scholarly journals A pilot precision medicine trial for children with diffuse intrinsic pontine glioma—PNOC003: A report from the Pacific Pediatric Neuro‐Oncology Consortium

2019 ◽  
Author(s):  
Sabine Mueller ◽  
Payal Jain ◽  
Winnie S. Liang ◽  
Lindsay Kilburn ◽  
Cassie Kline ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
The Pacific

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

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-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.

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

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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