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1.
Int J Mol Sci ; 23(3)2022 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-35163730

RESUMEN

Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in overall survival have remained elusive. Recent evidence has emerged that tumor-associated macrophage/microglia (TAM) involvement is likely an important factor contributing to OV treatment failure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenvironment thereby indirectly promoting tumor growth. In this focused review, we discuss the complicated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation-both immunostimulatory and immunosuppressant-and suggest future directions to maximize OV efficacy.


Asunto(s)
Glioblastoma , Viroterapia Oncolítica , Virus Oncolíticos , Glioblastoma/patología , Humanos , Microglía/patología , Viroterapia Oncolítica/métodos , Virus Oncolíticos/genética , Microambiente Tumoral , Macrófagos Asociados a Tumores
2.
Childs Nerv Syst ; 33(5): 833-838, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28332155

RESUMEN

Atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS) are rare, highly malignant neoplasms that carry a poor prognosis. Even with prompt diagnosis, gross total resection and early initiation of intensive adjuvant therapy, the majority of patients will succumb within 9-12 months of diagnosis. The CPA location in children harbors lesions along a wide spectrum varying from benign to highly malignant. Imaging features of lesions within the CPA that aid the diagnostic process will help to initiate early treatment in higher-grade lesions. We report three cases, in very young children, all with cranial nerve deficits, who displayed CPA lesions with restricted diffusion on diffusion-weighted imaging (DWI) with pathology confirming AT/RT. We propose that in young children with a CPA tumor diffusion-weighted imaging should be routinely evaluated to aid in prompt management. In addition, the diagnosis of AT/RT should be highly suggestive in infants presenting with cranial nerve findings as well as DWI restricted diffusion within the CPA.


Asunto(s)
Nervios Craneales/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Neuroma Acústico/diagnóstico por imagen , Tumor Rabdoide/diagnóstico por imagen , Teratoma/diagnóstico por imagen , Preescolar , Femenino , Humanos , Lactante , Masculino , Neuroma Acústico/complicaciones , Neuroma Acústico/terapia , Tumor Rabdoide/complicaciones , Tumor Rabdoide/terapia , Teratoma/complicaciones , Teratoma/terapia
3.
Front Surg ; 11: 1356660, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38840975

RESUMEN

Intrinsic, expansile pontine tumors typically occur in the pediatric population. These tumors characteristically present as diffuse intrinsic pontine glioma (DIPG), which is now considered as diffuse midline glioma (DMG), H3K27-mutated of the pons. DIPG has limited treatment options and a poor prognosis, and the value of tissue diagnosis from an invasive biopsy remains controversial. This study presents the case of a 19-year-old female with clinical and imaging hallmarks of DIPG, who underwent a biopsy of a tumor in the region of the right middle cerebellar peduncle. Her lesional cells were negative for H3K27M alterations and had low-grade histologic features. Next-generation sequencing revealed a frameshift mutation in the NF1 gene as the likely driver mutation. These features suggest a diagnosis of a low-grade glioma associated with NF1 loss of function, with far-reaching consequences regarding both treatment strategy and prognosis. This case provides support for the utility of diagnostic tissue biopsy in cases of suspected DIPG.

4.
Cancers (Basel) ; 16(8)2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38672676

RESUMEN

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

5.
Front Cell Dev Biol ; 11: 1271575, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37860820

RESUMEN

Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the "immune-cold" nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response.

6.
J Clin Oncol ; 41(36): 5524-5535, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-37722087

RESUMEN

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patología , Distribución Aleatoria , Teorema de Bayes , Neoplasias Encefálicas/terapia , Receptores ErbB/genética , Biomarcadores
7.
Neurooncol Adv ; 4(1): vdac099, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36196363

RESUMEN

Background: The landscape of glioma research has evolved in the past 20 years to include numerous large, multi-institutional, database efforts compiling either clinical data on glioma patients, molecular data on glioma specimens, or a combination of both. While these strategies can provide a wealth of information for glioma research, obtaining information regarding data availability and access specifications can be challenging. Methods: We reviewed the literature for ongoing clinical, molecular, and combined database efforts related to glioma research to provide researchers with a curated overview of the current state of glioma database resources. Results: We identified and reviewed a total of 20 databases with data collection spanning from 1975 to 2022. Surveyed databases included both low- and high-grade gliomas, and data elements included over 100 clinical variables and 12 molecular data types. Select database strengths included large sample sizes and a wide variety of variables available, while limitations of some databases included complex data access requirements and a lack of glioma-specific variables. Conclusions: This review highlights current databases and registries and their potential utility in clinical and genomic glioma research. While many high-quality resources exist, the fluid nature of glioma taxonomy makes it difficult to isolate a large cohort of patients with a pathologically confirmed diagnosis. Large, well-defined, and publicly available glioma datasets have the potential to expand the reach of glioma research and drive the field forward.

8.
Cancers (Basel) ; 15(1)2022 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-36612169

RESUMEN

World Health Organization (WHO) grade 4 gliomas of the cerebellum are rare entities whose understanding trails that of their supratentorial counterparts. Like supratentorial high-grade gliomas (sHGG), cerebellar high-grade gliomas (cHGG) preferentially affect males and prognosis is bleak; however, they are more common in a younger population. While current therapy for cerebellar and supratentorial HGG is the same, recent molecular analyses have identified features and subclasses of cerebellar tumors that may merit individualized targeting. One recent series of cHGG included the subclasses of (1) high-grade astrocytoma with piloid features (HGAP, ~31% of tumors); (2) H3K27M diffuse midline glioma (~8%); and (3) isocitrate dehydrogenase (IDH) wildtype glioblastoma (~43%). The latter had an unusually low-frequency of epidermal growth factor receptor (EGFR) and high-frequency of platelet-derived growth factor receptor alpha (PDGFRA) amplification, reflecting a different composition of methylation classes compared to supratentorial IDH-wildtype tumors. These new classifications have begun to reveal insights into the pathogenesis of HGG in the cerebellum and lead toward individualized treatment targeted toward the appropriate subclass of cHGG. Emerging therapeutic strategies include targeting the mitogen-activated protein kinases (MAPK) pathway and PDGFRA, oncolytic virotherapy, and immunotherapy. HGGs of the cerebellum exhibit biological differences compared to sHGG, and improved understanding of their molecular subclasses has the potential to advance treatment.

9.
Neuro Oncol ; 24(7): 1140-1149, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34878541

RESUMEN

BACKGROUND: Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center. METHODS: We identified 1011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013-2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results. RESULTS: Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a posthoc analysis. CONCLUSIONS: While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.


Asunto(s)
Glioblastoma , Adulto , Ensayos Clínicos como Asunto , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/terapia , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mutación , Patología Molecular , Estudios Retrospectivos
10.
Neurooncol Adv ; 3(1): vdab027, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33860227

RESUMEN

Though outcomes for pediatric cancer patients have significantly improved over the past several decades, too many children still experience poor outcomes and survivors suffer lifelong, debilitating late effects after conventional chemotherapy, radiation, and surgical treatment. Consequently, there has been a renewed focus on developing novel targeted therapies to improve survival outcomes. Cancer vaccines are a promising type of immunotherapy that leverage the immune system to mediate targeted, tumor-specific killing through recognition of tumor antigens, thereby minimizing off-target toxicity. As such, cancer vaccines are orthogonal to conventional cancer treatments and can therefore be used alone or in combination with other therapeutic modalities to maximize efficacy. To date, cancer vaccination has remained largely understudied in the pediatric population. In this review, we discuss the different types of tumor antigens and vaccine technologies (dendritic cells, peptides, nucleic acids, and viral vectors) evaluated in clinical trials, with a focus on those used in children. We conclude with perspectives on how advances in combination therapies, tumor antigen (eg, neoantigen) selection, and vaccine platform optimization can be translated into clinical practice to improve outcomes for children with cancer.

11.
Mol Ther ; 17(9): 1517-26, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19352323

RESUMEN

The microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes play central roles in neurodegenerative disorders. Mutations in each gene cause familial disease, whereas common genetic variation at both loci contributes to susceptibility to sporadic neurodegenerative disease. Here, we demonstrate exquisite gene regulation of the human MAPT and SNCA transgene loci and functional complementation in neuronal cell cultures and organotypic brain slices using the herpes simplex virus type 1 (HSV-1) amplicon-based infectious bacterial artificial chromosome (iBAC) vector to express complete loci >100 kb. Cell cultures transduced by iBAC vectors carrying a 143 kb MAPT or 135 kb SNCA locus expressed the human loci similar to the endogenous gene. We focused on analysis of the iBAC-MAPT vector carrying the complete MAPT locus. On transduction into neuronal cultures, multiple MAPT transcripts were expressed from iBAC-MAPT under strict developmental and cell type-specific control. In primary neurons from Mapt(-/-) mice, the iBAC-MAPT vector expressed the human tau protein, as detected by enzyme-linked immunosorbent assay and immunocytochemistry, and restored sensitivity of Mapt(-/-) neurons to Abeta peptide treatment in dissociated neuronal cultures and in organotypic slice cultures. The faithful retention of gene expression and phenotype complementation by the system provides a novel method to analyze neurological disease genes.


Asunto(s)
Enfermedades del Sistema Nervioso/terapia , Neuronas/patología , Transgenes/genética , Transgenes/fisiología , Animales , Células Cultivadas , Cromosomas Artificiales Bacterianos , Terapia Genética , Vectores Genéticos/genética , Humanos , Inmunohistoquímica , Ratones , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/metabolismo , Neuronas/metabolismo , Ratas , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/fisiología , Proteínas tau/genética , Proteínas tau/metabolismo , Proteínas tau/fisiología
12.
Trends Mol Med ; 20(8): 460-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25027972

RESUMEN

The emergence of microRNAs has been one of the defining developments in cancer biology over the past decade, and the explosion of knowledge in this area has brought forward new diagnostic and therapeutic opportunities. The importance of microRNAs in cancer has been underlined by the identification of alterations in microRNA target binding sites and the microRNA processing machinery in tumor cells. Clinical trials utilizing microRNA profiling for patient prognosis and clinical response are now underway, and the first microRNA mimic entered the clinic for cancer therapy in 2013. In this article we review the potential applications of microRNAs for the clinical assessment of patient outcome in cancer, as well as in cancer monitoring and therapy.


Asunto(s)
MicroARNs/genética , Neoplasias/genética , Animales , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Terapia Genética/métodos , Humanos , MicroARNs/sangre , Neoplasias/sangre , Neoplasias/diagnóstico , Neoplasias/terapia , Pronóstico
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