RESUMO
Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.
Assuntos
Elementos Facilitadores Genéticos/genética , Ependimoma/tratamento farmacológico , Ependimoma/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/genética , Terapia de Alvo Molecular , Oncogenes/genética , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Ependimoma/classificação , Ependimoma/patologia , Feminino , Humanos , Camundongos , Medicina de Precisão , Interferência de RNA , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although cancer is the leading cause of disease-related mortality in children, the relative rarity of pediatric cancers poses a significant challenge for developing novel therapeutics to further improve prognosis. Patient-derived xenograft (PDX) models, which are usually developed from high-risk tumors, are a useful platform to study molecular driver events, identify biomarkers and prioritize therapeutic agents. Here, we develop PDX for Childhood Cancer Therapeutics (PCAT), a new integrated portal for pediatric cancer PDX models. Distinct from previously reported PDX portals, PCAT is focused on pediatric cancer models and provides intuitive interfaces for querying and data mining. The current release comprises 324 models and their associated clinical and genomic data, including gene expression, mutation and copy number alteration. Importantly, PCAT curates preclinical testing results for 68 models and 79 therapeutic agents manually collected from individual agent testing studies published since 2008. To facilitate comparisons of patterns between patient tumors and PDX models, PCAT curates clinical and molecular data of patient tumors from the TARGET project. In addition, PCAT provides access to gene fusions identified in nearly 1000 TARGET samples. PCAT was built using R-shiny and MySQL. The portal can be accessed at http://pcat.zhenglab.info or http://www.pedtranscriptome.org.
Assuntos
Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Software , Animais , Criança , Variações do Número de Cópias de DNA/efeitos dos fármacos , Mineração de Dados , Bases de Dados Genéticas , Modelos Animais de Doenças , Genômica/métodos , Xenoenxertos , Humanos , Internet , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/metabolismo , Prognóstico , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Primary extrarenal Wilms tumors are rare neoplasms that are presumed to arise from metanephric or mesonephric remnants outside of the kidney. Their pathogenesis is debated but has not been studied, and there are no reports of genomic descriptions of extrarenal Wilms tumors. We describe a diffusely anaplastic extrarenal Wilms tumor that occurred in the lower abdomen and upper pelvis of a 10-year-old boy. In addition to the clinical, histopathologic, and radiologic features, we describe the cytogenetic changes and exomic profile of the tumor. The tumor showed loss of the tumor suppressor AMER1, loss of chromosome regions 1p, 16q, and 22q, gain of chromosome 8, and loss of function TP53 mutation-findings known to occur in renal Wilms tumors. This is the first description of the exomic profile of a primary extrarenal Wilms tumor. Our data indicate that primary extrarenal Wilms tumors may follow the same pathogenetic pathways that are seen in renal Wilms tumors. Finally, we describe the establishment of first ever tumor models (primary cell line and patient-derived xenograft) from an extrarenal Wilms tumor.
Assuntos
Neoplasias Renais , Tumor de Wilms , Criança , Feminino , Humanos , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Mutação , Tumor de Wilms/genética , Tumor de Wilms/patologiaRESUMO
Cancer in children is rare with approximately 15,700 new cases diagnosed in the United States annually. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be "cured" of their disease, and 5-year event-free survival exceeds 80%. However, for patients surviving their malignancy, therapy-related long-term adverse effects are severe, with an estimated 50% having chronic life-threatening toxicities related to therapy in their fourth or fifth decade of life. While overall intensive therapy with cytotoxic agents continues to reduce cancer-related mortality, new understanding of the molecular etiology of many childhood cancers offers an opportunity to redirect efforts to develop effective, less genotoxic therapeutic options, including agents that target oncogenic drivers directly, and the potential for use of agents that target the tumor microenvironment and immune-directed therapies. However, for many high-risk cancers, significant challenges remain.
Assuntos
Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Criança , Humanos , Microambiente Tumoral/efeitos dos fármacosRESUMO
The Pediatric Preclinical Testing Program (PPTP) previously reported the activity of the EZH2 inhibitor tazemetostat (EPZ6438) against xenograft models of rhabdoid tumors. Here, we determined whether an inhibitor of EZH2 enhanced the effect of standard of care chemotherapeutic agents: irinotecan, vincristine, and cyclophosphamide. EPZ011989 significantly prolonged time to event in all the six rhabdoid models studied but did not induce tumor regression. The addition of EPZ011989 to standard of care agents significantly improved time to event in at least one model for each of the agents studied, although this effect was observed in only a minority of the combination testing experiments.
Assuntos
Antineoplásicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Rabdomiossarcoma/tratamento farmacológico , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Irinotecano/farmacologia , Camundongos , Camundongos SCID , Morfolinas/farmacologia , Piridonas/farmacologia , Rabdomiossarcoma/patologia , Vincristina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite radiation therapy (RT) being an integral part of the treatment of most pediatric cancers and the recent discovery of novel molecular-targeted agents (MTAs) in this era of precision medicine with the potential to improve the therapeutic ratio of modern chemoradiotherapy regimens, there are only a few preclinical trials being conducted to discover novel radiosensitizers and radioprotectors. This has resulted in a paucity of translational clinical trials combining RT and novel MTAs. This report describes the opportunities and challenges of investigating RT together with MTAs in preclinical testing for immunotherapy, brain tumors, and sarcomas in pediatric oncology. We discuss the need for improving the collaboration between radiation oncologists, biologists, and physicists to improve the reliability, reproducibility, and translational potential of RT-based preclinical research. Current translational clinical trials using RT and MTAs for immunotherapy, brain tumors, and sarcomas are described. The technologic advances in experimental RT, availability of novel experimental tumor models, advances in immunology and tumor biology, and the discovery of novel MTAs together hold considerable promise for good quality preclinical and clinical multimodality research to improve the current rates of survival and toxicity in children afflicted with cancer.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Imunoterapia/métodos , Terapia de Alvo Molecular , Sarcoma/terapia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Criança , Humanos , Radiossensibilizantes/uso terapêutico , Sarcoma/imunologia , Sarcoma/patologiaRESUMO
SP-2577(Seclidemstat), an inhibitor of lysine-specific demthylase KDM1A (LSD1) that is overexpressed in pediatric sarcomas, was evaluated against pediatric sarcoma xenografts. SP-2577 (100 mg/kg/day × 28 days) statistically significantly (p < .05) inhibited growth of three of eight Ewing sarcoma (EwS), four of five rhabdomyosarcoma (RMS), and four of six osteosarcoma (OS) xenografts. The increase in EFS T/C was modest (<1.5) for all models except RMS Rh10 (EFS T/C = 2.8). There were no tumor regressions or consistent changes in dimethyl histone H3(K4), HOXM1, DAX1, c-MYC and N-MYC, or tumor histology/differentiation. SP-2577 has limited activity against these pediatric sarcoma models at the dose and schedule evaluated.
Assuntos
Neoplasias Ósseas , Inibidores Enzimáticos/uso terapêutico , Histona Desmetilases/antagonistas & inibidores , Rabdomiossarcoma , Sarcoma , Animais , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Criança , Humanos , Lisina , Rabdomiossarcoma/tratamento farmacológico , Sarcoma/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2-specific, CAR-reengineered T-cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR-T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Receptores de Antígenos Quiméricos/imunologia , Sarcoma de Ewing/tratamento farmacológico , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Terapia Baseada em Transplante de Células e Tecidos/métodos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Imunoterapia Adotiva/métodos , Camundongos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/imunologia , Sarcoma de Ewing/patologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BACKGROUND: VTP-50469 is a potent inhibitor of the menin-MLL1 interaction and is implicated in signaling downstream of EWSR1-FLI1. PROCEDURE: VTP-50469 was evaluated against seven Ewing sarcoma (EwS) xenograft models and in vitro against EwS cell lines. RESULTS: VTP-50469 showed limited antitumor activity, statistically significantly slowing tumor progression in four tumor models but with no evidence of tumor regression. In vitro, the IC50 concentration was 10 nM for the mixed lineage leukemia (MLL)-rearranged leukemia cell line MV4;11, but > 3 µM for EwS cell lines. CONCLUSIONS: In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Proteína de Leucina Linfoide-Mieloide/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Sarcoma de Ewing/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Pediatria , Proteínas Proto-Oncogênicas/metabolismo , Sarcoma de Ewing/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Regorafenib is a small molecule multikinase inhibitor that inhibits multiple kinases including BRAF, KIT, PDGFRB, RAF, RET, and VEGFR1-3. PROCEDURES: The in vivo anticancer effects of regorafenib were assessed in a panel of six osteosarcoma models, three rhabdomyosarcoma models, and one Ewing sarcoma model. RESULTS: Regorafenib induced modest inhibition of tumor growth in the models evaluated. CONCLUSION: The overall pattern of response to regorafenib appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models, limited to the period of agent administration, being the primary treatment effect.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Rabdomiossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Animais , Apoptose , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Proliferação de Células , Criança , Feminino , Humanos , Camundongos , Camundongos SCID , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: WEE1 is a serine kinase central to the G2 checkpoint. Inhibition of WEE1 can lead to cell death by permitting cell-cycle progression despite unrepaired DNA damage. AZD1775 is a WEE1 inhibitor that is in clinical development for children and adults with cancer. METHODS: AZD1775 was tested using a dose of 120 mg/kg administered orally for days 1 to 5. Irinotecan was administered intraperitoneally at a dose of 2.5 mg/kg for days 1 to 5 (one hour after AZD1775 when used in combination). AZD1775 and irinotecan were studied alone and in combination in neuroblastoma (n = 3), osteosarcoma (n = 4), and Wilms tumor (n = 3) xenografts. RESULTS: AZD1775 as a single agent showed little activity. Irinotecan induced objective responses in two neuroblastoma lines (PRs), and two Wilms tumor models (CR and PR). The combination of AZD1775 + irinotecan-induced objective responses in two neuroblastoma lines (PR and CR) and all three Wilms tumor lines (CR and 2 PRs). The objective response measure improved compared with single-agent treatment for one neuroblastoma (PR to CR), two osteosarcoma (PD1 to PD2), and one Wilms tumor (PD2 to PR) xenograft lines. Of note, the combination yielded CR (n = 1) and PR (n = 2) in all the Wilms tumor lines. The event-free survival was significantly longer for the combination compared with single-agent irinotecan in all models tested. The magnitude of the increase was greatest in osteosarcoma and Wilms tumor xenografts. CONCLUSIONS: AZD1775 potentiates the effects of irinotecan across most of the xenograft lines tested, with effect size appearing to vary across tumor panels.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Criança , Feminino , Humanos , Irinotecano/farmacologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Camundongos SCID , Neoplasias Experimentais/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Tumor de Wilms/metabolismo , Tumor de Wilms/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Denintuzumab mafodotin (SGN-CD19A) is a CD19-targeting antibody-drug conjugate, comprising a monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin F. Since denintuzumab mafodotin has previously shown activity against B-cell malignancies in early-stage clinical trials, it was of interest to test it against the Pediatric Preclinical Testing Program preclinical models of CD19+ pediatric acute lymphoblastic leukemia (ALL). PROCEDURES: Denintuzumab mafodotin was evaluated against eight B-cell lineage ALL patient-derived xenografts (PDXs), representing B-cell precursor ALL, Ph-like ALL, and mixed-lineage leukemia rearranged infant ALL. Denintuzumab mafodotin was administered weekly for 3 weeks at 3 mg/kg. It was also tested in combination with an induction-type chemotherapy regimen of vincristine, dexamethasone, and l-asparaginase (VXL) against three PDXs. The relationship between cell surface and gene expression of CD19 and drug activity was also assessed. RESULTS: Denintuzumab mafodotin significantly delayed the progression of seven of eight PDXs tested and achieved objective responses in five of eight. There was no apparent subtype specificity of denintuzumab mafodotin activity. No correlations were observed between CD19 mRNA or cell surface expression and denintuzumab mafodotin activity, perhaps due to small sample size, and denintuzumab mafodotin treatment did not select for reduced CD19 expression. Combining denintuzumab mafodotin with VXL achieved therapeutic enhancement compared to either treatment alone. CONCLUSIONS: Denintuzumab mafodotin showed single-agent activity against selected B-lineage ALL PDXs, although leukemia growth was evident in most models at 28 days from treatment initiation. This level of activity for denintuzumab mafodotin is consistent with that observed in adults with ALL.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD19/imunologia , Imunoconjugados/administração & dosagem , Oligopeptídeos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Animais , Antígenos CD19/metabolismo , Criança , Pré-Escolar , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Entinostat, a selective class I histone deacetylase inhibitor, has been reported to enhance the activity of cytotoxic agents and suppress expression of PAX3-FOXO1 in alveolar rhabdomyosarcoma (ARMS). PROCEDURES: Entinostat was tested against three rhabdomyosarcoma cell lines using 96-hour drug exposure. Entinostat alone or in binary combination with vincristine, actinomycin D or cyclophosphamide was tested in ARMS and two embryonal rhabdomyosarcoma (ERMS) xenograft models. Tumor growth was measured at weekly intervals. Drug-induced changes in acetylated histone H3(K9) and entinostat pharmacokinetics were determined. RESULTS: In vitro, the IC50 concentration of entinostat ranged from 280 to 1300 nM. In vivo, entinostat significantly inhibited the growth of only Rh10 xenografts. For most studies, entinostat did not potentiate the activity of the cytotoxic agent. Exceptions included the vincristine and entinostat combination for Rh10 and the entinostat and actinomycin D combination for Rh10 and Rh18, although the effects were modest. For Rh18, the combination of entinostat with vincristine showed evidence of an antagonistic interaction compared with single-agent vincristine. Pharmacokinetic studies showed the average Cmax was 569.4 ng/mL (1.51 µM) with Tmax at 15 minutes, and total exposure (AUC0-12 h ) was 435.6 h × ng/mL. Entinostat treatment increased acetylated histone H3. CONCLUSIONS: Entinostat demonstrated modest antitumor activity in only one of four models at dose and shedule that gave drug exposures relevant to human treatment. The addition of entinostat to standard-of-care cytotoxic agents was in most instances no more effective than the cytotoxic agents used alone. Entinostat demonstrated target inhibition with increased histone 2A acetylation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Padrão de Cuidado , Animais , Benzamidas/administração & dosagem , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Piridinas/administração & dosagem , Células Tumorais Cultivadas , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia-rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups.
Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Apoptose/genética , Western Blotting , Proliferação de Células/efeitos dos fármacos , Criança , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: M6620 is a novel inhibitor of the DNA damage repair enzyme ATR, and has potentiated the activity of cisplatin and irinotecan in non-small cell lung cancer and colon cancer xenografts, respectively. PROCEDURES: M6620 was tested in vitro at concentrations ranging from 1.0 nM to 10.0 µM and at 75 nM in combination with cisplatin or melphalan. M6620 was tested against 24 solid tumor xenografts alone and in combination with cisplatin. Cisplatin was administered intraperitoneally on days 1 and 8 at a dose of 5 mg/kg. M6620 was administered intravenously on days 2 and 9 at 20 mg/m2 approximately 16 hr after cisplatin. RESULTS: The median relative IC50 (rIC50 ) value for M6620 was 0.19 µM (range 0.03-1.38 µM). M6620 reduced the mean IC50 of cisplatin and melphalan by 1.48- and 1.95-fold, respectively. M6620 as a single agent in vivo induced significant differences in event-free survival (EFS) distribution in 5 of 24 (21%) solid tumor xenografts, but induced no objective responses. Cisplatin as a single agent induced significant differences in EFS distribution compared to control in 18 of 24 (75%) solid tumor xenografts. Three objective responses to cisplatin were observed. The M6620 and cisplatin combination induced significant differences in EFS distribution compared to control in 21 of 24 (88%), with four objective responses. CONCLUSIONS: M6620 showed modest potentiation of cisplatin and melphalan activity for some cell lines. M6620 showed little single-agent activity and the addition of M6620 to cisplatin significantly prolonged time to event for a minority of tested xenografts across several histologies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Isoxazóis/farmacologia , Melfalan/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos SCID , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents. PROCEDURES: Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program. RESULTS: Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E. CONCLUSIONS: P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Cloridrato de Erlotinib/farmacologia , Sarcoma de Ewing/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados , Neoplasias Ósseas/metabolismo , Anticorpos Amplamente Neutralizantes , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos SCID , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/metabolismo , Sarcoma de Ewing/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The mTOR complex-1 (mTORC1) coordinates cell growth and metabolism, acting as a restriction point under stress conditions such as low oxygen tension (hypoxia). Hypoxia suppresses mTORC1 signaling. However, the signals by which hypoxia suppresses mTORC1 are only partially understood, and a direct link between hypoxia-driven physiological stress and the regulation of mTORC1 signaling is unknown. Here we show that hypoxia results in ataxia telangiectasia mutated (ATM)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (HIF-1α) on serine(696) and mediates downregulation of mTORC1 signaling. Deregulation of these pathways in pediatric solid tumor xenografts suggests a link between mTORC1 dysregulation and solid tumor development and points to an important role for hypoxic regulation of mTORC1 activity in tumor development.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia , Hipóxia Celular , Dano ao DNA , Ativação Enzimática , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos , Fosforilação , Fosfosserina/metabolismo , Serina-Treonina Quinases TOR , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PR-104, a phosphate ester of the nitrogen mustard prodrug PR-104A, has shown evidence of efficacy in adult leukemia clinical trials. Originally designed to target hypoxic cells, PR-104A is independently activated by aldo-keto-reductase 1C3 (AKR1C3). The aim of this study was to test whether AKR1C3 is a predictive biomarker of in vivo PR-104 sensitivity. In a panel of 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 showed significantly greater efficacy against T-lineage ALL (T-ALL) than B-cell-precursor ALL (BCP-ALL) xenografts. Single-agent PR-104 was more efficacious against T-ALL xenografts compared with a combination regimen of vincristine, dexamethasone, and l-asparaginase. Expression of AKR1C3 was significantly higher in T-ALL xenografts compared with BCP-ALL, and correlated with PR-104/PR-104A sensitivity in vivo and in vitro. Overexpression of AKR1C3 in a resistant BCP-ALL xenograft resulted in dramatic sensitization to PR-104 in vivo. Testing leukemic blasts from 11 patients confirmed that T-ALL cells were more sensitive than BCP-ALL to PR-104A in vitro, and that sensitivity correlated with AKR1C3 expression. Collectively, these results indicate that PR-104 shows promise as a novel therapy for relapsed/refractory T-ALL, and that AKR1C3 expression could be used as a biomarker to select patients most likely to benefit from such treatment in prospective clinical trials.
Assuntos
3-Hidroxiesteroide Desidrogenases/biossíntese , Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Hidroxiprostaglandina Desidrogenases/biossíntese , Compostos de Mostarda Nitrogenada/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Adolescente , Membro C3 da Família 1 de alfa-Ceto Redutase , Animais , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Immunoblotting , Masculino , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Tazemetostat (EPZ-6438) is a selective inhibitor of the histone methyltransferase EZH2 and currently in clinical development for non-Hodgkin lymphoma and genetically defined tumors. PROCEDURES: Tazemetostat was tested against the Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using a dose of 400 mg/kg administered twice daily by oral gavage for 28 days. H3K27me3:H3 ratios were determined in control and treated tumors. RESULTS: Tazemetostat induced significant differences in event-free survival (EFS) distribution compared with control in nine of 30 (30%) of the xenografts studied. Significant differences in EFS distribution were observed in five of seven (71%) rhabdoid tumor xenograft lines compared with four of 23 (17%) nonrhabdoid xenograft lines (chi-square [χ2 ] test P = 0.006). Tazemetostat induced tumor growth inhibition meeting criteria for intermediate and high EFS treated-to-control (T/C) activity in two of 25 (8%) and one of 25 (4%) xenografts, respectively. Intermediate and high activity for the EFS T/C metric was observed exclusively among rhabdoid tumor xenografts (three of five rhabdoid tumor vs 0 of 22 nonrhabdoid tumors (χ² test P < 0.001). One rhabdoid tumor xenograft (G401) showed stable disease. For one rhabdoid tumor (G401), delayed tumor regression to tazemetostat was noted following 1 week of tumor growth. Tazemetostat induced significant reduction of H3K27me3 levels in the majority of tumors compared with controls. CONCLUSIONS: Tazemetostat demonstrated significant antitumor activity in rhabdoid tumor models but showed no consistent activity against any other histology. Tazemetostat reduced H3K27me3 levels irrespective of tumor response. Further preclinical testing to evaluate tazemetostat in combination with other anticancer agents is warranted.
Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Piridonas/farmacologia , Animais , Compostos de Bifenilo , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos , Camundongos SCID , Morfolinas , Neoplasias Experimentais/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: CBL0137 is a novel drug that modulates FAcilitates Chromatin Transcription (FACT), resulting in simultaneous nuclear factor-κB suppression, heat shock factor 1 suppression and p53 activation. CBL0137 has demonstrated antitumor effects in animal models of several adult cancers and neuroblastoma. PROCEDURES: CBL0137 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 µM and against the PPTP in vivo solid tumor xenograft and acute lymphocytic leukemia (ALL) panels at 50 mg/kg administered intravenously weekly for 4 weeks. RESULTS: The median relative IC50 (rIC50 ) value for the PPTP cell lines was 0.28 µM (range: 0.13-0.80 µM). There were no significant differences in rIC50 values by histotype. CBL0137 induced significant differences in event-free survival (EFS) distribution compared to control in 10 of 31 (32%) evaluable solid tumor xenografts and in eight of eight (100%) evaluable ALL xenografts. Significance differences in EFS distribution were observed in four of six osteosarcoma lines, three of three rhabdoid tumor lines and two of six rhabdomyosarcoma lines. No objective responses were observed among the solid tumor xenografts. For the ALL panel, one xenograft achieved complete response and four achieved partial response. CONCLUSIONS: The most consistent in vivo activity for CBL0137 was observed against ALL xenografts, with some solid tumor xenograft lines showing tumor growth delay. It will be important to relate the drug levels in mice at 50 mg/kg to those in humans at the recommended phase 2 dose.