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1.
Am J Cancer Res ; 14(5): 2453-2464, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859853

RESUMO

ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) and analogue ONC206 have been found to induce an integrated stress response with suggested primary targets and mechanisms involving targeting mitochondrial protein ClpP and antagonism of dopamine receptors D2/3 (DRD2/3). We hypothesized that dopamine, the agonist of DRD2, may counteract ONC201 or ONC206 for DRD2/3 and impair the anti-cancer effect of ONC201 or ONC206, thus protect the tumor cells from the cytotoxic effect of ONC201 or ONC206. We therefore pre-treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, and diffuse midline glioma (DMG) with dopamine, followed by treatment of ONC201, ONC206 or ONC212. We observed that 48 hours of pre-treatment with dopamine impaired the cell viability suppression effect of ONC201, ONC206 and ONC212 in pancreatic cancer cells and colorectal cancer cells. We pre-treated multiple cancer cell lines with dopamine for one week followed by ONC201, ONC206, or ONC212 treatment and performed colony assays. Pre-treatment with dopamine impaired the anti-cancer effect of ONC201 or ONC206 in pancreatic cancer and colorectal cancer. Impairment of ONC212 effect by pre-treatment with dopamine was also seen in colony assay for colorectal cancer, but not in pancreatic cancer cells by colony assay. No protection from killing by imipridones was observed with DRD2 agonist sumanirole in tumor cells, or with brain tumor cell lines pretreated with dopamine. Immunoblotting was conducted to investigate whether dopamine pre-treatment impacts signaling pathways reported to be affected by ONC201. The dopamine pre-treatment did not impact changes in ATF4, CHOP, DR5 and ClpX which were reported to be affected by ONC201. The mechanism of impairment of ONC201/206/212 effect caused by dopamine pre-treatment appears to involve upregulation of anti-apoptotic p-Bad, XIAP, FLIP and pAkt. Our results shed light on mechanisms of cancer cell protection by dopamine after imipridone treatment, heterogeneity among different tumor cell types, and suggest that effects of dopamine adaptation on tumor cells may impact on cell survival pathways in ways that may or may not depend on expression of dopamine receptors.

2.
Neurooncol Adv ; 6(1): vdae035, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38596718

RESUMO

Background: Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods: Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results: Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions: Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

3.
Cell Genom ; 3(7): 100340, 2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37492101

RESUMO

Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community.

4.
R I Med J (2013) ; 106(7): 31-36, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37494625

RESUMO

BACKGROUND: The pediatric population has suffered COVID-19 infections with measurable morbidity and mortality. Without oral options in those less than 12 years of age, practical treatment in this rapidly evolving disease is necessary. One treatment modality is monoclonal antibodies. Limited information describes the efficacy and safety of anti-SARS-CoV-2 monoclonal antibodies in pediatrics. This is the largest case series addressing efficacy and safety of monoclonal antibodies in this population. OBJECTIVE: To report patient characteristics, side effects encountered, and hospital admissions or emergency department visits within 30 days following treatment. DESIGN: This retrospective case series includes high-risk pediatric COVID-19 patients who received monoclonal antibody infusions in a tertiary care center as outpatients between January 2021 and January 2022. OUTCOMES: There were 108 patients included with seven patients (6.5%) having infusion-related reactions with no other adverse events reported. Following the monoclonal treatment, three patients presented to the emergency department for worsening symptoms, and one patient was admitted to the pediatric ICU for worsening respiratory status. No other admissions or emergency department visits were reported in the one month following the infusion. CONCLUSIONS: In this case series study, monoclonal antibody infusions were well tolerated.


Assuntos
COVID-19 , Humanos , Criança , Rhode Island , Estudos Retrospectivos , Pacientes Ambulatoriais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais
5.
Clin Cancer Res ; 29(14): 2651-2667, 2023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-36780194

RESUMO

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.


Assuntos
Glioblastoma , Glioma , Camundongos , Animais , Quinase do Linfoma Anaplásico/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Estudos Retrospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Glioma/tratamento farmacológico
6.
Am J Cancer Res ; 13(12): 6241-6255, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38187038

RESUMO

There is a demonstrated need for new chemotherapy options in pediatric oncology, as pediatric solid tumors continue to plateau at 60% with event-free survival. Imipridones, a novel class of small molecules, represent a potential new therapeutic option, with promising pre-clinical data and emerging clinical trial data in adult malignancies. ONC201, ONC206, and ONC212 are imipridones showing pro-apoptotic anti-cancer response. Using cell viability assays, and protein immunoblotting, we were able to demonstrate single-agent efficacy of all 3 imipridones inducing cell death in pediatric solid tumor cell lines, including osteosarcoma, malignant peripheral nerve sheath tumors, Ewing sarcoma (EWS), and neuroblastoma. ONC201 displayed IC50 values for non-H3K27M-mutated EWS cell lines ranging from 0.86 µM (SK-N-MC) to 2.76 µM (RD-ES), which were comparable to the range of IC50 values for H3K27M-mutated DIPG cells lines (range 1.06 to 1.56 µM). ONC212 demonstrated the highest potency in single-agent cell killing, followed by ONC206, and ONC201. Additionally, pediatric solid tumor cells were treated with single-agent therapy with histone deacetylase inhibitors (HDACi) vorinostat, entinostat, and panobinostat, showing cell killing with all 3 HDACi drugs, with panobinostat showing the greatest potency. We demonstrate that dual-agent therapy with combinations of imipridones and HDACi lead to synergistic cell killing and apoptosis in all pediatric solid tumor cell lines tested, with ONC212 and panobinostat combinations demonstrating maximal potency. The imipridones induced the integrated stress response with ATF4 and TRAIL receptor upregulation, as well as reduced expression of ClpX. Hyperacetylation of H3K27 was associated with synergistic killing of tumor cells following exposure to imipridone plus HDAC inhibitor therapies. Our results introduce a novel class of small molecules to treat pediatric solid tumors in a precision medicine framework. Use of impridones in pediatric oncology is novel and shows promising pre-clinical efficacy in pediatric solid tumors, including in combination with HDAC inhibitors.

9.
Am J Cancer Res ; 11(9): 4607-4623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659909

RESUMO

The H3K27M oncohistone mutation, identified in approximately 80% of diffuse intrinsic pontine gliomas (DIPG), is a potential target for therapy. Imipridone ONC201/TIC10 (TRAIL-Inducing Compound #10) induces apoptosis of cancer cells, and has clinical efficacy against H3K27M-mutant DIPG. We demonstrate synergy between ONC201, ONC206 and ONC212, and targeted therapies with known preclinical activity against DIPG. We hypothesized that imipridone combinations with HDAC or proteasome inhibitors may be superior to single agent ONC201 treatment in H3K27M mutant DIPG. Six patient-derived DIPG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SU-DIPG-36) were exposed to imipridones alone or combinations with histone de-acetylase inhibitors [HDACi], marizomib, etoposide, and temozolomide. Dose-dependent response to imipridones was observed in DIPG cells with half-maximal inhibitory concentration (IC50) of 1.46 µM, 0.11 µM, and 0.03 µM, for ONC201, ONC206, and ONC212, respectively. Upon treatment with the imipridones, DIPG cell lines engaged CLpP/CLPX, the integrated stress response with ATF4 activation, and TRAIL death receptor 5 (DR5) induction. Strong synergy was identified between ONC201 and HDACi panobinostat (combination index [CI] 0.01), romidepsin (CI 0.08) and proteasome inhibitor marizomib (CI 0.19). Synergy was demonstrated between ONC201 and etoposide (CI 0.54), although to a lesser degree than with panobinostat, romidepsin, and marizomib. ONC206 and ONC212 showed similar synergistic effects with panobinostat, romidepsin, and marizomib. Induction of apoptosis was demonstrated with imipridones and panobinostat or romidepsin combinations. Our results suggest increased sensitivity of H3K27M-mutant DIPG cell lines to second generation imipridone therapies, as compared to ONC201. Additionally, there is synergistic cell death with combination of imipridones and panobinostat, romidepsin, or marizomib, which may be further tested in vivo and in clinical trials.

10.
Neoplasia ; 23(8): 792-810, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34246076

RESUMO

ONC201/TIC10 activates TRAIL signaling through ATF4 and the integrated stress response (ISR). ONC201 demonstrated tumor regressions and disease stability in patients with histone H3K27M-mutated midline-glioma. H3K27M-mutation prevents H3K27-methylation on the mutated allele. EZH2 inhibitors (EZH2i) reduce H3K27 methylation and have anti-tumor effects. We hypothesized ONC201 sensitivity and tumor apoptosis may increase by reducing H3K27-methylation with EZH2i or HDACi as mimics of H3K27M-mutation. EZH2i EPZ-6438 (tazemetostat) or PF-06821497 and HDACi vorinostat were combined with ONC201 to treat multiple cancer cell lines and cell viability and histone modifications were analyzed. We observed synergistic effects towards cell viability in multiple cancers by EPZ-6438 or PF-06821497 plus ONC201 or triple therapy with vorinostat, EPZ-6438, and ONC201. EPZ-6438 and vorinostat synergized with ONC201 to enhance apoptosis. Activation of the ISR and TRAIL-DR5 were observed in cells treated with ONC201 -/+ epigenetic modulators. Knockdown of ATF4 reduced DR5 induction and apoptosis following EZH2i and ONC201 treatment of U251 glioma cells. mRNA expression of dopamine-receptors did not correlate with ONC201 sensitivity in the tumor cell lines tested (N = 12), including changes after epigenetic drugs. Dopamine did not rescue apoptosis by ONC201 in different tumor cell lines (N = 10) including 2 GBM, 3 DIPG and did not prevent DR5 activation or apoptosis. DRD2 agonist sumanirole did not protect brain tumor cells (N = 6 including 4 DIPG cell lines) from ONC201 reduction in viability. Although synergy was observed with ONC201 and vorinostat, there was no significant increase in H3K27 acetylation in cell lines including DIPG as compared to vorinostat alone, and in some cases the acetylation was less than vorinostat alone at 72 H. H3K27 methylation reduction correlated with synergy from combinations of either EPZ-6438 or vorinostat with ONC201 or triple combination. Our findings provide a rationale for combination of ONC201 and epigenetic modulators including triple therapy for in vivo and clinical testing in treatment of human malignancies including brain tumors and DIPG.


Assuntos
Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Endopeptidase Clp/metabolismo , Histonas/metabolismo , Imidazóis/farmacologia , Morfolinas/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Vorinostat/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Metilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
11.
Sci Rep ; 11(1): 5098, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658570

RESUMO

Diffuse midline glioma (DMG) is a highly morbid pediatric brain tumor. Up to 80% of DMGs harbor mutations in histone H3-encoding genes, associated with poor prognosis. We previously showed the feasibility of detecting H3 mutations in circulating tumor DNA (ctDNA) in the liquid biome of children diagnosed with DMG. However, detection of low levels of ctDNA is highly dependent on platform sensitivity and sample type. To address this, we optimized ctDNA detection sensitivity and specificity across two commonly used digital droplet PCR (ddPCR) platforms (RainDance and BioRad), and validated methods for detecting H3F3A c.83A > T (H3.3K27M) mutations in DMG CSF, plasma, and primary tumor specimens across three different institutions. DNA was extracted from H3.3K27M mutant and H3 wildtype (H3WT) specimens, including H3.3K27M tumor tissue (n = 4), CSF (n = 6), plasma (n = 4), and human primary pediatric glioma cells (H3.3K27M, n = 2; H3WT, n = 1). ctDNA detection was enhanced via PCR pre-amplification and use of distinct custom primers and fluorescent LNA probes for c.83 A > T H3F3A mutation detection. Mutation allelic frequency (MAF) was determined and validated through parallel analysis of matched H3.3K27M tissue specimens (n = 3). We determined technical nuances between ddPCR instruments, and optimized sample preparation and sequencing protocols for H3.3K27M mutation detection and quantification. We observed 100% sensitivity and specificity for mutation detection in matched DMG tissue and CSF across assays, platforms and institutions. ctDNA is reliably and reproducibly detected in the liquid biome using ddPCR, representing a clinically feasible, reproducible, and minimally invasive approach for DMG diagnosis, molecular subtyping and therapeutic monitoring.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , DNA Tumoral Circulante/genética , Glioma/diagnóstico , Glioma/genética , Taxa de Mutação , Reação em Cadeia da Polimerase/métodos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/patologia , Criança , DNA Tumoral Circulante/isolamento & purificação , Estudos de Viabilidade , Glioma/sangue , Glioma/patologia , Histonas/genética , Humanos , Biópsia Líquida/normas , Prognóstico , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
J Clin Invest ; 130(12): 6325-6337, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817593

RESUMO

BACKGROUNDPatients with diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+, H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine.METHODSNewly diagnosed patients, aged 3-21 years, with HLA-A*02.01+ and H3.3K27M+ status were enrolled in stratum A (DIPG) or stratum B (nonpontine DMG). Vaccine was administered in combination with polyinosinic-polycytidylic acid-poly-I-lysine carboxymethylcellulose (poly-ICLC) every 3 weeks for 8 cycles, followed by once every 6 weeks. Immunomonitoring and imaging were performed every 3 months. Imaging was centrally reviewed. Immunological responses were assessed in PBMCs using mass cytometry.RESULTSA total of 19 patients were enrolled in stratum A (median age,11 years) and 10 in stratum B (median age, 13 years). There were no grade-4 treatment-related adverse events (TRAEs). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22%-73%) for patients in stratum A and 39% (95% CI, 16%-93%) for patients in stratum B. The median OS was 16.1 months for patients who had an expansion of H3.3K27M-reactive CD8+ T cells compared with 9.8 months for their counterparts (P = 0.05). Patients with DIPG with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared with their counterparts (P < 0.01). Immediate pretreatment dexamethasone administration was inversely associated with H3.3K27M-reactive CD8+ T cell responses.CONCLUSIONAdministration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared with nonresponders.TRIAL REGISTRATIONClinicalTrials.gov NCT02960230.FUNDINGThe V Foundation, the Pacific Pediatric Neuro-Oncology Consortium Foundation, the Pediatric Brain Tumor Foundation, the Mithil Prasad Foundation, the MCJ Amelior Foundation, the Anne and Jason Farber Foundation, Will Power Research Fund Inc., the Isabella Kerr Molina Foundation, the Parker Institute for Cancer Immunotherapy, and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R35NS105068).


Assuntos
Neoplasias do Tronco Encefálico , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Citometria de Fluxo , Glioma , Histonas , Imunidade Celular/efeitos dos fármacos , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Adolescente , Adulto , Substituição de Aminoácidos , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/terapia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Criança , Pré-Escolar , Feminino , Glioma/genética , Glioma/imunologia , Glioma/terapia , Histonas/genética , Histonas/imunologia , Humanos , Imunidade Celular/genética , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia
14.
Clin Cancer Res ; 25(18): 5572-5583, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31227500

RESUMO

PURPOSE: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.Experimental Design: We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts. RESULTS: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy. CONCLUSIONS: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.


Assuntos
Glioma Pontino Intrínseco Difuso/metabolismo , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Tolerância a Radiação , Radiossensibilizantes/farmacologia , Animais , Benzazepinas/farmacologia , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/mortalidade , Glioma Pontino Intrínseco Difuso/radioterapia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , Recombinação Homóloga , Humanos , Camundongos , Prognóstico , Pirimidinas/farmacologia , Tolerância a Radiação/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Neuro Oncol ; 21(7): 934-943, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-30997512

RESUMO

BACKGROUND: Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT). METHODS: Pediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation-including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning-were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time. RESULTS: Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (ß = 10.6, P = 0.048) and processing speed (ß = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (ß = 9.9, P = 0.06) and general adaptive functioning (ß = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09). CONCLUSIONS: PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.


Assuntos
Neoplasias Encefálicas/radioterapia , Cognição/efeitos da radiação , Radiação Cranioespinal/métodos , Inteligência/efeitos da radiação , Memória de Curto Prazo/efeitos da radiação , Terapia com Prótons/métodos , Terapia por Raios X/métodos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/psicologia , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Prognóstico , Qualidade de Vida , Estudos Retrospectivos
17.
Neuro Oncol ; 21(4): 537-546, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30883662

RESUMO

BACKGROUND: Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. METHODS: This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. RESULTS: Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. CONCLUSIONS: GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00634231.


Assuntos
Neoplasias Encefálicas/terapia , Ependimoma/terapia , Terapia Genética/métodos , Glioma/terapia , Imunoterapia/métodos , Terapia Viral Oncolítica/métodos , Adenoviridae/genética , Adolescente , Antivirais/uso terapêutico , Criança , Pré-Escolar , Ependimoma/secundário , Feminino , Vetores Genéticos , Humanos , Masculino , Pró-Fármacos/uso terapêutico , Timidina Quinase/administração & dosagem , Proteínas Virais/administração & dosagem
18.
Sci Signal ; 12(565)2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670636

RESUMO

In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-ß (infants) subgroups. Neuronal maturation is greater in SHH-ß than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (RESTTG ) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1 +/- cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Ptch1 Expression of Arrb1, which encodes ß-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed RESTTG cells compared with wild-type proliferating CGNPs. Lineage-committed RESTTG cells also had decreased GLI1 activity and increased histone H3K9 methylation at the Ptch1 locus, which correlated with premature silencing of Ptch1 These cells also had decreased expression of Pten, which encodes a negative regulator of the kinase AKT. Expression of PTCH1 and GLI1 were less, and ARRB1 was somewhat greater, in patient SHH-ß than SHH-α MBs, whereas that of PTEN was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, PTCH1 silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.


Assuntos
Neoplasias Cerebelares/genética , Cromatina/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , Receptor Patched-1/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Repressoras/genética , Adulto , Animais , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Criança , Cromatina/metabolismo , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Lactente , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Estadiamento de Neoplasias , Receptor Patched-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/genética , Transplante Heterólogo
19.
Oncotarget ; 9(4): 5233-5250, 2018 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-29435175

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on anti-angiogenic therapies targeting GREM-1 in combination with drugs that target REST-associated chromatin remodeling activities.

20.
J Pediatr Hematol Oncol ; 40(8): 616-619, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29401100

RESUMO

We describe 2 cases of rapidly progressive primary central nervous system malignant melanoma, and summarize 18 previously reported cases of this extremely rare tumor in children. Both patients presented with focal neurologic symptoms, with no evidence of skin or other organ system involvement. One patient was treated with temozolomide and etoposide, whereas the other was treated with multiple surgical resections, radiation therapy, and a trial of ipilimumab. New molecularly targeted and immune-based therapies used in metastatic melanoma in adults are potential new treatment options, but their efficacy and safety in pediatric patients needs to be established.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Nervoso Central , Quimiorradioterapia , Melanoma , Adolescente , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Pré-Escolar , Etoposídeo/administração & dosagem , Humanos , Ipilimumab/administração & dosagem , Masculino , Melanoma/metabolismo , Melanoma/patologia , Melanoma/terapia , Temozolomida/administração & dosagem
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