MR-guided focused ultrasound increases antibody delivery to nonenhancing high-grade glioma

Abstract Background High-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood–brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor. Methods Structural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET–CT imaging techniques were then used to evaluate the efficacy of FUS to increase 89Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue. Results The PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected. Conclusions FUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.

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Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma

PLoS ONE ◽

10.1371/journal.pone.0122387 ◽

2015 ◽

Vol 10 (5) ◽

pp. e0122387 ◽

Cited By ~ 5

Author(s):

Benjamin H. Beck ◽

Hyunggoon Kim ◽

Rebecca O’Brien ◽

Martin R. Jadus ◽

G. Yancey Gillespie ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Cell Activity ◽

High Grade Glioma ◽

High Grade ◽

Γδ T Cell ◽

Immunocompetent Mouse

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Genetically Engineered Mouse Model of Brainstem High-Grade Glioma

STAR Protocols ◽

10.1016/j.xpro.2020.100165 ◽

2020 ◽

Vol 1 (3) ◽

pp. 100165

Author(s):

Fernando M. Nunez ◽

Jessica C. Gauss ◽

Flor M. Mendez ◽

Santiago Haase ◽

Pedro R. Lowenstein ◽

...

Keyword(s):

Mouse Model ◽

High Grade Glioma ◽

Genetically Engineered ◽

High Grade ◽

Genetically Engineered Mouse Model

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Is YKL-40 (CHI3-L1) a new possible biomarker prognosticator in high grade glioma?

Romanian Neurosurgery ◽

10.1515/romneu-2015-0033 ◽

2015 ◽

Vol 29 (3) ◽

pp. 247-253

Author(s):

A. Oslobanu ◽

St.I. Florian

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

Serum Level ◽

Imaging Techniques ◽

High Grade Glioma ◽

Cancer Cell Proliferation ◽

High Grade ◽

Antitumor Therapy ◽

Severity Of Disease ◽

Naturally Occurring

Abstract A biomarker is “a naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified” and it could be used a measurable indicator for the presence or severity of disease state. YKL-40 is a secreted glycoprotein associated with extracellular matrix, a member of the mammalian chitinase-like proteins that is expressed in a several types of solid tumors. Although the implication of this biomarker in tissue remodeling processes or the role in cancer cell proliferation, invasiveness, angiogenesis, and remodeling of the extracellular matrix is going to be well recognized, the regulation and role in glioblastoma multiforme (GBM) progression remains unknown. Using the serum level of YKL-40 as a single screening test in cancer cannot be used, but in association with other tumoral biomarkers and imaging techniques can be a useful tool as a “prognosticator.” Moreover, elucidation of the YKL-40 functions could be an attractive target for antitumor therapy.

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Abstract 869: Molecular characterization of a pediatric high-grade glioma (pHGG) mouse model harboring the H3.3 G34R mutation

10.1158/1538-7445.am2019-869 ◽

2019 ◽

Author(s):

Matthew J. Whalen ◽

Maria B. Garcia-Fabiani ◽

Felipe J. Núñez ◽

Pedro R. Lowenstein ◽

Maria G. Castro

Keyword(s):

Mouse Model ◽

Molecular Characterization ◽

High Grade Glioma ◽

High Grade ◽

Pediatric High Grade Glioma

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TMOD-36. THE DEVELOPMENT OF A NOVEL MOUSE MODEL TO STUDY THE ROLE OF HISTONE MUTATIONS AND MODIFICATIONS IN PEDIATRIC HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.986 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii235-ii235

Author(s):

Florina Grigore ◽

Charles Day ◽

Nicholas Hanson ◽

Alyssa Langfald ◽

Jann Sarkaria ◽

...

Keyword(s):

Mouse Model ◽

Clonal Selection ◽

Mutant Cell ◽

High Grade Glioma ◽

Early Event ◽

Low Grade ◽

High Grade ◽

Newborn Mice

Abstract Pediatric glioblastoma and diffuse intrinsic pontine glioma are high-grade gliomas of children (pHGG) with a median overall survival of under 15 months and among the most lethal cancers. Mutations in histone H3.3 and H3.1 occur as an early event in pHGG. H3.3G34R/V-mutations occur in pHGG of cerebral hemispheres, and H3.3K27M mutations occur in midline pHGGs. Post-translational histone modifications (PTMs) serve to regulate gene expression by relaxing or compacting chromatin and by recruiting proteins, with subsequent silencing or activating effects. H3.3 Serine 31 (S31) shows reduced phosphorylation during mitosis in H3.3G34R/V and H3.3K27M mutant cell. Phosphorylation at S31 is restored in wildtype H3.3K27 CRISPR revertants. Serine to alanine (A) mutant H3.3 S31A are nonphosphorylatable in vitro. To study the influence of histone mutations and the role of altered PTM and including the loss of methylation and phosphorylation on tumorigenesis, we have developed an innovative model based on the RCAS/N-TVA mouse model. In this system, the expression of an oncogenic driver is linked to mutant histone expression using a self-cleaving peptide, and tumors develop following viral delivery to neural stem cells in newborn mice. This approach is necessary, as otherwise, clonal selection could prevent tumors from forming with mutations detrimental to growth. To establish the model, N-TVA mice were injected with RCAS H3.3K27M-P2A-PDGFB, RCAS H3.3G34R-P2A-PDGFB, or H3.3WT-P2A-PDGFB. The mean survival of mice injected with H3.3K27M and H3.3S31A was 81 and 68 days, respectively, and 100% of S31A mice developed HGG. In contrast, H3.3WT caused only low-grade tumors in 46% of the mice, and all mice survived until 100 days. In ongoing experiments with H3.3G34R, 23% of mice succumb to tumors by 80 days. These results provide mechanistic insights into the early establishment of pHGGs and established a new mouse model to study the role of histone mutation and PTMs in tumor development.

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From Focused Ultrasound Tumor Ablation to Brain Blood Barrier Opening for High Grade Glioma: A Systematic Review

Cancers ◽

10.3390/cancers13225614 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5614

Author(s):

Luca Paun ◽

Alessandro Moiraghi ◽

Gianpaolo Jannelli ◽

Aria Nouri ◽

Francesco DiMeco ◽

...

Keyword(s):

Systematic Review ◽

Focused Ultrasound ◽

Case Series ◽

Major Complication ◽

High Grade Glioma ◽

Tumor Ablation ◽

Complication Rates ◽

High Grade ◽

Reliable Technique ◽

Bbb Opening

Background: Focused Ultrasound (FUS) is gaining a therapeutic role in neuro-oncology considering its novelty and non-invasiveness. Multiple pre-clinical studies show the efficacy of FUS mediated ablation and Blood-Brain Barrier (BBB) opening in high-grade glioma (HGG), but there is still poor evidence in humans, mainly aimed towards assessing FUS safety. Methods: With this systematic review our aim is, firstly, to summarize how FUS is proposed for human HGG treatment. Secondly, we focus on future perspectives and new therapeutic options. Using PRISMA 2020 guidelines, we reviewed case series and trials with description of patient characteristics, pre- and post-operative treatments and FUS outcomes. We considered nine case series (five about tumor ablation and four about BBB opening) with FUS-treated HGG patients between 1991 and 2021. Results: Sixty-eight patients were considered in total, mostly males (67.6%), with a mean age of 50.5 ± 15.3 years old. Major complication rates were found in the tumor ablation group (26.1%). FUS has been rarely applied for direct tumoral ablation in human HGG patients with controversial results, but at the best of current studies, FUS-mediated BBB opening is showing good results with very low complication rates, paving the way for a new reliable technique to improve local chemotherapy delivery and antitumoral immune response. Conclusions: FUS can become a complementary technique to surgical resection and standard radiochemotherapy in recurrent HGG. Ongoing trials could provide in the near future more data on FUS-mediated BBB opening impact on progression-free survival, overall survival and potential drug-delivery capacities.

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