Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience

2019 ◽  
Vol 114 ◽  
pp. 27-35 ◽  
Author(s):  
Elke Pfaff ◽  
Ahmed El Damaty ◽  
Gnana Prakash Balasubramanian ◽  
Mirjam Blattner-Johnson ◽  
Barbara C. Worst ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Study Experience ◽  
Brainstem Biopsy

scholarly journals DIPG-40. PNOC-003: PRECISION MEDICINE TRIAL FOR CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv14-iv14 ◽  
Author(s):  
Sabine Mueller ◽  
Winnie Liang ◽  
Nalin Gupta ◽  
Suresh Magge ◽  
Lindsay Kilburn ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma

scholarly journals Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care

2020 ◽  
Vol 48 (1) ◽  
pp. E4 ◽  
Author(s):  
John R. Williams ◽  
Christopher C. Young ◽  
Nicholas A. Vitanza ◽  
Margaret McGrath ◽  
Abdullah H. Feroze ◽  
...  
Keyword(s):  
Stereotactic Biopsy ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Brainstem Tumor ◽  
T Cell Therapy ◽  
The Us ◽  
Brainstem Tumors ◽  
Prospective Trials ◽  
Brainstem Biopsy

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor affecting approximately 300 children in the US annually. Median survival is less than 1 year, and radiation therapy has been the mainstay of treatment for decades. Recent advances in the biological understanding of the disease have identified the H3K27M mutation in nearly 80% of DIPGs, leading to the 2016 WHO classification of diffuse midline glioma H3K27M-mutant, a grade IV brainstem tumor. Developments in epigenetic targeting of transcriptional tendencies have yielded potential molecular targets for clinical trials. Chimeric antigen receptor T cell therapy has also shown preclinical promise. Recent clinical studies, including prospective trials, have demonstrated the safety and feasibility of pediatric brainstem biopsy in the setting of DIPG and other brainstem tumors. Given developments in the ability to analyze DIPG tumor tissue to deepen biological understanding of this disease and develop new therapies for treatment, together with the increased safety of stereotactic brainstem biopsy, the authors present a case for offering biopsy to all children with suspected DIPG. They also present their standard operative techniques for image-guided, frameless stereotactic biopsy.

scholarly journals DIPG-15. PNOC-003: CLINICAL IMPACT OF A PRECISION MEDICINE STRATEGY FOR CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA

2019 ◽  
Vol 21 (Supplement_2) ◽  
pp. ii71-ii71
Author(s):  
Sabine Mueller ◽  
Cassie Kline ◽  
Lindsay Kilburn ◽  
Winnie S Liang ◽  
Payal Jain ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Clinical Impact ◽  
Pontine Glioma

scholarly journals EXTH-46. ARTIFICIAL INTELLIGENCE-BASED IDENTIFICATION OF COMBINED VANDETANIB AND EVEROLIMUS IN THE TREATMENT OF ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii97-ii97
Author(s):  
Diana Carvalho ◽  
Peter Richardson ◽  
Nagore Gene Olaciregui ◽  
Reda Stankunaite ◽  
Cinzia Emilia Lavarino ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Cell Viability ◽  
Xenograft Model ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Serine Threonine Kinase ◽  
Orthotopic Xenografts ◽  
Extended Survival

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.

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

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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