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Purpose: Standard-of-care for glioblastoma remains surgical debulking followed by temozolomide and radiation. However, many tumors become radio-resistant while radiation damages surrounding brain tissue. Novel therapies are needed to increase the effectiveness of radiation and reduce the required radiation dose. Drug candidate CBL0137 is efficacious against glioblastoma by inhibiting histone chaperone FACT, known to be involved in DNA damage repair. We investigated the combination of CBL0137 and radiation on glioblastoma., Methods: In vitro, we combined CBL0137 with radiation on U87MG and A1207 glioblastoma cells using the clonogenic assay to evaluate the response to several treatment regimens, and the Fast Halo Assay to examine DNA repair. In vivo, we used the optimum combination treatment regimen to evaluate the response of orthotopic tumors in nude mice., Results: In vitro, the combination of CBL0137 and radiation is superior to either alone and administering CBL0137 two hours prior to radiation, having the drug present during and for a prolonged period post-radiation, is an optimal schedule. CBL0137 inhibits DNA damage repair following radiation and affects the subcellular distribution of histone chaperone ATRX, a molecule involved in DNA repair. In vivo, one dose of CBL0137 is efficacious and the combination of CBL0137 with radiation increases median survival over either monotherapy., Conclusions: CBL0137 is most effective with radiation for glioblastoma when present at the time of radiation, immediately after and for a prolonged period post-radiation, by inhibiting DNA repair caused by radiation. The combination leads to increased survival making it attractive as a dual therapy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The presence of a TP53 mutation is a predictor of poor outcome in leukaemia, and efficacious targeted therapies for these patients are lacking. The curaxin CBL0137 has demonstrated promising antitumour activities in multiple cancers such as glioblastoma, acting through p53 activation, NF‑κB inhibition and chromatin remodelling. In the present study, it was revealed using Annexin‑V/7‑AAD apoptosis assays that CBL0137 has efficacy across several human acute leukaemia cell lines with wild‑type TP53 , but sensitivity is reduced in TP53 ‑mutated subtypes. A heterozygous TP53 loss‑of‑function mutation in the KMT2A‑AFF1 human RS4;11 cell line was generated, and it was demonstrated that heterozygous TP53 loss‑of‑function is sufficient to cause a significant reduction in CBL0137 sensitivity. To the best of our knowledge, this is the first evidence to suggest a clinically significant role for functional p53 in the efficacy of CBL0137 in acute leukaemia. Future CBL0137 clinical trials should include TP53 mutation screening, to establish the clinical relevance of TP53 mutations in CBL0137 efficacy.

Glioblastoma (GBM) is an incurable brain tumor with inevitable recurrence. This is in part due to a highly malignant cancer stem cell (CSC) subpopulation of tumor cells that is particularly resistant to conventional treatments, including radiotherapy. Here we show that CBL0137, a small molecule anti-cancer agent, sensitizes GBM CSCs to radiotherapy. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex to chromatin, resulting in cytotoxicity preferentially within tumor cells. We show that when combined with radiotherapy, CBL0137 inhibited GBM CSC growth and resulted in more DNA damage in the CSCs compared to irradiation or drug alone. Using an in vivo subcutaneous model, we showed that the frequency of GBM CSCs was reduced when tumors were pretreated with CBL0137 and then exposed to irradiation. Survival studies with orthotopic GBM models resulted in significantly extended survival for mice treated with combinatorial therapy. As GBM CSCs contribute to the inevitable recurrence in patients, targeting them is imperative. This work establishes a new treatment paradigm for GBM that sensitizes CSCs to irradiation and may ultimately reduce tumor recurrence., (Copyright © 2020. Published by Elsevier B.V.)

Background: The survival rate for patients with glioblastoma (GBM) remains dismal. New therapies targeting molecular pathways dysregulated in GBM are needed. One such clinical-stage drug candidate, CBL0137, is a curaxin, small molecules which simultaneously downregulate nuclear factor-kappaB (NF-ĸB) and activate p53 by inactivating the chromatin remodeling complex, Facilitates Chromatin Transcription (FACT)., Methods: We used publicly available databases to establish levels of FACT subunit expression in GBM. In vitro, we evaluated the toxicity and effect of CBL0137 on FACT, p53, and NF-ĸB on U87MG and A1207 human GBM cells. In vivo, we implanted the cells orthotopically in nude mice and administered CBL0137 in various dosing regimens to assess brain and tumor accumulation of CBL0137, its effect on tumor cell proliferation and apoptosis, and on survival of mice with and without temozolomide (TMZ)., Results: FACT subunit expression was elevated in GBM compared with normal brain. CBL0137 induced loss of chromatin-unbound FACT, activated p53, inhibited NF-ĸB-dependent transcription, and was toxic to GBM cells. The drug penetrated the blood-brain barrier and accumulated in orthotopic tumors significantly more than normal brain tissue. It increased apoptosis and suppressed proliferation in both U87MG and A1207 tumors. Intravenous administration of CBL0137 significantly increased survival in models of early- through late-stage TMZ-responsive and -resistant GBM, with a trend toward significantly increasing the effect of TMZ in TMZ-responsive U87MG tumors., Conclusion: CBL0137 targets GBM according to its proposed mechanism of action, crosses the blood-brain barrier, and is efficacious in both TMZ-responsive and -resistant orthotopic models, making it an attractive new therapy for GBM., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cancer is a global concern, and there is a need for effective drugs. CBL0137 is a small water-soluble molecule and a new secondgeneration compound in the family of curaxins with potential anti-cancer activity. Curaxins in general, including CBL0137, intercalate into DNA, act by targeting the histone chaperone 'facilitates chromatin transcription' (FACT) complex, and have the potential to treat tumors by reducing the growth of cancer cells which is shown in a variety of cell lines and animal models. CBL0137 is found to activate the tumor suppressor gene p53. However, the mechanism of p53 activation is poorly understood. Utilizing bioinformatics analysis on available datasets of CBL0137 treated cancer cells of glioma, cervical and multiple myeloma, differentially expressed genes (DEGs) that may lead to the activation of p53 were examined. Three GEO datasets of cells treated with various concentrations of CBL0137 were analyzed, namely HSJD-DIPG007 (GSE153441), MM1.S (GSE117611), and HeLa S3 (GSE117611). The DEGs were identified based on p-values less than 0.05, logFC values greater than 1 and less than -1 and analyzed using GEO2R, Enrichr, and STRING, and data visualization was performed on Tableau. Compared to the controls, a total of 229, 1425, and 1005 genes were upregulated while 368, 2322, and 1673 genes were downregulated for HSJD-DIPG007, MM1.S, and HeLa S3 datasets, respectively. Further collective analysis revealed a total of 38 common DEGs among the three datasets. Using Enrichr and STRING on these 38 DEGs, seven hub genes were obtained, SKP2, RGS16, CSRP2, CENPA, HJURP, DTL, and HEXIM1 with these possible mechanisms: inhibition of AKT phosphorylation by upregulated genes RGS16 and CSRP2, p300-mediated acetylation of p53 via SKP2, inhibition of MDM2 by DTL downregulation and HEXIM1 upregulation, and inhibition of AURKB via CENPA and HJURP downregulation. This study analyzed the three datasets and highlighted how these identified hub genes might play a role in leading to p53 activation by CBL0137. [ABSTRACT FROM AUTHOR]