Advances in local therapy for glioblastoma - taking the fight to the tumour

Despite advances in neurosurgery, chemotherapy and radiotherapy, glioblastoma remains one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs. The majority of recurrences appear in or near the resection cavity, usually within the area that received the highest dose of radiation. Many new therapies focus on combatting these local recurrences by implementing treatments directly in or near the tumour bed. In this Review, we discuss the latest developments in local therapy for glioblastoma, focusing on recent preclinical and clinical trials. The approaches that we discuss include novel intraoperative techniques, various treatments of the surgical cavity, stereotactic injections directly into the tumour, and new developments in convection-enhanced delivery and intra-arterial treatments.Glioblastoma is one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs, usually in or near the resection cavity. Here, the authors discuss local therapies for glioblastoma, examining treatment of the resection cavity and other direct approaches to the tumour.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Advances in local therapy for glioblastoma - taking the fight to the tumour

Despite advances in neurosurgery, chemotherapy and radiotherapy, glioblastoma remains one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs. The majority of recurrences appear in or near the resection cavity, usually within the area that received the highest dose of radiation. Many new therapies focus on combatting these local recurrences by implementing treatments directly in or near the tumour bed. In this Review, we discuss the latest developments in local therapy for glioblastoma, focusing on recent preclinical and clinical trials. The approaches that we discuss include novel intraoperative techniques, various treatments of the surgical cavity, stereotactic injections directly into the tumour, and new developments in convection-enhanced delivery and intra-arterial treatments.Glioblastoma is one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs, usually in or near the resection cavity. Here, the authors discuss local therapies for glioblastoma, examining treatment of the resection cavity and other direct approaches to the tumour

Cellular Automaton of Idealized Brain Tumor Growth Dynamics

A novel cellular automaton model of proliferative brain tumor growth has been developed. This model is able to simulate Gompertzian tumor growth over nearly three orders of magnitude in radius using only four microscopic parameters. The predicted composition and growth rates are in agreement with a test case pooled from the available medical literature. The model incorporates several new features, improving previous models, and also allows ready extension to study other important properties of tumor growth, such as clonal competition. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cellular automaton; Tumor modeling; Proliferative dynamics www.elsevier.com/locate/biosystems 1. Introduction The incidence of primary malignant brain tumors remains high. The majority consists of highgrade malignant neuroepithelial tumors such as glioblastoma multiforme (GBM), with a median survival time of only 8 months (Black 1991; Whittle 1996). Tumors such as GBM have such a grim ou..

Radiation-induced targeted nanoparticle-based gene delivery for brain tumor therapy

###EgeUn###Targeted therapy against the programmed cell death ligand-1 (PD-L1) blockade holds considerable promise for the treatment of different tumor types; however, little effect has been observed against gliomas thus far. Effective glioma therapy requires a delivery vehicle that can reach tumor cells in the central nervous system, with limited systemic side effect. In this study, we developed a cyclic peptide iRGD (CCRGDKGPDC)-conjugated solid lipid nanoparticle (SLN) to deliver small interfering RNAs (siRNAs) against both epidermal growth factor receptor (EGFR) and PD-L1 for combined targeted and immunotherapy against glioblastoma, the most aggressive type of brain tumors. Building on recent studies showing that radiation therapy alters tumors for enhanced nanotherapeutic delivery in tumor-associated macrophage-dependent fashion, we showed that low-dose radiation primes targeted SLN uptake into the brain tumor region, leading to enhanced downregulation of PD-L1 and EGFR. Bioluminescence imaging revealed that radiation therapy followed by systemic administration of targeted SLN leads to a significant decrease in glioblastoma growth and prolonged mouse survival. This study combines radiation therapy to prime the tumor for nanoparticle uptake along with the targeting effect of iRGD-conjugated nanoparticles to yield a straightforward but effective approach for combined EGFR inhibition and immunotherapy against glioblastomas, which can be extended to other aggressive tumor types. © 2019 American Chemical Society.P30NS04776 Massachusetts General Hospital Center for Outcomes Research and Evaluation, Yale School of Medicine P01CA069246 FAS Center for Systems Biology, Harvard University Massachusetts General HospitalThis work was supported by grant from NIH/NCI P01CA069246 (B.A.T., E.A.C., and R.W.) and NIH/NINDS P30NS04776 (B.A.T.). G.E.A. was supported by TUBITAK (The Scientific and Technological Research Council of Turkey) 2214/A scholarship. The authors would like to thank Michael F. Cuccarese from the Center for Systems Biology at the Massachusetts General Hospital for his help with DLS measurement experiments, the MGH Neuroscience Image Analysis Core (for confocal microscopy), and the MGH Vector Core (for producing the viral vector), and Ellen Sapp at the MGH EM core (supported by NIH/NINDS P30NS04776) as well as 1S10RR025504 Shared Instrumentation Grant for the IVIS imaging system. -

Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV

Item does not contain fulltextEpstein-Barr virus (EBV)-associated B-cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. As PKR is a major cellular defense against Herpes simplex virus (HSV), and oncolytic HSV-1 (oHSV) mutants have shown promising antitumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was the most susceptible, NB122R was intermediate and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas downregulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a NB cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases, due to low virus receptor expression but also due to intact antiviral PKR signaling