The small molecule drug CBL0137 increases the level of DNA damage and the efficacy of radiotherapy for glioblastoma

Tallman, Miranda M.; Zalenski, Abigail A.; Deighen, Amanda; Schrock, Morgan S.; Mortach, Sherry; Grubb, Treg; Kastury, Preetham; Huntoon, Kristin; Summers, Matthew K.; Venere, Monica

doi:10.1016/j.canlet.2020.11.027

Cited by 12 publications

(14 citation statements)

References 41 publications

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“…All cells were cultured at 37 C at 5% CO 2 . Mo-HO and Boo-HA cells were cultured as described previously using Neural Stem Cell (NSC) medium on plates pre-treated with Geltrex (Thermo Fisher) and passaged using TrypLE Express Enzyme (no phenol red; Gibco) 15 . G06-A, J3T-Bg, SDT-3G cells were cultured as described and passaged with 0.25% Trypsin (Sigma).…”

Section: Cells and Culture Conditionsmentioning

confidence: 99%

Establishment and characterization of two novel patient‐derived lines from canine high‐grade glioma

Schrock

Zalenski

Tallman

et al. 2023

Vet Comparative Oncology

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High‐grade glioma is an aggressive cancer that occurs naturally in pet dogs. Canine high‐grade glioma (cHGG) is treated with radiation, chemotherapy or surgery, but has no curative treatment. Within the past eight years, there have been advances in our imaging and histopathology standards as well as genetic charactereization of cHGG. However, there are only three cHGG cell lines publicly available, all of which were derived from astrocytoma and established using methods involving expansion of tumour cells in vitro on plastic dishes. In order to provide more clinically relevant cell lines for studying cHGG in vitro, the goal of this study was to establish cHGG patient‐derived lines, whereby cancer cells are expanded in vivo by injecting cells into immunocompromized laboratory mice. The cells are then harvested from mice and used for in vitro studies. This method is the standard in the human field and has been shown to minimize the acquisition of genetic alterations and gene expression changes from the original tumour. Through a multi‐institutional collaboration, we describe our methods for establishing two novel cHGG patient‐derived lines, Boo‐HA and Mo‐HO, from a high‐grade astrocytoma and a high‐grade oligodendroglioma, respectively. We compare our novel lines to G06‐A, J3T‐Bg, and SDT‐3G (traditional cHGG cell lines) in terms of proliferation and sensitivity to radiation. We also perform whole genome sequencing and identify an NF1 truncating mutation in Mo‐HO. We report the characterization and availability of these novel patient‐derived lines for use by the veterinary community.

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Section: Cells and Culture Conditionsmentioning

confidence: 99%

Establishment and characterization of two novel patient‐derived lines from canine high‐grade glioma

Schrock

Zalenski

Tallman

et al. 2023

Vet Comparative Oncology

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“…DNA damage was detectable two hours post curaxin treatment ( Fig 5A ) but had reduced to pre-treatment levels after 18 hours ( Fig 5B ). Whilst curaxins were initially reported not to cause DNA damage [ 14 ] and this was not observed in neuroblastoma cells [ 13 ] more recently CBL0137 has been shown to cause DNA damage in Glioblastoma [ 32 ]. This is perhaps not surprising given the role that the FACT complex plays in the DNA damage response to both double and single strand breaks [ 33 , 34 ].…”

Section: Resultsmentioning

confidence: 99%

“…This is perhaps not surprising given the role that the FACT complex plays in the DNA damage response to both double and single strand breaks [ 33 , 34 ]. In their work on Glioblastoma cells Tallman et al [ 32 ] propose that the curaxin induced chromatin trapping [ 14 ] of the FACT complex reduces the pool of FACT available to respond to DNA damage. This may be occurring in the hematopoietic cells we are studying.…”

Section: Resultsmentioning

confidence: 99%

Combination of curaxin and tyrosine kinase inhibitors display enhanced killing of primitive Chronic Myeloid Leukaemia cells

2022

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Despite the big increase in precision medicine targeted therapies developing curative treatments for many cancers is still a major challenge due mainly to the development of drug resistance in cancer stem cells. The cancer stem cells are constantly evolving to survive and targeted drug treatment often increases the selective pressure on these cells from which the disease develops. Chronic myeloid leukaemia is a paradigm of cancer stem cell research. Targeted therapies to the causative oncogene, BCR/ABL, have been developed but drug resistance remains a problem. The introduction of tyrosine kinase inhibitors targeting BCR/ABL were transformative in the management of CML. However, patients are rarely cured as the tyrosine kinase inhibitors fail to eradicate the leukaemic stem cell which often leads to loss of response to therapy as drug resistance develops and progression to more fatal forms of acute leukaemia occurs. New treatment strategies targeting other entities within the leukemic stem cell either alone or in combination with tyrosine kinase are therefore required. Drawing on our previous published work on the development of potential novel targets in CML and other myeloproliferative diseases along with analysis of the facilitates chromatin transcription (FACT) complex in CML we hypothesised that curaxin, a drug that targets the FACT complex and is in clinical trial for the treatment of other cancers, could be of use in the treatment of CML. We therefore assessed the curaxin CBL0137 as a new agent to extinguish CML primitive cells and show its ability to preferentially target CML cells compared to healthy control cells, especially in combination with clinically relevant tyrosine kinase inhibitors.

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“…Since then, the research rapidly expanded into other human cancers in the preclinical studies for the small molecule drug CBLC137 (CBL0137). This includes human pancreatic cancer [ 145 ]; neuroblastoma [ 146 ]; glioblastoma [ 147 – 149 ]; extremity melanomas [ 150 ]; small cell lung cancer [ 151 , 152 ]; hepatocellular carcinoma [ 153 ]; leukemia [ 154 ]; and medulloblastoma [ 155 ]. Importantly, a phase 1 clinical trial result of CBL0137 from cancer patients with solid tumors was communicated at the ASCO 2020 Annual meeting [ 156 ].…”

Section: Tp53/p53mentioning

confidence: 99%

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

Aljahdali

Zhang

et al. 2021

J Exp Clin Cancer Res

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The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.

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The small molecule drug CBL0137 increases the level of DNA damage and the efficacy of radiotherapy for glioblastoma

Cited by 12 publications

References 41 publications

Establishment and characterization of two novel patient‐derived lines from canine high‐grade glioma

Establishment and characterization of two novel patient‐derived lines from canine high‐grade glioma

Combination of curaxin and tyrosine kinase inhibitors display enhanced killing of primitive Chronic Myeloid Leukaemia cells

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

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