scholarly journals Combining the DNA Repair Inhibitor Dbait With Radiotherapy for the Treatment of High Grade Glioma: Efficacy and Protein Biomarkers of Resistance in Preclinical Models

2019 ◽  
Vol 9 ◽  
Author(s):  
Julian Biau ◽  
Emmanuel Chautard ◽  
Nathalie Berthault ◽  
Leanne de Koning ◽  
Frank Court ◽  
...  
Keyword(s):  
Dna Repair ◽  
High Grade Glioma ◽  
High Grade ◽  
Preclinical Models ◽  
Protein Biomarkers ◽  
Dna Repair Inhibitor

ONC201 in previously irradiated pediatric H3 K27M-mutant glioma or newly diagnosed DIPG.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3619-3619
Author(s):  
Sharon L. Gardner ◽  
Carl Johannes Koschmann ◽  
Rohinton Tarapore ◽  
Jeffrey C. Allen ◽  
Wafik Tharwat Zaky ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Single Agent ◽  
High Grade Glioma ◽  
Biologically Active ◽  
High Grade ◽  
Newly Diagnosed ◽  
Preclinical Models ◽  
Open Label ◽  
The Impact

3619 Background: ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that has demonstrated promising activity in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 in recurrent H3 K27M-mutant glioma patients . The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients as well tolerated and biologically active. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This open-label, multi-center trial for pediatric H3 K27M-mutant glioma or non-biopsied DIPG employed a 3+3 dose-escalation and dose-expansion design with 6 arms. Arms A and E, which have completed accrual, determined the RP2D of ONC201 using oral capsule and liquid formulations in post-radiation pediatric H3 K27M-mutant glioma patients ONC201, respectively. Arm B aims to determine the RP2D for ONC201 in combination with radiotherapy in patients with newly diagnosed DIPG. Arms C and D aim to measure intratumoral ONC201 concentrations in midline glioma patients and the impact of ONC201 on H3 K27M DNA levels in CSF, respectively. Arm F was recently opened to study ONC201 as a single agent in patients with progressive H3 K27M-mutant tumors (excluding DIPG and spinal cord tumors) following radiotherapy. After determining the RP2D, a dose-expansion cohort will evaluate the safety, radiographic response, and activity of ONC201. Results: An RP2D of weekly 625mg ONC201 scaled by body weight as a capsule or in liquid formulation was established in the primary endpoints of arms A, B and E alone or in combination with radiation, without incidence of dose-limiting toxicity (DLT). Pharmacokinetic profiles were similar to those observed in adults (T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL), with similar exposure across body weights. Conclusions: ONC201 was well tolerated without DLTs at the same adult RP2D scaled by body weight as monotherapy or in combination with radiotherapy in pediatric H3 K27M-mutant glioma patients. Further investigation of ONC201 to treat H3 K27M-mutant glioma and DIPG is warranted. Clinical trial information: NCT03416530 .

Potentiation of doxorubicin efficacy in hepatocellular carcinoma by the DNA repair inhibitor DT01 in preclinical models

2017 ◽  
Vol 27 (10) ◽  
pp. 4435-4444 ◽  
Author(s):  
Nirmitha I. Herath ◽  
Flavien Devun ◽  
Aurélie Herbette ◽  
Marie-Christine Lienafa ◽  
Philippe Chouteau ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Repair ◽  
Preclinical Models ◽  
Dna Repair Inhibitor

scholarly journals HGG-45. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF PEDIATRIC TREATMENT-INDUCED HIGH-GRADE GLIOMA: GERMLINE DNA REPAIR DEFECTS AS A POTENTIAL ETIOLOGY

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i98-i98
Author(s):  
John DeSisto ◽  
John Lucas ◽  
Andrew Donson ◽  
Bridget Sanford ◽  
Gang Wu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Molecular Characterization ◽  
High Grade Glioma ◽  
High Grade ◽  
Pediatric Treatment

scholarly journals CBIO-18. G-QUADRUPLEX STABILIZATION TARGETS ATRX-DEFICIENT HIGH-GRADE GLIOMA VIA INDUCTION OF p53-INDEPENDENT APOPTOSIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii19-ii19
Author(s):  
Sharvari Dharmaiah ◽  
Ahsan Farooqi ◽  
Christian Alvarez ◽  
Vladislav Sharin ◽  
David Irvin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Flow Analysis ◽  
High Grade Glioma ◽  
Replication Stress ◽  
High Grade ◽  
Preclinical Models ◽  
Current Standard ◽  
G Quadruplex

Abstract Gliomas are the most common primary malignant brain tumor in adults and mutational inactivation of histone chaperone ATRX is a critical molecular marker in the classification of high-grade glioma (HGG). ATRX loss occurs with concurrent mutations in TP53 and IDH1/2, altering genome-wide accessibility of chromatin and inducing replication stress and DNA damage via accumulations of abnormal G-quadruplex (G4) DNA secondary structures. While G4 stabilizers in particular hold strong therapeutic promise, the genomic consequences and efficacy of this treatment are poorly understood. We previously showed that chemical stabilization of G4s in ATRX-deficient normal human astrocytes (NHAs) results in lethality due to induction of replication stress, but it is unknown what drives this lethality in ATRX-deficient patient-derived preclinical models. We therefore sought to evaluate the mechanisms that underlie cell death in ATRX- and p53-deficient preclinical in vitro models following G4 stabilization. We found that ATRX-deficient glioma stem cells (GSCs) demonstrated dose-dependent enhanced sensitivity to G4 stabilization, compared to ATRX-intact controls. Evaluation of cell death mechanisms following G4 stabilization revealed a significant increase in cleaved caspase 3 expression and no p21 expression in ATRX-deficient GSCs, suggesting p53-independent apoptotic activation. Cell cycle flow analysis demonstrated G2/M checkpoint arrest in ATRX-deficient GSCs upon G4 stabilization, suggesting that p53 is nonfunctional at the G1/S checkpoint. Our preliminary findings now suggest that p73, a functional and structural homologue of p53, is activated and drives apoptosis in these ATRX-deficient GSCs. Furthermore, ATRX-deficient GSCs demonstrated upregulated expression of both pATR/pChk1 and pATM/pChk2, indicating enhanced replication stress and DNA damage via double-stranded breaks, respectively. These findings indicate that G4 stabilizers could potentially synergize with ionizing radiation, the current standard of care, as both therapies are DNA-damaging. Taken together, this study elucidates mechanisms of cytotoxicity and efficacy of a novel therapeutic strategy in ATRX-deficient preclinical models.

scholarly journals Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

2020 ◽  
Vol 21 (19) ◽  
pp. 7193 ◽  
Author(s):  
Maya S. Graham ◽  
Ingo K. Mellinghoff
Keyword(s):  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Malignant Gliomas ◽  
High Grade Glioma ◽  
High Grade ◽  
Cancer Death ◽  
Preclinical Models ◽  
Molecular Alterations ◽  
Potential Impact ◽  
Pediatric High Grade Glioma

Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.

The role of MGMT promotor hypermethylation as a predictive factor for response to temozolomide in recurrent high-grade glioma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12509-12509
Author(s):  
J. Sadones ◽  
A. Michotte ◽  
C. Chaskis ◽  
P. In ’t Veld ◽  
S. Califice ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dna Methyltransferase ◽  
Mononuclear Cells ◽  
Methylation Status ◽  
High Grade Glioma ◽  
High Grade ◽  
Repair Gene ◽  
Peripheral Blood Mononuclear ◽  
Tissue Samples ◽  
Dna Repair Gene

12509 Background: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promotor hypermethylation (MGMT-meth) compromises DNA repair of high-grade glioma (HGG) and has been associated with a survival benefit in patients treated with temozolomide (TMZ) for newly diagnosed glioblastoma multiforme (GBM). It remains undetermined if the MGMT-meth status correlates with response to temozolomide at recurrence and whether extended dosing of TMZ (known to deplete MGMT in peripheral blood mononuclear cells) can overcome resistance in unmethylated HGG. Methods: We are investigating the MGMT-meth status on glioma tissue samples collected at diagnosis from 64 patients (pts). Fifty pts were treated at the time of recurrence with conventional TMZ (5 out of 28d regimen) and 14 pts with extended dosing of TMZ (100 mg/m2/d, 21 out of 28d regimen). Following DNA isolation from archival glioma tissues by phenol/chloroform extraction and a bisulphite conversion of genomic DNA, real-time methylation-specific PCR quantification of the methylation status of the MGMT promotor region is performed by OncoMethylome Sciences S.A. (according to OMS proprietary methodology). Results: At present, results have been obtained for 15 pts (13 M/ 2 W, median age: 46y). From 3 pts a biopsy at recurrence was available for analysis. The result was discordant with the MGMT-meth status at diagnosis in 2 pts (1x meth to unmeth and 1x unmeth to meth). Of the 6 (40%) pts with MGMT-meth gliomas, none had immediate progression on TMZ (respectively 4x SD, 1x CR, 1x PR). Of the 9 pts with an unmethylated MGMT promotor, 4 pts had immediate progression on TMZ and 5 pts had SD (of which 4 had been treated with the 21/28d regimen). All pts, except one, with MGMT-meth had a TTP that was above the median of our study population. The two pts with an MGMT-unmeth status that had a TTP above the median had received the extended dosing regimen. Conclusions: Our preliminary data indicate that MGMT promotor hypermethylation at diagnosis might correlate with sensitivity to TMZ in the recurrent setting. Extended dosing of TMZ might be more active against MGMT-unmethylated glioma. Final data from this study will be available for presentation at the meeting. No significant financial relationships to disclose.

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