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1.
Genes Dev ; 36(5-6): 368-389, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35301220

RESUMEN

Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.


Asunto(s)
Leucemia Mieloide Aguda , Proteína de la Leucemia Mieloide-Linfoide , Reordenamiento Génico , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Oncogenes/genética
2.
Genes Dev ; 35(7-8): 556-572, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33766983

RESUMEN

Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why ∼50% of Ewing sarcomas, driven by the EWS-FLI1 fusion oncogene, harbor chromosome 8 gains. Expression of the EWS-FLI1 fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates EWS-FLI1-induced replication stress through gain of a copy of RAD21. Low-level ectopic expression of RAD21 is sufficient to dampen replication stress and improve proliferation in EWS-FLI1-expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that RAD21 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.


Asunto(s)
Carcinogénesis/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Sarcoma de Ewing/genética , Estrés Fisiológico/genética , Trisomía/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Cromosomas Humanos Par 8/genética , Replicación del ADN/genética , Proteínas de Unión al ADN/genética , Duplicación de Gen/genética , Regulación Neoplásica de la Expresión Génica , Humanos
3.
Blood ; 142(24): 2079-2091, 2023 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-37595362

RESUMEN

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.


Asunto(s)
Daño del ADN , Proteína p53 Supresora de Tumor , Adulto , Humanos , Animales , Ratones , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína Fosfatasa 2C , Mutación , Monoéster Fosfórico Hidrolasas/genética , Ciclo Celular
4.
Nat Chem Biol ; 19(7): 815-824, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36823351

RESUMEN

Creatine kinases (CKs) provide local ATP production in periods of elevated energetic demand, such as during rapid anabolism and growth. Thus, creatine energetics has emerged as a major metabolic liability in many rapidly proliferating cancers. Whether CKs can be targeted therapeutically is unknown because no potent or selective CK inhibitors have been developed. Here we leverage an active site cysteine present in all CK isoforms to develop a selective covalent inhibitor of creatine phosphagen energetics, CKi. Using deep chemoproteomics, we discover that CKi selectively engages the active site cysteine of CKs in cells. A co-crystal structure of CKi with creatine kinase B indicates active site inhibition that prevents bidirectional phosphotransfer. In cells, CKi and its analogs rapidly and selectively deplete creatine phosphate, and drive toxicity selectively in CK-dependent acute myeloid leukemia. Finally, we use CKi to uncover an essential role for CKs in the regulation of proinflammatory cytokine production in macrophages.


Asunto(s)
Creatina Quinasa , Creatina , Creatina Quinasa/química , Creatina Quinasa/metabolismo , Creatina/farmacología , Cisteína , Fosfotransferasas , Isoformas de Proteínas
5.
Blood ; 139(4): 538-553, 2022 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-34624079

RESUMEN

Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/metabolismo , Glicina Hidroximetiltransferasa/antagonistas & inhibidores , Glicina Hidroximetiltransferasa/metabolismo , Animales , Linfoma de Burkitt/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Descubrimiento de Drogas , Formiatos/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glicina/metabolismo , Glicina Hidroximetiltransferasa/genética , Humanos , Ratones , Terapia Molecular Dirigida , Proteolisis/efectos de los fármacos
6.
Nature ; 555(7696): 387-391, 2018 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-29513652

RESUMEN

Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 and the elongating transcription machinery. Finally, we uncover a role for EWSR1 in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Our findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors) and highlight a class of BRCA-deficient-like tumours.


Asunto(s)
Proteína BRCA1/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Conformación de Ácido Nucleico , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Reparación del ADN por Recombinación , Sarcoma de Ewing/genética , Transcripción Genética , Proteína BRCA1/metabolismo , Línea Celular Tumoral , Daño del ADN , Humanos , Proteínas de Fusión Oncogénica/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteína EWS de Unión a ARN/genética , Sarcoma de Ewing/metabolismo
7.
Nature ; 559(7715): E11, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29950716

RESUMEN

In this Letter, the sentence beginning "This work was funded…." in the Acknowledgements should have read "CPRIT (RP140105) to J.C.R." rather than "CPRIT (RP150445) to J.C.R." This error has been corrected online.

8.
Br J Cancer ; 127(12): 2220-2226, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36221002

RESUMEN

BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with no validated molecular biomarkers. We aimed to determine the frequency of STAG2 protein loss by immunohistochemistry (IHC) and whether loss of expression is associated with outcome. METHODS: We performed a retrospective cohort study of patients with EWS enrolled to Children's Oncology Group studies. We obtained unstained slides from 235 patients and DNA for sequencing from 75 patients. STAG2 expression was tested for association with clinical features and survival was estimated using Kaplan-Meier methods with log-rank tests. RESULTS: In total, 155 cases passed quality control for STAG2 IHC. STAG2 expression in 20/155 cases could not be categorised with the limited available tissue, leaving 135 patients with definitive STAG2 IHC. In localised and metastatic disease, STAG2 was lost in 29/108 and 6/27 cases, respectively. Among patients with IHC and sequencing, 0/17 STAG2 expressing cases had STAG2 mutations, and 2/7 cases with STAG2 loss had STAG2 mutations. Among patients with localised disease, 5-year event-free survival was 54% (95% CI 34-70%) and 75% (95% CI 63-84%) for patients with STAG2 loss vs. expression (P = 0.0034). CONCLUSION: STAG2 loss of expression is identified in a population of patients without identifiable STAG2 mutations and carries a poor prognosis.


Asunto(s)
Sarcoma de Ewing , Niño , Humanos , Pronóstico , Sarcoma de Ewing/genética , Estudios Retrospectivos , Proteínas de Ciclo Celular
9.
Blood ; 135(1): 56-70, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31697837

RESUMEN

Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a salt-inducible kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF myocyte enhancer factor (MEF2C). In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. In this study, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitro and in vivo conditions. Similar phenotypes were obtained when cells were exposed to YKL-05-099, which caused cell-cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele of SIK3, we found that the antiproliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated 2 different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progression in vivo and extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-addicted AML and provide a rationale for developing druglike inhibitors of SIK3 for definitive preclinical investigation and for studies in human patients.


Asunto(s)
Compuestos de Anilina/farmacología , Leucemia Mieloide Aguda/prevención & control , Factores de Transcripción MEF2/metabolismo , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Pirimidinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Apoptosis , Ciclo Celular , Proliferación Celular , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Factores de Transcripción MEF2/genética , Ratones , Ratones Endogámicos C57BL , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Nucleic Acids Res ; 47(18): 9619-9636, 2019 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-31392992

RESUMEN

Connections between epigenetic reprogramming and transcription or splicing create novel mechanistic networks that can be targeted with tailored therapies. Multiple subunits of the chromatin remodeling BAF complex, including ARID1A, play a role in oncogenesis, either as tumor suppressors or oncogenes. Recent work demonstrated that EWS-FLI1, the oncogenic driver of Ewing sarcoma (ES), plays a role in chromatin regulation through interactions with the BAF complex. However, the specific BAF subunits that interact with EWS-FLI1 and the precise role of the BAF complex in ES oncogenesis remain unknown. In addition to regulating transcription, EWS-FLI1 also alters the splicing of many mRNA isoforms, but the role of splicing modulation in ES oncogenesis is not well understood. We have identified a direct connection between the EWS-FLI1 protein and ARID1A isoform protein variant ARID1A-L. We demonstrate here that ARID1A-L is critical for ES maintenance and supports oncogenic transformation. We further report a novel feed-forward cycle in which EWS-FLI1 leads to preferential splicing of ARID1A-L, promoting ES growth, and ARID1A-L reciprocally promotes EWS-FLI1 protein stability. Dissecting this interaction may lead to improved cancer-specific drug targeting.


Asunto(s)
Carcinogénesis/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteína EWS de Unión a ARN/genética , Sarcoma de Ewing/genética , Factores de Transcripción/genética , Empalme Alternativo/genética , Línea Celular Tumoral , Ensamble y Desensamble de Cromatina/genética , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Epigénesis Genética/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Nucleares/química , Proteínas de Fusión Oncogénica/química , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estabilidad Proteica , Proteína Proto-Oncogénica c-fli-1/química , Proteína EWS de Unión a ARN/química , Sarcoma de Ewing/patología , Factores de Transcripción/química
11.
Br J Cancer ; 122(8): 1121-1123, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32015509

RESUMEN

Targeted protein degradation has emerged as a strategy in cancer therapy. Yang et al. discovered that HBX19818, an inhibitor of the deubiquitinase (DUB) USP10, leads to the dual degradation of spleen tyrosine kinase (SYK) and FLT3, resulting in death of AML cells.


Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Quinasa Syk/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/metabolismo , Humanos , Leucemia Mieloide Aguda/patología
12.
Blood ; 132(12): 1241-1247, 2018 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-30049809

RESUMEN

Despite continued progress in drug development for acute leukemias, outcomes for patients with some subtypes have not changed significantly in the last decade. Recurrent chromosomal translocations have long been recognized as driver events in leukemia, and many of these oncogenic fusions portend high-risk disease. Improved understanding of the molecular underpinnings of these fusions, coupled with novel chemistry approaches, now provide new opportunity for therapeutic inroads into the treatment of leukemia driven by these fusions.


Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia/tratamiento farmacológico , Leucemia/genética , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Enfermedad Aguda , Antineoplásicos/farmacología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Terapia Molecular Dirigida/métodos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Translocación Genética/efectos de los fármacos
13.
Br J Cancer ; 120(8): 869, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30880335

RESUMEN

The authors have noticed that the final paragraph of the Results section contains errors in the number of patients involved. The correct number of patients is included in the text below. These errors do not affect the Figure referenced.In osteosarcoma, we focused on 8q gain as a specific biological feature of interest. Among the 41 patients with detectable ctDNA in the osteosarcoma cohort, 8q gain was detected in 73.2% (30/41). The 3-year EFS for patients with 8q gain (n = 30) in ctDNA was 60.0% (95% CI 40.5-75.0) compared to 80.8 (95% CI 42.4-94.9) in patients without 8q gain (n = 11) in ctDNA (p = 0.18; Fig. 3).

14.
Int J Cancer ; 143(4): 958-970, 2018 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-29508386

RESUMEN

Dysregulated NOTCH1 signaling, by either gene mutations or microenvironment interactions, has been increasingly linked to chronic lymphocytic leukemia (CLL). Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity for this disease. Using gene expression-based screening, we identified the calcium channel modulator bepridil as a new NOTCH1 pathway inhibitor. In primary CLL cells, bepridil induced selective apoptosis even in the presence of the protective stroma. Cytotoxic effects of bepridil were independent of NOTCH1 mutation and other prognostic markers. The antitumor efficacy of bepridil was associated with inhibition of NOTCH1 activity through a decrement in trans-membrane and activated NOTCH1 protein levels with unchanged NOTCH2 protein levels. In a CLL xenotransplant model, bepridil significantly reduced the percentage of leukemic cells infiltrating the spleen via enhanced apoptosis and decreased NOTCH1 activation. In conclusion, we report in vitro and in vivo anti-leukemic activity of bepridil associated with inhibition of the NOTCH1 pathway in CLL. These data provide a rationale for the clinical development of bepridil as anti-NOTCH1 targeted therapy for CLL patients.


Asunto(s)
Antineoplásicos/farmacología , Bepridil/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Quimiotaxis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Mutación , Pronóstico , Receptor Notch1/genética , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Br J Cancer ; 119(5): 615-621, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30131550

RESUMEN

BACKGROUND: New prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays. METHODS: A NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome. RESULTS: The analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels. CONCLUSIONS: NGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , ADN Tumoral Circulante/análisis , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Osteosarcoma/genética , Adolescente , Biomarcadores de Tumor/sangre , Neoplasias Óseas/sangre , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Osteosarcoma/sangre , Pronóstico , Estudios Retrospectivos , Sarcoma de Ewing/sangre , Sarcoma de Ewing/genética , Análisis de Secuencia de ADN/métodos , Análisis de Supervivencia
16.
Pediatr Blood Cancer ; 65(7): e27062, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29603593

RESUMEN

BACKGROUND: We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. PROCEDURE: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2 /day). Additional patients were enrolled at the 3- and 5 mg/m2 /day DLs to further evaluate toxicity (dose expansion). RESULTS: Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2 /day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10-3 by polymerase chain reaction-based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. CONCLUSIONS: Everolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end-reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m2 /day. This promising combination should be further evaluated in a larger patient cohort.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Everolimus/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Everolimus/efectos adversos , Femenino , Humanos , Lactante , Masculino , Dosis Máxima Tolerada , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Prednisona/administración & dosificación , Prednisona/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inducción de Remisión/métodos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Vincristina/administración & dosificación , Vincristina/efectos adversos , Adulto Joven
17.
Bioorg Med Chem ; 25(24): 6479-6485, 2017 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29089257

RESUMEN

The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers. Here, we employ high-throughput screening to discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenic phosphatase by simultaneously engaging the C-SH2 and PTP domains. We improved our lead to generate an analogue that better suppresses SHP2 activity in vitro. Suppression of Erk phopsphorylation by the lead compound is also consistent with SHP2 inhibition in AML cells. Our findings provide an alternative starting point for therapeutic intervention and will catalyze investigations into the relationship between SHP2 conformational regulation, activity, and disease progression.


Asunto(s)
Benzotiazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Pirimidinonas/farmacología , Regulación Alostérica/efectos de los fármacos , Benzotiazoles/síntesis química , Benzotiazoles/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-Actividad
18.
Blood ; 123(5): 734-42, 2014 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-24282218

RESUMEN

Blasts from approximately one-third of patients with acute myeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells. Targeting MUC1-C with the cell-penetrating peptide inhibitor GO-203 disrupts MUC1-C/FLT3 complexes and downregulates FLT3 activation. GO-203 treatment of AML cells was also associated with inhibition of the FLT3 downstream effectors AKT, extracellular signal-regulated kinase, and STAT5. The results further show that AML cells with FLT3-activating mutations and resistant to the FLT3 inhibitor midostaurin/PKC412 are sensitive to GO-203-induced growth arrest and death. Moreover, GO-203 increases sensitivity of mutant FLT3 AML cells to FLT3 inhibitor treatment. These results indicate that MUC1-C contributes to FLT3 activation in AML cells and that targeting MUC1-C inhibits the FLT3 signaling pathway. Our findings support the development of MUC1-C inhibitors alone and in combination with agents that target FLT3 for the treatment of wild-type and mutant FLT3 AML.


Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Mucina-1/metabolismo , Proteínas Oncogénicas/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Ratones , Ratones Endogámicos BALB C , Péptidos/farmacología , Péptidos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Tirosina Quinasa 3 Similar a fms/genética
19.
Cancer Cell ; 10(4): 321-30, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17010675

RESUMEN

Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Expresión Génica/efectos de los fármacos , Genoma Humano , Proteínas HSP90 de Choque Térmico/metabolismo , Receptores Androgénicos/metabolismo , Antibióticos Antineoplásicos/farmacología , Benzoquinonas/farmacología , Técnicas de Cultivo de Célula , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Perfilación de la Expresión Génica , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Lactamas Macrocíclicas/farmacología , Limoninas/farmacología , Masculino , Metribolona/farmacología , Triterpenos Pentacíclicos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Mensajero/análisis , Reproducibilidad de los Resultados , Triterpenos/farmacología , Tirosina Quinasa 3 Similar a fms/metabolismo
20.
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
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