Importance of immune monitoring approaches and the use of immune checkpoints for the treatment of diffuse intrinsic pontine glioma: From bench to clinic and vice versa (Review)

Abstract Somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, are found in a quarter of children with the currently incurable brain tumour diffuse intrinsic pontine glioma (DIPG). Treatment of ACVR1-mutant DIPG patient-derived models with multiple inhibitor chemotypes leads to a reduction in cell viability in vitro and extended survival in orthotopic xenografts in vivo, though there are currently no specific ACVR1 inhibitors licensed for DIPG. Using an Artificial Intelligence-based platform to search for approved compounds which could be used to treat ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an approved inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has been trialed in DIPG patients with limited success, in part due to an inability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits both ABCG2 (BCRP) and ABCB1 (P-gp) transporter, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumour burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Based on these preclinical data, three patients with ACVR1-mutant DIPG were treated with vandetanib and everolimus. These cases may inform on the dosing and the toxicity profile of this combination for future clinical studies. This bench-to-bedside approach represents a rapidly translatable therapeutic strategy in children with ACVR1 mutant DIPG.

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EPCT-16. A PHASE IB STUDY OF PTC596 IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA AND HIGH GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.138 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii306-iii307

Author(s):

Natasha Pillay Smiley ◽

Patricia Baxter ◽

Shiva Kumar ◽

Eugene Hwang ◽

John Breneman ◽

...

Keyword(s):

Cell Cycle ◽

Dose Level ◽

Diffuse Intrinsic Pontine Glioma ◽

High Grade ◽

Newly Diagnosed ◽

Post Translational Modification ◽

Pontine Glioma ◽

M Cell ◽

Drug Induced ◽

Level 1

Abstract BACKGROUND BMI-1 is highly expressed in DIPG. Downregulation leads to inhibition of cell proliferation, cell cycle signaling, self-renewal, telomerase expression, activity, and suppression of DIPG cell migration. Targeted inhibition of BMI-1 sensitizes DIPG cells to radiation and drug-induced DNA damage. PTC596 (formulated by PTC Therapeutics, Inc.) is a novel, orally available drug that inhibits microtubule polymerization, resulting in G2/M cell cycle arrest and post-translational modification of BMI-1 protein and reduced BMI-1 protein levels. OBJECTIVES: To estimate the maximum tolerated dose and describe dose limiting toxicities, pharmacokinetics and pharmacodynamics of PTC596 in children 3–21 years of age with newly diagnosed diffuse intrinsic pontine glioma and high-grade gliomas. METHODS PTC596 is administered twice per week orally during radiotherapy and as maintenance for up to two years. The starting dose of PTC596 was 200 mg/m2, with a subsequent dose level of 260mg/m2/dose. Pharmacokinetics are performed in Cycles 1 and 2. RESULTS This study is currently ongoing. Nine patients (7 with DIPG, 2 with HGG), 8 evaluable, have been enrolled. At dose level 1, 200 mg/m2, three evaluable patients were enrolled and experienced no DLTs. At dose level 2, among 5 evaluable patients, 2 experienced dose-limiting grade 4 neutropenia. PTC596 has been otherwise well tolerated. Five patients remain in Cycles 2–11. CONCLUSION This phase I trial is ongoing. PTC596 is tolerable at dose level 1. We are amending the protocol to introduce tablets that can be dissolved in liquid to allow enrollment of younger patients and those unable to swallow whole tablets.

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DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.087 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii294-iii295

Author(s):

Jovana Pavisic ◽

Chankrit Sethi ◽

Chris Jones ◽

Stergios Zacharoulis ◽

Andrea Califano

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Treatment Options ◽

Diffuse Intrinsic Pontine Glioma ◽

Low Grade ◽

Precision Oncology ◽

Pontine Glioma ◽

Convection Enhanced Delivery ◽

Master Regulator

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of >100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

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Diffuse intrinsic pontine glioma: current insights and future directions

Chinese Neurosurgical Journal ◽

10.1186/s41016-020-00218-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dilakshan Srikanthan ◽

Michael S. Taccone ◽

Randy Van Ommeren ◽

Joji Ishida ◽

Stacey L. Krumholtz ◽

...

Keyword(s):

Brain Tumor ◽

Gene Mutations ◽

Pediatric Brain Tumor ◽

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma ◽

Current Standard ◽

In Vivo Models ◽

Landscape Models

AbstractDiffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor–related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

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DIPG-03. THERAPEUTIC TARGETING OF TRANSCRIPTIONAL ELONGATION IN DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.055 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii287-iii287

Author(s):

Hiroaki Katagi ◽

Nozomu Takata ◽

Yuki Aoi ◽

Yongzhan Zhang ◽

Emily J Rendleman ◽

...

Keyword(s):

Rna Polymerase Ii ◽

Transcription Elongation ◽

Xenograft Model ◽

Diffuse Intrinsic Pontine Glioma ◽

Transcriptional Elongation ◽

Pontine Glioma ◽

Elongation Complex ◽

Pol Ii ◽

Repair Genes ◽

Novel Therapeutic

Abstract Diffuse intrinsic pontine glioma (DIPG) is highly aggressive brain stem tumor and needed to develop novel therapeutic agents for the treatment. The super elongation complex (SEC) is essential for transcription elongation through release of RNA polymerase II (Pol II). We found that AFF4, a scaffold protein of the SEC, is required for the growth of H3K27M-mutant DIPG cells. In addition, the small molecule SEC inhibitor, KL-1, increased promoter-proximal pausing of Pol II, and reduced transcription elongation, resulting in down-regulate cell cycle, transcription and DNA repair genes. KL-1 treatment decreased cell growth and increased apoptosis in H3K27M-mutant DIPG cells, and prolonged animal survival in our human H3K27M-mutant DIPG xenograft model. Our results demonstrate that the SEC disruption by KL-1 is a novel therapeutic strategy for H3K27M-mutant DIPG.

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MODL-12. DEVELOPMENT OF A NOVEL IMMUNOCOMPETENT MOUSE MODEL FOR DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.586 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii413-iii413

Author(s):

Maggie Seblani ◽

Markella Zannikou ◽

Katarzyna Pituch ◽

Liliana Ilut ◽

Oren Becher ◽

...

Keyword(s):

Flow Cytometry ◽

Mouse Model ◽

Growth Factor Receptor ◽

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma ◽

Time Of Application ◽

Tumor Associated Antigen ◽

Sarcoma Virus

Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor affecting young children. Immunotherapies hold promise however the lack of immunocompetent models recreating a faithful tumor microenvironment (TME) remains a challenge for development of targeted immunotherapeutics. We propose to generate an immunocompetent DIPG mouse model through induced overexpression of interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen overexpressed by glioma cells. A model with an intact TME permits comprehensive preclinical assessment of IL13Rα2-targeted immunotherapeutics. Our novel model uses the retroviral avian leucosis and sarcoma virus (RCAS) for in vivo gene delivery leading to IL13Rα2 expression in proliferating progenitor cells. Transfected cells expressing IL13Rα2 and PDGFB, a ligand for platelet derived growth factor receptor, alongside induced p53 loss via the Cre-Lox system are injected in the fourth ventricle in postnatal pups. We validated the expression of PDGFB and IL13Rα2 transgenes in vitro and in vivo and will characterize the TME through evaluation of the peripheral and tumor immunologic compartments using immunohistochemistry and flow cytometry. We confirmed expression of transgenes via flow cytometry and western blotting. Comparison of survival dynamics in mice inoculated with PDGFB alone with PDGFB+IL13Rα2 demonstrated that co-expression of IL13Rα2 did not significantly affect mice survival compared to the PDGFB model. At time of application, we initiated experiments to characterize the TME. Preliminary data demonstrate establishment of tumors within and adjacent to the brainstem and expression of target transgenes. Preclinical findings in a model recapitulating the TME may provide better insight into outcomes upon translation to clinical application.

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IMG-09. RESPONSE ASSESSMENT IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY COMMITTEE

Neuro-Oncology ◽

10.1093/neuonc/noaa222.345 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii356-iii357

Author(s):

Tabitha Cooney ◽

Kenneth J Cohen ◽

Carolina V Guimaraes ◽

Girish Dhall ◽

James Leach ◽

...

Keyword(s):

Drug Delivery ◽

Clinical Trials ◽

Response Duration ◽

Response Assessment ◽

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma ◽

Response Data ◽

International Panel ◽

Children And Young Adults ◽

Magnetic Resonance Imaging Mri

Abstract Optimizing the conduct of clinical trials for diffuse intrinsic pontine glioma (DIPG) involves use of consistent, objective disease assessments and standardized response criteria. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, an international panel of pediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response in children with CNS tumors. A subcommittee of RAPNO was formed to specifically address response assessment in children and young adults with DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its definition and recent molecular classifications, dearth of imaging response data, the phenomena of pseudoprogression, and measuring response in the era of focal drug delivery. The committee has recommended response be assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and anti-angiogenic agents. Clinical imaging standards and imaging quality control are defined. Unique recommendations for DIPG response include an eight-week response duration, a twenty-five percent decrease for partial response, and the distinction of pontine and extra-pontine response for trials that use focal drug delivery. The recommendations presented here represent an initial effort to uniformly collect and evaluate response assessment criteria; these recommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.

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