scholarly journals DIPG-75. PRECISION MEDICINE FOR PAEDIATRIC HIGH-GRADE DIFFUSE MIDLINE GLIOMAS - RESULTS FROM THE ZERO CHILDHOOD CANCER COMPREHENSIVE PRECISION MEDICINE PROGRAM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii302-iii302
Author(s):  
Dong-Anh Khuong-Quang ◽  
Sumanth Nagabushan ◽  
Neevika Manoharan ◽  
Greg Arndt ◽  
Paulette Barahona ◽  
...  
Keyword(s):  
Childhood Cancer ◽  
Precision Medicine ◽  
Drug Testing ◽  
Kinase Inhibitors ◽  
Mtor Inhibitors ◽  
High Grade Glioma ◽  
Molecular Profiling ◽  
Response To Treatment ◽  
High Grade

Abstract The Australian Zero Childhood Cancer (ZERO) program aims to assess the feasibility of a comprehensive precision medicine approach to improve outcomes for patients with an expected survival <30%. ZERO combines molecular profiling (whole genome sequencing, whole transcriptome sequencing, DNA methylation profiling) with in vitro high-throughput drug screening (HTS) and patient-derived xenograft drug efficacy testing. We report on the cohort of patients with midline high-grade glioma (HGG), including H3-K27M DMG, enrolled on the pilot study (TARGET) and on the ongoing ZERO clinical trial (PRISM). We identified 48 patients with midline HGG. Fresh or cryopreserved samples were submitted in 37 cases and cell culture was attempted in 30/37 cases with 45% success rate. The most commonly mutated genes/pathways identified by molecular profiling include H3-K27M mutations, DNA repair pathway, and PI3K/mTOR pathway. Two targetable fusions (NTRK and FGFR1) were reported. Five patients with germline alterations were identified. Thirty-five (72%) patients received a therapeutic recommendation from the ZERO molecular tumour board and the main recommended therapies were mTOR inhibitors, PARP inhibitors or tyrosine kinase inhibitors. HTS added evidence for the recommended therapy (n=3) or identified novel potential therapy (n=1). Out of the 35 patients, 16 received a recommended drug. Response to treatment was complete response for five months (n=1), partial response for nine months (n=1), stable disease (n=4), and progressive disease (n=10). These results highlight the feasibility of the ZERO platform and the value of fresh biopsy, necessary for pre-clinical drug testing. Targetable alterations were identified leading to clinical benefit in six patients.

scholarly journals HGG-36. HIF-2: A NEW DRUG TARGET IN PEDIATRIC HIGH-GRADE GLIOMA WITH PROMISING PRECLINICAL RESULTS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii350-iii350
Author(s):  
Quentin Fuchs ◽  
Marina Pierrevelcin ◽  
Christophe Papin ◽  
Monique Dontenwill ◽  
Natacha Entz-Werlé
Keyword(s):  
Drug Testing ◽  
Treatment Resistance ◽  
High Grade Glioma ◽  
Clinical Work ◽  
Driver Mutations ◽  
High Grade ◽  
Innovative Strategy ◽  
Dismal Prognosis ◽  
Cell Arrest ◽  
And Migration

Abstract Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis and need new innovative strategy for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies wish to go further discovering new targetable proteins in pHGG. In our past clinical work, we were able to link significantly HIF-2alpha to a worse pHGG outcome and to their treatment resistance. We designed this new work to determine in several patient-derived cell lines (6 PDCLs) with or without H3.3 mutation the variation of HIF-2alpha, its role, its induction in normoxic and hypoxic microenvironment and its transcriptional targets using RNAseq, metabolomics and ChipSeq analyses. Complementary functional analyses were performed using siRNA strategy during cultures and migration assays. Finally, preclinical drug testing involving commercialized and non-commercialized HIF-2alpha specific inhibitors in the same PDCLs were evaluating their antiproliferative and pro-apoptotic effect. Our results confirmed the central role of HIF-2alpha in cell resistance to treatment, in pHGG stemness features and its direct link with metabolism adaptation and histone interaction. After the confirmation of its frequent presence in multiple PDCLs initiated from thalamic pHGGs and DIPG, we were using inhibitors in a single and combinatorial strategy targeting HIF-2alpha plus another hypoxia biomarker (mTor). This preclinical targeting was highly effective to favor cell arrest, apoptosis and to stop cell migration. In conclusion, HIF-2alpha seem to be a major biomarker in pHGGs that might be targeted giving a useful new opportunity for pHGG treatments.

scholarly journals Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

2021 ◽  
Vol 22 (6) ◽  
pp. 2962
Author(s):  
Louise Orcheston-Findlay ◽  
Samuel Bax ◽  
Robert Utama ◽  
Martin Engel ◽  
Dinisha Govender ◽  
...  
Keyword(s):  
Life Expectancy ◽  
High Throughput Screening ◽  
High Grade Glioma ◽  
Tumour Microenvironment ◽  
In Vitro Models ◽  
Treatment Modalities ◽  
High Grade ◽  
Future Improvement ◽  
Complex Models

The life expectancy of patients with high-grade glioma (HGG) has not improved in decades. One of the crucial tools to enable future improvement is advanced models that faithfully recapitulate the tumour microenvironment; they can be used for high-throughput screening that in future may enable accurate personalised drug screens. Currently, advanced models are crucial for identifying and understanding potential new targets, assessing new chemotherapeutic compounds or other treatment modalities. Recently, various methodologies have come into use that have allowed the validation of complex models—namely, spheroids, tumouroids, hydrogel-embedded cultures (matrix-supported) and advanced bioengineered cultures assembled with bioprinting and microfluidics. This review is designed to present the state of advanced models of HGG, whilst focusing as much as is possible on the paediatric form of the disease. The reality remains, however, that paediatric HGG (pHGG) models are years behind those of adult HGG. Our goal is to bring this to light in the hope that pGBM models can be improved upon.

CBIO-11. HISTONE H3.3 G34R/V MUTATIONS STIMULATE PEDIATRIC HIGH-GRADE GLIOMA FORMATION THROUGH THE INDUCTION OF CHROMOSOMAL INSTABILITY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi29-vi29
Author(s):  
Charles Day ◽  
Florina Grigore ◽  
Alyssa Langfald ◽  
Edward Hinchcliffe ◽  
James Robinson
Keyword(s):  
Gene Regulation ◽  
Chromosomal Instability ◽  
High Grade Glioma ◽  
Kinase Assay ◽  
High Grade ◽  
Newborn Mice ◽  
Cycle Arrest ◽  
Epigenetic Gene Regulation ◽  
Diploid Cells

Abstract H3.3 G34R/V mutations are drivers of high-grade pediatric glioma (pHGG). H3.3 G34R/V mutations are linked to altered H3.3 K36 trimethylation (H3K36me3); implicating epigenetic gene regulation as a possible contributor to pHGG formation. Here we show that H3.3 G34R/V also induces chromosomal instability (CIN); a hallmark of pHGG. If CIN promotes pHGG formation is unknown. We observed that H3.3 G34 mutant pHGG cells have reduced mitotic H3.3 S31 phosphorylation compare to WT H3.3 cell lines. And, H3.3 G34R reduced Chk1 phosphorylation at S31 by >90% in an in vitro kinase assay. Chk1 regulates chromosome segregation through phosphorylation of pericentromeric H3.3 S31 during early mitosis. Overexpression of H3.3 G34R or non-phosphorylatable S31A in H3.3 WT, diploid cells caused a significant increase in CIN. Likewise, H3.3 G34 mutant pHGG cells have significantly elevated rates of CIN as compare to H3.3 WT pHGG cells. During normal cell division, phospho-S31 is lost in anaphase. However, following chromosome missegregation, phospho-S31 spreads and stimulates p53-induced cell cycle arrest. Here we show that WT p53 cells expressing mutant G34 fail to arrest following chromosome mis-segregation. These studies demonstrate that H3.3 G34R/V mutations are sufficient to transform normal, diploid cells into proliferating CIN cells. To determine if this process contributes to tumorigenesis, we used RCAS Nestin-TVA mice to overexpress H3.3 WT, G34R, or S31A – P2A-linked to PDGFB expression in glial precursor cells of newborn mice. Over 100 days, S31A and G34R mice had drastically reduced survival (averaging 77, 81, and 100 days for S31A, G34R, and WT). Furthermore, most G34R and S31A mice developed HGG, while H3.3 WT mice remained tumor-free. Our work implicates CIN as a driver of H3.3 G34 mutant pHGG formation. Our ongoing studies utilize K36M and double mutants to further define the contributions of S31 phosphorylation (CIN) and H3K36me3 (epigenetic gene regulation) to tumorigenesis.

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

β-arrestin 1 transfection induced cell death in high grade glioma in vitro

2020 ◽  
pp. 1-12
Author(s):  
Catalin Folcuti ◽  
Cristina Horescu ◽  
Edmond Barcan ◽  
Oana Alexandru ◽  
Cristian Tuta ◽  
...  
Keyword(s):  
Cell Death ◽  
High Grade Glioma ◽  
High Grade

scholarly journals HGG-23. DRUG SCREENING LINKED TO MOLECULAR PROFILING IDENTIFIES NOVEL DEPENDENCIES IN PATIENT-DERIVED PRIMARY CULTURES OF PAEDIATRIC HIGH GRADE GLIOMA AND DIPG

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i93-i94
Author(s):  
Alan Mackay ◽  
Valeria Molinari ◽  
Diana Carvalho ◽  
Helen Pemberton ◽  
Sara Temelso ◽  
...  
Keyword(s):  
Drug Screening ◽  
Primary Cultures ◽  
High Grade Glioma ◽  
Molecular Profiling ◽  
High Grade

Tolerability and preliminary efficacy of BXQ-350 for refractory solid tumors and high-grade gliomas: First-in-human, first-in-class phase I trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3505-3505
Author(s):  
Olivier Rixe ◽  
John Charles Morris ◽  
Robert Wesolowski ◽  
Emrullah Yilmaz ◽  
Richard Curry ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Human Study ◽  
Treatment Protocol ◽  
High Grade Glioma ◽  
Maximum Tolerated Dose ◽  
High Grade ◽  
Serious Adverse Events

3505 Background: BXQ-350 is a first-in-class agent comprised of Saposin C (SapC) and dioleoyl phosphatidylserine (DOPS). SapC, a multifunctional lysosomal-activator glycoprotein that preferentially interacts with tumor cell phospholipids, has demonstrated anti-tumor effects in both in vitro and in vivo preclinical models. The tolerability and preliminary efficacy of BXQ-350 in the first-in-human study are summarized here. Methods: Eighty-six refractory solid tumor (ST) or high-grade glioma (HGG) patients age ≥18 (36F:50M, age 24-81) were enrolled in a 3-part first-in-human trial (NCT02859857) from 2016-2019 and received at least one dose of BXQ-350. Doses were administered via intravenous infusion during 28-day cycles until disease progression occurred. The previously reported part 1 dose escalation portion of the study (9 HGG, 9 ST patients) established the highest planned dose of 2.4mg/kg as safe but did not identify a maximum tolerated dose. The part 2 expansion cohort treated 37 patients (18 HGG and 19 ST) and an additional part 3 cohort treated 31 ST gastrointestinal (GI) patients, both at the 2.4 mg/kg dose level. Preliminary antitumor activity was evaluated (RECISTv1.1 or RANO). Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals with the exception of 1 allergic type reaction. Three patients (Glioblastoma, Ependymoma, Appendiceal) demonstrated a partial response per RECIST/RANO. Two HGG patients with progressive radiologic enhancement were seen to have treatment effect at surgery, and hence considered to have stable disease. Seven patients (2 HGG, 3 GI, 2 other ST) remain on study and have received treatment for 9+ to 41+ months, with 5 patients treated for > 1 year. A continuing treatment protocol is planned in order to allow these patients to remain on BXQ-350 treatment. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. Preliminary results indicate this novel agent demonstrated possible anti-tumor activity in refractory solid tumors and HGG. Clinical trial information: NCT03967093) .

scholarly journals ABCG1 maintains high-grade glioma survival in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 7 (17) ◽  
pp. 23416-23424 ◽  
Author(s):  
Yi-Hsien Chen ◽  
Patrick J. Cimino ◽  
Jingqin Luo ◽  
Sonika Dahiya ◽  
David H. Gutmann
Keyword(s):  
High Grade Glioma ◽  
High Grade

In Vitro Evaluation of Iodine-125-Labeled Monoclonal Antibody (MAb 425) in Human High-Grade Glioma Cells

1996 ◽  
Vol 19 (6) ◽  
pp. 601-608 ◽  
Author(s):  
Jacqueline G. Emrich ◽  
Hans Bender ◽  
Reiner Class ◽  
Jeffrey Eshleman ◽  
Curtis Miyamoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
High Grade ◽  
In Vitro Evaluation ◽  
Iodine 125

scholarly journals Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

2020 ◽  
Vol 10 (4) ◽  
pp. 290
Author(s):  
Lisa Mayr ◽  
Armin S. Guntner ◽  
Sibylle Madlener ◽  
Maria T. Schmook ◽  
Andreas Peyrl ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Combination Therapy ◽  
Clinical Experience ◽  
Clinical Studies ◽  
High Grade Glioma ◽  
Treatment Modalities ◽  
Intrathecal Therapy ◽  
High Grade ◽  
Promising Therapeutic Approach

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.

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