Diffuse Intrinsic Pontine Gliomas

Bredlau, Amy Lee; Korones, David N.

doi:10.1016/b978-0-12-800249-0.00006-8

Cited by 18 publications

(4 citation statements)

References 114 publications

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“…Standard of care for pHGG consists of radiation often combined with chemotherapy and experimental therapeutics ( Fangusaro, 2009 ; Jones et al, 2012 ; Adamski et al, 2014 ; Bredlau and Korones, 2014 ). Many of these treatments have adverse consequences, including cognitive deficits, endocrine disorders, and vasculopathies, and none of these therapeutic strategies are curative ( Armstrong et al, 2004 ; Merchant et al, 2009 ; Mueller et al, 2013 ).…”

Section: Profiling Treatment-associated Changes In the Intratumoral H...mentioning

confidence: 99%

Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma

Murdaugh

Anastas

2023

Front. Pharmacol.

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Despite improvements in cancer patient outcomes seen in the past decade, tumor resistance to therapy remains a major impediment to achieving durable clinical responses. Intratumoral heterogeneity related to genetic, epigenetic, transcriptomic, proteomic, and metabolic differences between individual cancer cells has emerged as a driver of therapeutic resistance. This cell to cell heterogeneity can be assessed using single cell profiling technologies that enable the identification of tumor cell clones that exhibit similar defining features like specific mutations or patterns of DNA methylation. Single cell profiling of tumors before and after treatment can generate new insights into the cancer cell characteristics that confer therapeutic resistance by identifying intrinsically resistant sub-populations that survive treatment and by describing new cellular features that emerge post-treatment due to tumor cell evolution. Integrative, single cell analytical approaches have already proven advantageous in studies characterizing treatment-resistant clones in cancers where pre- and post-treatment patient samples are readily available, such as leukemia. In contrast, little is known about other cancer subtypes like pediatric high grade glioma, a class of heterogeneous, malignant brain tumors in children that rapidly develop resistance to multiple therapeutic modalities, including chemotherapy, immunotherapy, and radiation. Leveraging single cell multi-omic technologies to analyze naïve and therapy-resistant glioma may lead to the discovery of novel strategies to overcome treatment resistance in brain tumors with dismal clinical outcomes. In this review, we explore the potential for single cell multi-omic analyses to reveal mechanisms of glioma resistance to therapy and discuss opportunities to apply these approaches to improve long-term therapeutic response in pediatric high grade glioma and other brain tumors with limited treatment options.

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Section: Profiling Treatment-associated Changes In the Intratumoral H...mentioning

confidence: 99%

Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma

Murdaugh

Anastas

2023

Front. Pharmacol.

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“…Several studies have attempted to improve the efficacy of conventional therapy using dose escalation as well as alternative fractionation schedules (with increased biologically effective doses) and concurrent/adjuvant chemotherapy. Unfortunately, results have been uniformly disappointing, as none of these approaches improve survival more than palliative treatment alone (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Rapid Peroxide Removal Limits the Radiosensitization of Diffuse Intrinsic Pontine Glioma (DIPG) Cells by Pharmacologic Ascorbate

Solst,

Mapuskar,

Graham

et al. 2023

Radiation Research

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Diffuse intrinsic pontine gliomas (DIPG) are an aggressive type of pediatric brain tumor with a very high mortality rate. Surgery has a limited role given the tumor’s location. Palliative radiation therapy alleviates symptoms and prolongs survival, but median survival remains less than 1 year. There is no clear role for chemotherapy in DIPGs as trials adding chemotherapy to palliative radiation therapy have failed to improve survival compared to radiation alone. Thus, there is a critical need to identify tissue-specific radiosensitizers to improve clinical outcomes for patients with DIPGs. Pharmacologic (high dose) ascorbate (P-AscH–) is a promising anticancer therapy that sensitizes human tumors, including adult high-grade gliomas, to radiation by acting selectively as a generator of hydrogen peroxide (H2O2) in cancer cells. In this study we demonstrate that in contrast to adult glioma models, P-AscH– does not radiosensitize DIPG. DIPG cells were sensitive to bolus of H2O2 but have faster H2O2 removal rates than GBM models which are radiosensitized by P-AscH–. These data support the hypothesis that P-AscH– does not enhance DIPG radiosensitivity, likely due to a robust capacity to detoxify and remove hydroperoxides.

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“…Clinical trials assessing both single agent and combination chemotherapies have failed to improve the survival of patients with DIPG [4,5]. A key factor believed to be limiting the efficacy of these agents is an intact blood brain barrier (BBB) [6].…”

Section: Introductionmentioning

confidence: 99%

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery

Alli

Figueiredo

Golbourn

et al. 2018

Journal of Controlled Release

112

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Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H&E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions.

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Diffuse Intrinsic Pontine Gliomas

Cited by 18 publications

References 114 publications

Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma

Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma

Rapid Peroxide Removal Limits the Radiosensitization of Diffuse Intrinsic Pontine Glioma (DIPG) Cells by Pharmacologic Ascorbate

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery

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