1/genética , Transducción de Señal , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Terapia Molecular Dirigida , Complejos Multiproteicos/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias de Tejido Nervioso/diagnóstico , Neoplasias de Tejido Nervioso/tratamiento farmacológico , Neoplasias de Tejido Nervioso/genética , Neoplasias de Tejido Nervioso/metabolismo , Neoplasias de la Vaina del Nervio/diagnóstico , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/metabolismo , Neurofibromina 1/metabolismo , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
12.
Cancer Cell ; 20(3): 400-13, 2011 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-21907929

RESUMEN

Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1-deficient malignancies and Kras/p53 mutant lung cancer. We show that agents that enhance proteotoxic stress, including the HSP90 inhibitor IPI-504, induce tumor regression in aggressive mouse models, but only when combined with rapamycin. These agents synergize by promoting irresolvable ER stress, resulting in catastrophic ER and mitochondrial damage. This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations.


Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzoquinonas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Lactamas Macrocíclicas/farmacología , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Sirolimus/farmacología , Proteínas ras/metabolismo , Animales , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Glutatión/antagonistas & inhibidores , Glutatión/biosíntesis , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Etiquetado Corte-Fin in Situ , Ratones , Mitocondrias/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias de la Vaina del Nervio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismo , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA