Functionally defined therapeutic targets in diffuse intrinsic pontine glioma

Grasso, Catherine S.; Tang, Yujie; Truffaux, Nathalène; Berlow, Noah; Liu, Lining; Debily, Marie Anne; Quist, Michael J.; Davis, Lara E.; Huang, Elaine; Woo, Pamelyn; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa; Sun, Wenchao; Kogiso, Mari; Du, Yuchen; Qi, Lin; Huang, Yulun; Hütt-Cabezas, Marianne; Warren, Katherine E.; Dret, Ludivine Le; Meltzer, Paul S.; Mao, Hua; Quezado, Martha; Vuurden, Dannis G. van; Abraham, Jinu; Fouladi, Maryam; Svalina, Matthew N.; Wang, Nicholas; Hawkins, Cynthia; Nazarian, Javad; Alonso, Marta M.; Raabe, Eric H.; Hulleman, Esther; Spellman, Paul T.; Li, Xiao Nan; Keller, Charles; Pal, Ranadip; Grill, Jacques; Monje, Michelle

doi:10.1038/nm.3855

Cited by 515 publications

(584 citation statements)

References 25 publications

Supporting

Mentioning

547

Contrasting

Unclassified

Order By: Relevance

“…Performed in biological triplicate. d , mRNA expression levels of ADAM10 in primary tumor and cultures of DIPG by RNA-seq with values reported as FPKM 12,28 (left; n =8 primary samples, n =7 culture samples) and in 493 individual adult glioblastoma samples from TCGA 29 (right). Values are reported as robust multi-array averages (RMA; right).…”

Section: Extended Datamentioning

confidence: 99%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

Self Cite

368

359

View full text Add to dashboard Cite

Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy.

show abstract

Section: Extended Datamentioning

confidence: 99%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

Self Cite

368

359

View full text Add to dashboard Cite

show abstract

“…116 A recent study aimed to screen 83 drugs selected by pediatric neuro-oncologists as either promising targeted agents for cancer or traditional chemotherapeutic agents in use for pediatric brain tumor therapy. 117 The chemical screen and subsequent validation experiments revealed patient-derived DIPG cell sensitivity to HDAC inhibitors. Indeed, Western blot analyses of cells expressing the H3.3K27M mutation demonstrated a dosedependent increase in global H3 acetylation and H3K27 trimethylation following panobinostat treatment, suggesting that the drug produced partial rescue of the H3K27M-induced hypotrimethylation phenotype 117 (Fig.…”

Section: Histone Acetyltransferases and Deacetylasesmentioning

confidence: 99%

“…117 The chemical screen and subsequent validation experiments revealed patient-derived DIPG cell sensitivity to HDAC inhibitors. Indeed, Western blot analyses of cells expressing the H3.3K27M mutation demonstrated a dosedependent increase in global H3 acetylation and H3K27 trimethylation following panobinostat treatment, suggesting that the drug produced partial rescue of the H3K27M-induced hypotrimethylation phenotype 117 (Fig. 2).…”

Section: Histone Acetyltransferases and Deacetylasesmentioning

confidence: 99%

“…Consistent with previous findings, 108 the study confirmed that GSK-J4 decreased cell viability in H3K27M DIPG cell cultures, and further demonstrated that panobinostat synergized with GSK-J4 to significantly decrease cell viability in H3K27M mutant DIPG cell cultures. 117 In addition to glioma therapy, the therapeutic potential of HDAC inhibitors has also been investigated in ATRT. The rationale was that SNF5 protein loss leads to direct impairment of chromatin remodeling and changes in histone acetylation.…”

Section: Histone Acetyltransferases and Deacetylasesmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Maury

Hashizume

2017

Epigenetics

View full text Add to dashboard Cite

Malignancies are characterized by the reprogramming of epigenetic patterns. This reprogramming includes gains or losses in DNA methylation and disruption of normal patterns of covalent histone modifications, which are associated with changes in chromatin remodeling processes. This review will focus on the mechanisms underlying this reprogramming and, specifically, on the role of histone modification in chromatin machinery and the modifications in epigenetic processes occurring in brain cancer, with a specific focus on epigenetic therapies for pediatric brain tumors.

show abstract

“…17,18 A recent drug screen of genetically diverse and clinically relevant ex vivo DIPG cell lines revealed panobinostat as the most efficacious drug currently in clinical use. 19 Panobinostat therefore may be a particularly suitable drug candidate for both supratentorial and brainstem HGG chemotherapy in both adults and children.…”

Section: Introductionmentioning

confidence: 99%

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

Singleton¹,

Collins²,

Bienemann³

et al. 2017

IJN

View full text Add to dashboard Cite

Background The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood–brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). Materials and methods The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. Results Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P <0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. Conclusion CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.

show abstract

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma

Cited by 515 publications

References 25 publications

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

Contact Info

Product

Resources

About