Histone chaperone FACT complex inhibitor CBL0137 interferes with DNA damage repair and enhances sensitivity of medulloblastoma to chemotherapy and radiation

Song, Heyu; Xi, Shaoyan; Chen, Yingling; Pramanik, Suravi; Zeng, Jiping; Roychoudhury, Shrabasti; Harris, Hannah L.; Akbar, Anum; Elhag, Salma S.; Coulter, Donald W.; Ray, Sutapa; Bhakat, Kishor K.

doi:10.1016/j.canlet.2021.07.020

Cited by 15 publications

(12 citation statements)

References 48 publications

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“…Herein we showed that CBL0137 and carboplatin combination treatment significantly prolonged the survival of mice bearing cisplatin-resistant SSRP1-high LP28 HGSC patient-derived tumors. These results are in line with previous studies where CBL0137 treatment enhanced the efficacy of platinum-based chemotherapy in medulloblastoma and non-small cell lung carcinomas [ 24 , 58 ]. Hence, using CBL0137 in combination with carboplatin, a front-line treatment for HGSCs, may improve treatment outcomes in SSRP1-high ovarian cancer patients and deserves investigation.…”

Section: Discussionsupporting

confidence: 92%

CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors

Johnston

et al. 2022

J Exp Clin Cancer Res

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Background High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs. Experimental design We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo. Results We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts. Conclusion Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

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Section: Discussionsupporting

confidence: 92%

CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors

Johnston

et al. 2022

J Exp Clin Cancer Res

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“…Curaxin is an inhibitor of the FACT complex by intercalating into DNA and causing indirect chromatin-trapping of this histone chaperone [ 159 ]. Curaxin not only inhibits tumor growth, but also enhances sensitivity to chemotherapy and radiation therapy [ 160 , 161 ]. Currently, three clinical trials of Curaxin for the treatment of tumors are ongoing or have been concluded ( Identifier: NCT03727789, NCT01905228, and NCT04870944).…”

Section: Histone Chaperones In Digestive Cancersmentioning

confidence: 99%

Histone Chaperones and Digestive Cancer: A Review of the Literature

Zhao

Cai

Jiang

et al. 2022

Cancers

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Background: The global burden of digestive cancer is expected to increase. Therefore, crucial for the prognosis of patients with these tumors is to identify early diagnostic markers or novel therapeutic targets. There is accumulating evidence connecting histone chaperones to the pathogenesis of digestive cancer. Histone chaperones are now broadly defined as a class of proteins that bind histones and regulate nucleosome assembly. Recent studies have demonstrated that multiple histone chaperones are aberrantly expressed and have distinct roles in digestive cancers. Objective: The purpose of this review is to present the current evidence regarding the role of histone chaperones in digestive cancer, particularly their mechanism in the development and progression of esophageal, gastric, liver, pancreatic, and colorectal cancers. In addition, the prognostic significance of particular histone chaperones in patients with digestive cancer is discussed. Methods: According to PRISMA guidelines, we searched the PubMed, Embase, and MEDLINE databases to identify studies on histone chaperones and digestive cancer from inception until June 2022. Results: A total of 104 studies involving 21 histone chaperones were retrieved. Conclusions: This review confirms the roles and mechanisms of selected histone chaperones in digestive cancer and suggests their significance as potential prognostic biomarkers and therapeutic targets. However, due to their non-specificity, more research on histone chaperones should be conducted in the future to elucidate novel strategies of histone chaperones for prognosis and treatment of digestive cancer.

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“…Our recent study demonstrated that APE1 interacts with a chromatin remodeling histone chaperone Facilitates Chromatin Transcription (FACT) complex to facilitate radiation and cisplatin-induced DNA repair in group 3 MB cells in vitro. Notably, MB tissues have elevated levels of post-transitionally modified acetylated APE1 (AcAPE1) and FACT complex, both associated with poor prognosis [ 142 ]. Inhibition of FACT with small-molecule CBL0137 (also known as curaxin) sensitized MB cell lines and orthotopic tumors to radiation and cisplatin [ 142 , 143 ].…”

Section: Drug Resistance and Recurrence In Mbsmentioning

confidence: 99%

“…Notably, MB tissues have elevated levels of post-transitionally modified acetylated APE1 (AcAPE1) and FACT complex, both associated with poor prognosis [ 142 ]. Inhibition of FACT with small-molecule CBL0137 (also known as curaxin) sensitized MB cell lines and orthotopic tumors to radiation and cisplatin [ 142 , 143 ]. Curaxin modulates an important pathway for cancer stem cell proliferation, i.e., NOTCH signaling, [ 144 , 145 ].…”

Section: Drug Resistance and Recurrence In Mbsmentioning

confidence: 99%

“…Recent transcriptome analyses in group 3 MB cells showed that curaxin preferentially suppressed cell cycle and DNA repair-related biological processes. Treatment with curaxin downregulated the expression of hundreds of genes, including MYC and OTX genes that are known to be major activators of highly aggressive MB [ 142 ]. Further investigations as to whether curaxin can improve the efficacy of interventions for MB and outcomes in high-risk patients is warranted.…”

Section: Drug Resistance and Recurrence In Mbsmentioning

confidence: 99%

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Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment

et al. 2021

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Medulloblastoma (MB) is the most common malignant central nervous system tumor in pediatric patients. Mainstay of therapy remains surgical resection followed by craniospinal radiation and chemotherapy, although limitations to this therapy are applied in the youngest patients. Clinically, tumors are divided into average and high-risk status on the basis of age, metastasis at diagnosis, and extent of surgical resection. However, technological advances in high-throughput screening have facilitated the analysis of large transcriptomic datasets that have been used to generate the current classification system, dividing patients into four primary subgroups, i.e., WNT (wingless), SHH (sonic hedgehog), and the non-SHH/WNT subgroups 3 and 4. Each subgroup can further be subdivided on the basis of a combination of cytogenetic and epigenetic events, some in distinct signaling pathways, that activate specific phenotypes impacting patient prognosis. Here, we delve deeper into the genetic basis for each subgroup by reviewing the extent of cytogenetic events in key genes that trigger neoplastic transformation or that exhibit oncogenic properties. Each of these discussions is further centered on how these genetic aberrations can be exploited to generate novel targeted therapeutics for each subgroup along with a discussion on challenges that are currently faced in generating said therapies. Our future hope is that through better understanding of subgroup-specific cytogenetic events, the field may improve diagnosis, prognosis, and treatment to improve overall quality of life for these patients.

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Histone chaperone FACT complex inhibitor CBL0137 interferes with DNA damage repair and enhances sensitivity of medulloblastoma to chemotherapy and radiation

Cited by 15 publications

References 48 publications

CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors

CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors

Histone Chaperones and Digestive Cancer: A Review of the Literature

Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment

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