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BACKGROUND: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. METHODS: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. RESULTS: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. CONCLUSIONS: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).
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Neoplasias del Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Viroterapia Oncolítica , Virus Oncolíticos , Adenoviridae , Adolescente , Astrocitoma/radioterapia , Astrocitoma/terapia , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/patología , Neoplasias del Tronco Encefálico/radioterapia , Neoplasias del Tronco Encefálico/terapia , Niño , Preescolar , Glioma Pontino Intrínseco Difuso/mortalidad , Glioma Pontino Intrínseco Difuso/radioterapia , Glioma Pontino Intrínseco Difuso/terapia , Glioma/radioterapia , Glioma/terapia , Humanos , Infusiones Intralesiones , Viroterapia Oncolítica/efectos adversos , Viroterapia Oncolítica/métodos , Calidad de Vida , Microambiente TumoralRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to give an overview of early clinical studies addressing the safety and efficacy of oncolytic immunovirotherapy in adults and children with brain gliomas, and to highlight the extensive potential for the development of this therapeutic alternative. RECENT FINDINGS: The lack of curative treatments and poor prognosis of high-grade glioma patients warrants research on innovative therapeutic alternatives such as oncolytic immunovirotherapy. Engineered modified oncolytic viruses exert both a direct lytic effect on tumor cells and a specific antitumor immune response. Early clinical trials of different DNA and RNA oncolytic viruses, mainly Herpes Simplex Virus Type-1 and adenovirus based platforms, have consistently demonstrated an acceptable safety profile, hints of efficacy and the potential of this therapy to reshape the tumor microenvironment in both adult and pediatric patients with glioma, thus constituting the basis for the development of more advanced clinical trials. SUMMARY: The future landscape of oncolytic immunovirotherapy is still plenty of challenges and opportunities to enable its full therapeutic potential in both adult and children with brain gliomas.
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Neoplasias Encefálicas , Glioma , Herpesvirus Humano 1 , Viroterapia Oncolítica , Virus Oncolíticos , Adulto , Humanos , Niño , Glioma/terapia , Virus Oncolíticos/genética , Herpesvirus Humano 1/genética , Encéfalo , Neoplasias Encefálicas/terapia , Microambiente TumoralRESUMEN
Background Genomic alterations studies in cell-free DNA (cfDNA) have increasing clinical use in oncology. Next-generation sequencing (NGS) technology provides the most complete mutational analysis, but nowadays limited data are available related to the comparison of results reported by different platforms. Here we compare two NGS panels for cfDNA: Oncomine™ Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific), suitable for clinical laboratories, and Guardant360® (GuardantHealth), with more genes targeted but only available in an outsourcing laboratory. Methods Peripheral blood was obtained from 16 advanced cancer patients in which Guardant360® (G360) was requested as part of their clinical assistance. Blood samples were sent to be analyzed with G360 panel, and an additional blood sample was drawn to obtain and analyze cfDNA with Oncomine™ Pan-Cancer (OM) panel in an Ion GeneStudio S5™ System. Results cfDNA analysis globally rendered 101 mutations. Regarding the 55/101 mutations claimed to be included by manufacturers in both panels, 17 mutations were reported only by G360, 10 only by OM and 28 by both. In those coincident cases, there was a high correlation between the variant allele fractions (VAFs) calculated with each panel (r = 0.979, p < 0.01). Regarding the six actionable mutations with an FDA-approved therapy reported by G360, one was missed with OM. Also, 12 mutations with clinical trials available were reported by G360 but not by OM. Conclusions In summary, G360 and OM can produce different mutational profile in the same sample, even in genes included in both panels, which is especially important if these mutations are potentially druggable.
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Ácidos Nucleicos Libres de Células/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Neoplasias/genética , HumanosRESUMEN
Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
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Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Resistencia a Antineoplásicos , Neoplasias Renales/genética , Mutación , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Exones , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/metabolismo , Ratones , Trasplante de Neoplasias , Análisis de Secuencia de ADN , SunitinibRESUMEN
BACKGROUND: Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells. METHODS: Modified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC. RESULTS: CYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rß levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rß/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities. CONCLUSIONS: Taken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway.
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Neoplasias Óseas/etiología , Neoplasias Óseas/metabolismo , Proteína 61 Rica en Cisteína/genética , Transición Epitelial-Mesenquimal/genética , Osteosarcoma/etiología , Osteosarcoma/metabolismo , Receptores de Somatomedina/metabolismo , Animales , Biomarcadores de Tumor , Neoplasias Óseas/patología , Cadherinas/metabolismo , Adhesión Celular/genética , Comunicación Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proteína 61 Rica en Cisteína/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/secundario , Sistema de Señalización de MAP Quinasas , Ratones , Osteosarcoma/patología , Receptor IGF Tipo 1RESUMEN
Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41-2.18, p = 4.84 × 10-7 ). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5-2.4; p = 1.3 × 10-8 ), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.
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Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Interleucina-33/genética , Osteosarcoma/genética , Osteosarcoma/mortalidad , Adulto , Alelos , Brasil , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Modelos de Riesgos Proporcionales , Tasa de Supervivencia , Población Blanca/genéticaRESUMEN
PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial ß-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.
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Antraciclinas/efectos adversos , Neoplasias de la Mama/genética , Cardiotoxicidad/genética , Flavoproteínas Transportadoras de Electrones/genética , Adulto , Anciano , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Supervivientes de Cáncer , Cardiotoxicidad/fisiopatología , Exoma/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Humanos , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/patologíaRESUMEN
BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and young adults that produces aberrant osteoid. The aim of this study was to assess the utility of 2-deoxy-2-[18F-] fluoro-D-glucose ([18F] FDG) and sodium [18F] Fluoride (Na [18F] F) PET scans in orthotopic murine models of osteosarcoma to describe the metabolic pattern of the tumors, to detect and diagnose tumors and to evaluate the efficacy of a new treatment based in oncolytic adenoviruses. METHODS: Orthotopic osteosarcoma murine models were created by the injection of 143B and 531MII cell lines. [18F]FDG and Na [18F] F PET scans were performed 30 days (143B) and 90 days (531MII) post-injection. The antitumor effect of two doses (107 and 108 pfu) of the oncolytic adenovirus VCN-01 was evaluated in 531 MII model by [18F] FDG PET studies. [18F] FDG uptake was quantified by SUVmax and Total Lesion Glycolysis (TLG) indexes. For Na [18F] F, the ratio tumor SUVmax/hip SUVmax was calculated. PET findings were confirmed by histopathological techniques. RESULTS: The metabolic pattern of tumors was different between both orthotopic models. All tumors showed [18F] FDG uptake, with a sensitivity and specificity of 100%. The [18F] FDG uptake was significantly higher for the 143B model (p < 0.001). Sensitivity for Na [18F] F was around 70% in both models, with a specificity of 100%. 531MII tumors showed a heterogeneous Na [18F] F uptake, significantly higher than 143B tumors (p < 0.01). Importantly, [18F] FDG and Na [18F] F uptake corresponded to highly cellular or osteoid-rich tumors in the histopathological analysis, respectively. [18F] FDG data confirmed that the oncolytic treatment of 531MII tumors produced a significant reduction in growth even with the 107 pfu dose. CONCLUSIONS: PET studies demonstrated that the different osteosarcoma xenograft models developed tumors with diverse metabolic patterns that can be described by multitracer PET studies. Since not all tumors produced abundant osteoid, [18F] FDG demonstrated a better sensitivity for tumor detection and was able to quantitatively monitor in vivo response to the oncolytic adenovirus VCN-01.
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Metabolismo Energético , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/metabolismo , Tomografía de Emisión de Positrones , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Ratones , Osteosarcoma/patología , Osteosarcoma/terapia , RadiofármacosRESUMEN
OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.
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Antraciclinas/efectos adversos , Antineoplásicos/efectos adversos , Exoma , Predisposición Genética a la Enfermedad , Corazón/efectos de los fármacos , Leucemia/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Receptores Acoplados a Proteínas G/genética , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Leucemia/fisiopatología , Masculino , Osteosarcoma/complicaciones , Sarcoma de Ewing/complicacionesRESUMEN
Osteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo-naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix-Gla protein (MGP), a non-collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans-endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFß-induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep.usal.es/osteosarcoma/ Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Neoplasias Óseas/patología , Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Neoplasias Pulmonares/secundario , Osteosarcoma/secundario , Animales , Neoplasias Óseas/metabolismo , Movimiento Celular/fisiología , Humanos , Neoplasias Pulmonares/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Desnudos , Osteosarcoma/metabolismo , Fosforilación , Pronóstico , Proteínas Smad/metabolismo , Proteína Gla de la MatrizRESUMEN
BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.
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Neoplasias de las Glándulas Suprarrenales/genética , Pruebas Genéticas , Mutación de Línea Germinal , Neoplasias de Cabeza y Cuello/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias Torácicas/genética , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Niño , Práctica Clínica Basada en la Evidencia , Femenino , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/diagnóstico , Humanos , Masculino , Mutación , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias Torácicas/diagnósticoRESUMEN
BACKGROUND: The possible associations between genetic variants and osteosarcoma risk have been analyzed without conclusive results. Those studies were focused mainly on genes of biologically plausible pathways. However, recently, another pathway has acquired relevance in cellular transformation and tumorigenesis, the microRNA (miRNA) processing pathway. Dysregulation of the expression levels of genes in this pathway has been described in cancer. Consequently, single nucleotide polymorphisms (SNPs) in genes that codify for proteins involved in the miRNA processing pathway may affect miRNAs, and therefore their target genes, which might be associated with cancer development and progression. The aim of this study was to evaluate whether SNPs in miRNA processing genes confer predisposition to osteosarcoma. PROCEDURE: We analyzed 72 SNPs in 21 miRNA processing genes in a total of 99 osteosarcoma patients and 387 controls. RESULTS: A total of three SNPs were associated with osteosarcoma susceptibility. Interestingly, these SNPs were located in miRNA processing genes (CNOT1, CNOT4 and SND1) which are part of the RISC complex. Among them, the association of rs11866002 in CNOT1 was nearly significant after Bonferroni correction. CONCLUSIONS: This study suggests that SNPs in RISC complex genes may be involved in osteosarcoma susceptibility, especially rs11866002 in CNOT1.
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Neoplasias Óseas/genética , MicroARNs/genética , Proteínas Nucleares/genética , Osteosarcoma/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Transcripción/genética , Adolescente , Adulto , Neoplasias Óseas/patología , Estudios de Casos y Controles , Niño , Preescolar , Endonucleasas , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Osteosarcoma/patología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: We studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed. METHODS: Twenty-five patients treated with pemetrexed-based regimens were included. Genomic DNA was isolated prior to treatment. The variable number of tandem repeat (VNTR) polymorphisms, the G > C single nucleotide polymorphisms (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) polymorphisms were analyzed and correlated with overall response rate (ORR), progression-free survival (PFS), overall-survival (OS) and toxicity. RESULTS: The genotype +6/+6 predicted a higher ORR among active/former smokers compared to +6/-6 genotype (100% vs. 50%; p = 0.085). Overall, the 3R/3R genotype predicted a higher ORR (100%) over the rest VNTR polymorphisms (p = 0.055). The presence of 3R/3R genotype significantly correlated with a superior ORR in patients without EGFR activating mutations (100%) compared to 2R/2R, 2R/3R and 3R/4R genotype (77.8%, 33.3% and 0% respectively; p = 0.017). After a median follow-up of 21 months, a trend towards a better PFS, although not significant, was found among subjects showing 3R/3R polymorphisms (p = 0.089). A significantly superior OS was found in patients showing 3R/3R genotype rather than other VNTR polymorphisms (p = 0.019). No significant correlation with the toxicity was observed. CONCLUSION: In our series, 3R/3R polymorphism correlated with a superior OS. Also, this polymorphism, when associated to wild type EGFR, was related to a higher ORR to pemetrexed. Toxicity was not significantly correlated with a specific TS genotype.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Polimorfismo Genético , Timidilato Sintasa/genética , Secuencia de Bases , Carcinoma de Pulmón de Células no Pequeñas/genética , Cartilla de ADN , Femenino , Guanina/uso terapéutico , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Pemetrexed , Reacción en Cadena de la Polimerasa , Población BlancaRESUMEN
Pediatric diffuse midline gliomas (DMG) with H3-K27M-altered are aggressive brain tumors that arise during childhood. Despite advances in genomic knowledge and the significant number of clinical trials testing new targeted therapies, patient outcomes are still insufficient. Immune checkpoint blockades with small molecules, such as aptamers, are opening new therapeutic options that represent hope for this orphan disease. Here, we demonstrated that a TIM-3 aptamer as monotherapy increased the immune infiltration and elicited a strong specific immune response with a tendency to improve the overall survival of treated DMG-bearing mice. Importantly, combining TIM-3 Apt with radiotherapy increased the overall median survival and led to long-term survivor mice in two pediatric DMG orthotopic murine models. Interestingly, TIM-3 aptamer administration increased the number of myeloid populations and the pro-inflammatory ratios of CD8: Tregs in the tumor microenvironment as compared to non-treated groups after radiotherapy. Importantly, the depletion of T-cells led to a major loss of the therapeutic effect achieved by the combination. This work uncovers TIM-3 targeting as an immunotherapy approach to improve the radiotherapy outcome in DMGs and offers a strong foundation for propelling a phase I clinical trial using radiotherapy and TIM-3 blockade combination as a treatment for these tumors.
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Pancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included. Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients. Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings.
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Carcinoma Ductal Pancreático , ADN Tumoral Circulante , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/sangre , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Masculino , Femenino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/sangre , Anciano , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Frecuencia de los Genes , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano de 80 o más Años , Proteína p53 Supresora de Tumor/genética , MutaciónRESUMEN
BACKGROUND: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at a young age, other heavy smokers never develop it, even at an advanced age, suggesting a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). METHODS: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases) or who did not develop lung cancer at an advanced age (extreme controls), selected from databases including over 6600 subjects. We selected individual coding genetic variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We validated the results from our discovery cohort, in which we analysed by WES extreme cases and controls presenting similar phenotypes. We developed ML models using both cohorts. FINDINGS: Mean age for extreme cases and controls was 50.7 and 79.1 years respectively, and mean tobacco consumption was 34.6 and 62.3 pack-years. We validated 16 individual variants and 33 variant-rich genes. The gene harbouring the most validated variants was HLA-A in extreme controls (4 variants in the discovery cohort, p = 3.46E-07; and 4 in the validation cohort, p = 1.67E-06). We trained ML models using as input the 16 individual variants in the discovery cohort and tested them on the validation cohort, obtaining an accuracy of 76.5% and an AUC-ROC of 83.6%. Functions of validated genes included candidate oncogenes, tumour-suppressors, DNA repair, HLA-mediated antigen presentation and regulation of proliferation, apoptosis, inflammation and immune response. INTERPRETATION: Individuals presenting extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma show different germline profiles. Our strategy may allow the identification of high-risk subjects and the development of new therapeutic approaches. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Persona de Mediana Edad , Anciano , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Fenotipo , Células Germinativas/patologíaRESUMEN
BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated. METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq, and multiplexed immunofluorescence staining. RESULTS: The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype. CONCLUSIONS: The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.
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Neoplasias Encefálicas , Glioma , Viroterapia Oncolítica , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Humanos , Ratones , Viroterapia Oncolítica/métodos , Glioma/terapia , Glioma/patología , Glioma/virología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/virología , Neoplasias Encefálicas/tratamiento farmacológico , Microambiente Tumoral , Adenoviridae/genética , Terapia Combinada , Virus Oncolíticos , Células Tumorales Cultivadas , Niño , Replicación ViralRESUMEN
Dravet syndrome is an epileptic encephalopathy characterized by multiple types of seizures. We report the first case of musicogenic reflex seizures in a 7-year-old male with a mutation in the SCN1A gene causing Dravet syndrome. Reflex seizures have been reported in patients with Dravet syndrome provoked by body temperature elevation, looking at visual patterns, or under intermittent photic stimulation. The case we report widens the spectrum of reflex seizures recorded in patients with Dravet syndrome. Cortical hyperexcitability of genetic origin could explain the tendency of these patients to experience reflex seizures.
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Epilepsias Mioclónicas/fisiopatología , Música , Convulsiones/fisiopatología , Niño , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/genética , Humanos , Masculino , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Reflejo/genética , Convulsiones/etiología , Convulsiones/genéticaRESUMEN
Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans´ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome.
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Sarcoma , Neoplasias de los Tejidos Blandos , Adolescente , Adulto Joven , Humanos , Niño , Síndrome , Sarcoma/diagnóstico , Sarcoma/genética , Genotipo , Genes p16 , Predisposición Genética a la Enfermedad , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina , ADN Helicasas , Proteínas Nucleares , Factores de TranscripciónRESUMEN
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation.