scholarly journals MODL-02. TARGETING REPLICATION STRESS IN PEDIATRIC BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii412-iii412
Author(s):  
Sonja Krausert ◽  
Sander Lambo ◽  
Norman Mack ◽  
Benjamin Schwalm ◽  
Stefan Pfister ◽  
...  
Keyword(s):  
Dna Damage ◽  
Brain Tumors ◽  
Tumor Growth ◽  
Cell Lines ◽  
Survival Benefit ◽  
Replication Stress ◽  
Pediatric Brain Tumors ◽  
Ic50 Values ◽  
Group 3 ◽  
Pediatric Brain

Abstract Pediatric brain tumors harboring amplifications or high overexpression of MYC-/MYCN are often associated with poor outcome. High MYC(N) expression in these tumors leads to increased transcription, which can be in conflict with DNA replication and subsequently can cause replication stress, R-loops and DNA damage. We hypothesize that high MYC(N) expression makes them vulnerable to DNA damage response inhibitors (DDRi) and even more vulnerable to combinations of DDRi and chemotherapeutics. To test this hypothesis we performed in vitro drug experiments using Group 3 medulloblastoma (MB) and ETMR cell lines. IC50-values were evaluated of topoisomerase inhibitor Irinotecan (SN-38) and Pamiparib (BGB-290), a brain-penetrant PARP-inhibitor, in monotherapy. All cell lines were sensitive for SN-38 and showed IC50-values in the low nM-range but PARP-inhibitors were ineffective. However, a significant decrease in IC50 can be observed when SN-38 and Pamiparib are used in combination. For in vivo treatments, we injected NSG mice with luciferase labelled patient-derived xenograft- (PDX-) cells of various models (MB Group 3, MB SHH, ETMR, RELA EPN), monitored tumor growth via IVIS and randomized the mice into four groups (vehicle, BGB-290, Irinotecan and Irinotecan+Pamiparib) when a predefined threshold of tumor growth was reached. Mice were treated with Irinotecan (or vehicle) once per day i.p. and Pamiparib (or vehicle) twice per day per oral gavage. Treatment with Pamiparib did not show any survival benefit, but mice treated with Irinotecan or the combination showed a clear survival benefit. Treatments are ongoing and more results will be presented at the conference.

Clinicopathological Significance of HO-1 and HO-2 Expression in Medulloblastoma

2014 ◽  
Vol 881-883 ◽  
pp. 469-472
Author(s):  
Li Tang ◽  
Li Yu
Keyword(s):  
Brain Tumors ◽  
Tumor Growth ◽  
Pediatric Brain Tumors ◽  
Potential Therapeutic Target ◽  
Intracellular Enzyme ◽  
Promote Tumor Growth ◽  
Clinicopathological Significance ◽  
Tumor Growth And Metastasis ◽  
Rate Limiting ◽  
Pediatric Brain

Heme oxygenase (HO) is the rate-limiting intracellular enzyme of heme catabolism. Overexpressed HO-1 can inhibit the apoptosis of tumor cells and promote tumor growth and metastasis, and (HO-1) has been considereded to play a major role in the pathogenesis of many tumors. Medulloblastomas (MB) are the most common malignant brain tumors in children and constitute 20% of all pediatric brain tumors. However, there is no report about clinicopathological significance of HO-1 and HO-2 expression in medulloblastoma (MB). In the present study, to explore the expression and potential function of HO in MBs, immunohistochemistry was used to examine the HO-1 and HO-2 expression in 41 MBs. The result showed that immunoreactivity of HO-1 was detected in 32 of 41 MBs and HO-2 was detected in 30 of 41 MBs, and their expression level had no significant correlations with the clinical features of the patients and subtypes of MB. In addition, the prognoses were better in those high HO-1 expression and low HO-2 expression cases. Taken together, the expression of HO-1 and HO-2 protein is significantly correlated with tumor growth in MB. The co-ordinated expression of HO-1 and HO-2 may affect the survival of MB patients. These results suggest that HO-1 may be a potential therapeutic target for MB.

scholarly journals THER-02. TARGETING DNA DAMAGE REPAIR IN MYC-DRIVEN PEDIATRIC BRAIN TUMORS

2019 ◽  
Vol 21 (Supplement_2) ◽  
pp. ii114-ii114
Author(s):  
Sonja Krausert ◽  
Sander Lambo ◽  
Sebastian Brabetz ◽  
Norman Mack ◽  
Benjamin Schwalm ◽  
...  
Keyword(s):  
Dna Damage ◽  
Brain Tumors ◽  
Dna Damage Repair ◽  
Pediatric Brain Tumors ◽  
Damage Repair ◽  
Pediatric Brain

scholarly journals BIOL-03. PROTEIN TRANSLATION FROM NON-CODING GENOMIC LOCI PRODUCE BIOLOGICALLY-ACTIVE PROTEINS IMPLICATED IN CANCER CELL SURVIVAL IN PEDIATRIC BRAIN TUMORS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i3-i3
Author(s):  
John Prensner ◽  
Todd Golub
Keyword(s):  
Brain Tumors ◽  
Cell Survival ◽  
Cell Lines ◽  
Cancer Cell ◽  
Biological Effects ◽  
Protein Translation ◽  
Pediatric Brain Tumors ◽  
Biologically Active ◽  
Cancer Cell Survival ◽  
Pediatric Brain

Abstract Protein translation is both a fundamental cellular process essential for life as well as an oncogenic mechanism employed by tumors to enact cancer cell biology. While protein translation is most readily manifest in the ~20,000 known human protein coding genes, there are, in fact, several thousand additional regions of the cancer genome that are translated and contribute the complexity of the molecular milieu of cancer. Here, we systematically addressed the question of whether such uncharacterized genomic regions encode truly biologically active proteins and applied these findings to pediatric brain tumors. We experimentally interrogated 553 candidates selected from non-canonical open reading frame (ORF) datasets. Of these, 57 induced viability defects when knocked out in a broad array of human cancer cell lines. Upon ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes. CRISPR tiling and start codon mutagenesis indicated that their biological effects required translation as opposed to RNA-mediated effects. We characterized several of these in the context of pediatric brain tumors, where dense CRISPR tiling screens revealed unique functional relevance of dozens of non-canonical ORFs in pediatric brain cancer cell survival. We found that one of these ORFs, ASNSD1 uORF, encodes a well-folded protein whose translation is a selective genetic dependency distinct from the adjacent ASNSD1 annotated protein. In vitro molecular biology assays confirmed the MYC-amplified medulloblastoma cell lines had a heightened dependency on this protein, and that MYC binds to the promoter of this gene, with MYC expression correlating with ASNSD1 in patient tumors. Co-immunoprecipitation assays defined ASNSD1 uORF as a novel member of the prefoldin complex of cytoplasmic protein stability regulators. Overall, our experiments suggest that the abundant protein translation found in the “non-coding” genome may produce biologically active non-canonical ORFs that are potential therapeutic targets.

scholarly journals HGG-33. PATIENT DERIVED CELL LINES TO STUDY ATRX AND ALT IN PEDIATRIC BRAIN TUMORS

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i96-i96
Author(s):  
Heba Ijaz ◽  
Robert Dilley ◽  
Mateusz Koptra ◽  
Gonzalo Garcia ◽  
Yuankun Zhu ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Cell Lines ◽  
Pediatric Brain Tumors ◽  
Pediatric Brain

scholarly journals P11.23 Oncolytic adenovirus Delta-24-RGD exerts a potent anti-tumor effect in preclinical models of atypical teratoid/rhabdoid tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii47-iii47
Author(s):  
M Garcia Moure ◽  
M González Huarriz ◽  
L Marrodán ◽  
A Patiño-García ◽  
M M Alonso
Keyword(s):  
Overall Survival ◽  
Brain Tumors ◽  
Phase I ◽  
Cell Lines ◽  
Pediatric Brain Tumors ◽  
Preclinical Models ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Pediatric Brain

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD is an oncolytic adenovirus that has already demonstrated its efficacy as in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has also been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT. MATERIAL AND METHODS Our studies have been carried out in three stablished AT/RT cell lines (BT-12, CHLA-06 and CHLA-266). In vitro, AT/RT cultures were infected with Delta-24-RGD-GFP to confirm the infectivity of the virus by flow cytometry. Replication of Delta-24-RGD was ensured by titrating the PFUs generated in AT/RT infected cultures. In regard to cytolytic effect, viability assays (MTS) were conducted in AT/RT cultures infected at increasing MOIs of Delta-24-RGD. In vivo, AT/RT cell lines were engrafted in Rag-2 mice in supratentorial and infratentorial locations, and the animals were treated with Delta-24-RGD at 107 or 108 PFU/animal (intra-tumor administration), or PBS. The therapeutic benefit of Delta-24-RGD was evaluated comparing the overall survival obtained for treated and untreated animals using the Log-rank test. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus to facilitate the follow up of these tumors. Mice bearing disseminated AT/RT were treated with Delta-24-RGD at 107 or 108 PFU/animal, or PBS (control). The therapeutic effect was monitored by bioluminescence and by comparison of the survival curves (Log-rank). RESULTS The virus was able to infect and replicate in tumor three different cell culture models of AT/RT, inducing a potent cytotoxic effect that resulting in IC50 values below 1 PFU/cell. Administration of the virus in mice bearing localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in virus treated animals, resulting in an increased overall survival. CONCLUSION In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.

scholarly journals Novel cell lines established from pediatric brain tumors

2011 ◽  
Vol 107 (2) ◽  
pp. 269-280 ◽  
Author(s):  
Jingying Xu ◽  
Anat Erdreich-Epstein ◽  
Ignacio Gonzalez-Gomez ◽  
Elizabeth Y. Melendez ◽  
Goar Smbatyan ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Cell Lines ◽  
Pediatric Brain Tumors ◽  
Pediatric Brain

scholarly journals MBRS-71. ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN ATTENUATES DNA DAMAGE AND IS A THERAPEUTIC TARGET IN Myc-DRIVEN MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii411-iii411
Author(s):  
Ahmed Abdel-Hafiz ◽  
Krishna Madhavan ◽  
Ilango Balakrishnan ◽  
Angela Pierce ◽  
Dong Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cell Lines ◽  
Ataxia Telangiectasia ◽  
Replication Stress ◽  
Chemotherapeutic Agents ◽  
Related Protein ◽  
Dna Replication Stress ◽  
Group 3 ◽  
Orthotopic Xenografts

Abstract Group 3 medulloblastoma tumors (Myc-MB), and particularly the 3γ subtype, have the worst prognosis and show a 5-year overall survival of less than 40%. Group 3 tumors are often accompanied by Myc amplification and have a higher rate of metastatic disease and relapse. Unfortunately, therapeutic strategies to target Mychave remained elusive. Further, the relapse of the MB has been linked to DNA replication stress. Ataxia telangiectasia and Rad3-related protein (ATR) senses persistent DNA damage, which arises due to replication stress, and activates damage checkpoints, thereby leading to increased cell survival. ATR is highly expressed in MB and is thought to contribute to undisturbed DNA replication to protect genomic integrity. Yet, the exact underlying mechanisms involving ATR are still unclear in MB. Inhibition of ATR (ATRi) using the ATR inhibitor, AZD6738, suppressed clonogenicity and cell self-renewal in Myc-MB. ATRi in Myc-MB cell lines downregulated Chk1 and upregulated P21. ATRi also induced cell cycle arrest and increased apoptosis in Myc-MB cell lines. Further, mice with orthotopic xenografts treated with ATR inhibitor survived significantly longer than control mice. High-throughput drug screening showed ATRi to be synergistic with chemotherapeutic agents including gemcitabine, cisplatin and topotecan. The treatment of Myc-MB cells with ATR inhibitor in combination with gemcitabine and with radiation increased in expression of DNA damage markers. These findings emphasize the role of ATR in alleviating DNA replication stress and that its inhibition is critical to the treatment of Myc-MB.

Sign in / Sign up

Export Citation Format

Share Document