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Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma.

ABSTRACT: Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK. In vivo experiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor penetration of the inhibitors into the brain. Further testing of this anti-DIPG strategy with compounds that penetrate the BBB is warranted.

SUBMITTER: Tsoli M

PROVIDER: S-EPMC5800923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Therapeutic targeting of transcriptional elongation in diffuse intrinsic pontine glioma.

Project description:BackgroundDiffuse intrinsic pontine glioma (DIPG) is associated with transcriptional dysregulation driven by H3K27 mutation. The super elongation complex (SEC) is required for transcriptional elongation through release of RNA polymerase II (Pol II). Inhibition of transcription elongation by SEC disruption can be an effective therapeutic strategy of H3K27M-mutant DIPG. Here, we tested the effect of pharmacological disruption of the SEC in H3K27M-mutant DIPG to advance understanding of the molecular mechanism and as a new therapeutic strategy for DIPG.MethodsShort hairpin RNAs (shRNAs) were used to suppress the expression of AF4/FMR2 4 (AFF4), a central SEC component, in H3K27M-mutant DIPG cells. A peptidomimetic lead compound KL-1 was used to disrupt a functional component of SEC. Cell viability assay, colony formation assay, and apoptosis assay were utilized to analyze the effects of KL-1 treatment. RNA- and ChIP-sequencing were used to determine the effects of KL-1 on gene expression and chromatin occupancy. We treated mice bearing H3K27M-mutant DIPG patient-derived xenografts (PDXs) with KL-1. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival.ResultsDepletion of AFF4 significantly reduced the cell growth of H3K27M-mutant DIPG. KL-1 increased genome-wide Pol II occupancy and suppressed transcription involving multiple cellular processes that promote cell proliferation and differentiation of DIPG. KL-1 treatment suppressed DIPG cell growth, increased apoptosis, and prolonged animal survival with H3K27M-mutant DIPG PDXs.ConclusionsSEC disruption by KL-1 increased therapeutic benefit in vitro and in vivo, supporting a potential therapeutic activity of KL-1 in H3K27M-mutant DIPG.

| S-EPMC8328031 | biostudies-literature

Diffuse intrinsic pontine glioma: time for therapeutic optimism.

Project description:Diffuse intrinsic pontine glioma (DIPG) is an aggressive tumor that is universally fatal, and to-date we are at a virtual standstill in improving its grim prognosis. Dearth of tissue due to rarity of biopsy has precluded understanding the elusive biology and frustration continues in reproducing faithful animal models for translational research. Furthermore the intricate anatomy of the pons has forestalled locoregional therapy and drug penetration. Over the last few years, biopsy-driven targeted therapy, development of vitro and xenograft animal models for therapeutic testing, profiling immunotherapeutic strategies and locoregional infusion of drugs in brain stem tumors, now provide a sense of hope in the years ahead. This review aims to discuss current status and advances in the management of these tumors.

| S-EPMC6113938 | biostudies-other

Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma.

Project description:Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease. We have developed non-persistent gold nano-architectures (NAs) functionalised with human serum albumin (HSA) for the delivery of doxorubicin. Doxorubicin has been previously reported to be cytotoxic in DIPG cells. In this study, we have preclinically evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoarchitectures (NAs-HSA-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and doxorubicin-loaded NAs. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on colony formation compared to doxorubicin. Western blot analysis indicated increased apoptotic markers cleaved Parp, cleaved caspase 3 and phosphorylated H2AX in NAs-HSA-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of NAs-HSA-Dox into DIPG neurospheres compared to doxorubicin alone. Despite the potency of the NAs in vitro, treatment of an orthotopic model of DIPG showed no antitumour effect. This disparate outcome may be due to the integrity of the blood-brain barrier and highlights the need to develop therapies to enhance penetration of drugs into DIPG.

| S-EPMC7999568 | biostudies-literature

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.

Project description:Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.

| S-EPMC4862411 | biostudies-literature

The dual mTOR kinase inhibitor TAK228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma.

Project description:Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKTS473 and p-S6S240/244 and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis. TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p = 0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment.

| S-EPMC5569904 | biostudies-literature

Diffuse Intrinsic Pontine Glioma

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-03-31 | E-GEOD-50025 | biostudies-arrayexpress

Diffuse intrinsic pontine glioma: molecular landscape and emerging therapeutic targets.

Project description:Purpose of reviewDiffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem malignancy. Despite advances in understanding of the molecular underpinnings of the tumor in the past decade, the dismal prognosis of DIPG has thus far remained unchanged. This review seeks to highlight promising therapeutic targets within three arenas: DIPG cell-intrinsic vulnerabilities, immunotherapeutic approaches to tumor clearance, and microenvironmental dependencies that promote tumor growth.Recent findingsPromising therapeutic strategies from recent studies include epigenetic modifying agents such as histone deacetylase inhibitors, bromodomain and extra-terminal motif (BET) protein inhibitors, and CDK7 inhibitors. Tumor-specific immunotherapies are emerging. Key interactions between DIPG and normal brain cells are coming to light, and targeting critical microenvironmental mechanisms driving DIPG growth in the developing childhood brain represents a new direction for therapy.SummarySeveral DIPG treatment strategies are being evaluated in early clinical trials. Ultimately, we suspect that a multifaceted therapeutic approach utilizing cell-intrinsic, microenvironmental, and immunotherapeutic targets will be necessary for eradicating DIPG.

| S-EPMC7242222 | biostudies-literature

Diffuse Intrinsic Pontine Glioma

Project description:This SuperSeries is composed of the SubSeries listed below.

2014-03-31 | GSE50025 | GEO

Diffuse Intrinsic Pontine Glioma: New Pathophysiological Insights and Emerging Therapeutic Targets.

Project description:BACKGROUND:Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor-related death in children, with median survival of less than one year. Despite decades of clinical trials, there has been no improvement in prognosis since the introduction of radiotherapy over thirty years ago. OBJECTIVE:To review the clinical features and current treatment challenges of DIPG, and discuss emerging insights into the unique genomic and epigenomic mechanisms driving DIPG pathogenesis that present new opportunities for the identification of therapeutic targets. CONCLUSION:In recent years, an increased availability of biopsy and rapid autopsy tissue samples for preclinical investigation has combined with the advent of new genomic and epigenomic profiling tools to yield remarkable advancements in our understanding of DIPG disease mechanisms. As well, a deeper understanding of the developmental context of DIPG is shedding light on therapeutic targets in the microenvironment of the childhood brain.

| S-EPMC5327455 | biostudies-literature

Targeting Sphingosine Kinase by ABC294640 against Diffuse Intrinsic Pontine Glioma (DIPG).

Project description:As a highly aggressive pediatric brainstem tumor, diffuse intrinsic pontine glioma (DIPG) accounts for 10% to 20% of childhood brain tumors. The survival rate for DIPG remains very low, with a median survival time as less than one year even under radiotherapy, the current standard treatment. Moreover, over than 250 clinical trials have failed when trying to improve the survival compared to radiotherapy. The sphingolipid metabolism and related signaling pathways have been found closely related to cancer cell survival; however, the sphingolipid metabolism targeted therapies have never been investigated in DIPG. In the current study, the anti-DIPG activity of ABC294640, the only first-in-class orally available Sphingosine kinase (SphK) inhibitor was explored. Treatment with ABC294640 significantly repressed DIPG cell growth by inducing intracellular pro-apoptotic ceramides production and cell apoptosis. We also profiled ABC294640-induced changes in gene expression within DIPG cells and identified many new genes tightly controlled by sphingolipid metabolism, such as IFITM1 and KAL1. These genes are required for DIPG cell survival and display clinical relevance in DIPG patients' samples. Together, our findings in this study indicate that targeting sphingolipid metabolism may represent a promising strategy to improve DIPG treatment.

| S-EPMC7330698 | biostudies-literature

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