Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas

King, A.O.; Corso, Christopher D.; Chen, Evan M.; Song, Eric; Bongiorni, Paul; Chen, Zhe; Sundaram, Ranjini K.; Bindra, Ranjit S.; Saltzman, W. Mark

doi:10.1158/1535-7163.mct-16-0788

Cited by 27 publications

(21 citation statements)

References 74 publications

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“…It is also a highly infiltrative tumor and chemotherapy has modest efficacy at best. Therefore, focal radiation therapy is the current accepted standard of care [ 1 , 9 , 10 ]. Thus, there is a clear need for new therapies based on a better understanding of tumor biology.…”

Section: Introductionmentioning

confidence: 99%

REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

et al. 2017

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Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on anti-angiogenic therapies targeting GREM-1 in combination with drugs that target REST-associated chromatin remodeling activities.

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Section: Introductionmentioning

confidence: 99%

REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

et al. 2017

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“…Polyethylene glycol (PEG)-b-Polylactic acid (PLA) nanoparticles (NP) were synthesized using diblock polymer (Mw PEG ¼ 5 kDa, Mw PLA ¼ 10 kDa; Polysciences, Inc.) and Polyethyeleneimine (PEI; branchedaverage Mw $800, average Mn $600; Sigma-Aldrich) using a nanoprecipitation technique, similar to one previously reported (26). For control NPs, 100 mg of polymer was dissolved in 5 mL DMSO at room temperature for 2 hours and a 200 mL aliquot was added dropwise to 1 mL deionized (DI) water under strong vortex to create an NP suspension.…”

Section: Ngi-1 Nanoparticle Preparation and Evaluationmentioning

confidence: 99%

Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity

Baro

Sambrooks

Quijano

et al. 2019

Clinical Cancer Research

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Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)-targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera. NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect. This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radiosensitize malignant gliomas with enhanced RTK signaling.

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“…PEGylated nanoparticles loaded with paclitaxel [30], cisplatin [31], and gemcitabine [32] have been demonstrated to enhance drug distribution, prolong release, and enhance anti-tumor effects in animal models. CED of PLA-PEG nanoparticles loaded with VE822, a DNA repair inhibitor, provided effective radiosensitization and survival benefit in animals treated with fractionated radiation therapy [33]. It is important to note that PEGylation—which can facilitate penetration of certain nanoparticle compositions—can also diminish cell uptake, so the effect of these competing factors must be considered.…”

Section: Nanocarriers Encapsulating Therapeutic Agentsmentioning

confidence: 99%

Nanomaterials for convection-enhanced delivery of agents to treat brain tumors

Seo

Saltzman

2017

Current Opinion in Biomedical Engineering

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Nanomaterials represent a promising and versatile platform for the delivery of therapeutics to the brain. Treatment of brain tumors has been a long-standing challenge in the field of neuro-oncology. The current standard of care – a multimodal approach of surgery, radiation and chemotherapy – yields only a modest therapeutic benefit for patients with malignant gliomas. A major obstacle for treatment is the failure to achieve sufficient delivery of therapeutics at the tumor site. Recent advances in local drug delivery techniques, along with the development of highly effective brain-penetrating nanocarriers, have significantly improved treatment and imaging of brain tumors in preclinical studies. The major advantage of this combined strategy is the ability to optimize local therapy, by maintaining an effective and sustained concentration of therapeutics in the brain with minimal systemic toxicity. This review highlights some of the latest developments, significant advancements and current challenges in local delivery of nanomaterials for the treatment of brain tumors.

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Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas

Cited by 27 publications

References 74 publications

REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity

Nanomaterials for convection-enhanced delivery of agents to treat brain tumors

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