Dianhydrogalactitol induces replication-dependent DNA damage in tumor cells preferentially resolved by homologous recombination

Zhai, Beibei; Steinø, Anne; Bacha, Jeffrey; Brown, Dennis; Daugaard, Mads

doi:10.1038/s41419-018-1069-9

Cited by 13 publications

(11 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We further tested dianhydrogalactitol (VAL-083), a bifunctional compound able to alkylate N 7 -guanine and form interstrand crosslinks and DNA double strand breaks [ 117 ]. VAL-083 is known to penetrate the blood–brain barrier and to accumulate in the cerebrospinal fluid and brain parenchyma [ 39 ]; it is currently tested in clinical trials for recurrent GBM (NCT02717962) as well as for treatment-naïve MGMT promoter unmethylated GBM patients (NCT03050736).…”

Section: Resultsmentioning

confidence: 99%

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

et al. 2020

Self Cite

View full text Add to dashboard Cite

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.

show abstract

Section: Resultsmentioning

confidence: 99%

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…DAG has previously been shown to have cytotoxic effects in lung cancer cells 25 . To investigate if DAG exerts a similar cytotoxic activity in GBM and PCa cells, we tested DAG cytotoxicity and determined half-maximal inhibitory concentration (IC 50 ) values in two GBM and four PCa cell lines, among which PC-3-DR is resistant to docetaxel 26 .…”

Section: Resultsmentioning

confidence: 99%

“…In lung cancer, DAG-induced DNA DSBs are predominantly repaired by the HR pathway 25 . To determine whether HR is also active in repair of DAG-induced DNA damage in GBM and PCa cells, we preformed western blot analysis to check the DNA DSB sensors and effectors involved in the HR pathway after DAG treatment in both PC-3 and M059K cells.…”

Section: Resultsmentioning

confidence: 99%

Dianhydrogalactitol synergizes with topoisomerase poisons to overcome DNA repair activity in tumor cells

Zhai

Kotapalli

et al. 2020

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

1,2:5,6-Dianhydrogalactitol (DAG) is a bi-functional DNA-targeting agent currently in phase II clinical trial for treatment of temozolomide-resistant glioblastoma (GBM). In the present study, we investigated the cytotoxic activity of DAG alone or in combination with common chemotherapy agents in GBM and prostate cancer (PCa) cells, and determined the impact of DNA repair pathways on DAG-induced cytotoxicity. We found that DAG produced replication-dependent DNA lesions decorated with RPA32, RAD51, and γH2AX foci. DAG-induced cytotoxicity was unaffected by MLH1, MSH2, and DNA-PK expression, but was enhanced by knockdown of BRCA1. Acting in S phase, DAG displayed selective synergy with topoisomerase I (camptothecin and irinotecan) and topoisomerase II (etoposide) poisons in GBM, PCa, and lung cancer cells with no synergy observed for docetaxel. Importantly, DAG combined with irinotecan treatment enhanced tumor responses and prolonged survival of tumor-bearing mice. This work provides mechanistic insight into DAG cytotoxicity in GBM and PCa cells and offers a rational for exploring combination regimens with topoisomerase I/II poisons in future clinical trials.

show abstract

“…Many anti-cancer drugs work by inducing DNA damage in rapidly dividing cancer cells. 28 Figure 4D). Together, these data showed that HJC0152 induces DNA damage in NSCLC cells.…”

Section: Hjc0152 Triggers Dna Damage In Human Lung Cancer Cellsmentioning

confidence: 96%

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

et al. 2020

Cell Proliferation

View full text Add to dashboard Cite

Objectives Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and overexpressed in many cancers, including non–small‐cell lung cancer (NSCLC). We recently developed HJC0152 as an orally active STAT3 inhibitor. This study focused on investigating HJC0152's effect and mechanism of action in NSCLC. Materials and methods We analysed cell proliferation by MTT assays, cell migration by wound healing and transwell assays, protein levels by Western blot, and apoptosis and reactive oxygen species (ROS) level by flow cytometry. A nude mouse tumorigenesis model was established for in vivo experiment. UHPLC‐QTOF/MS was used for untargeted metabolomic relative quantitation analysis. Results We found that HJC0152 exhibited activity against human NSCLC cells in vitro and NSCLC xenograft tumours in vivo via regulating STAT3 signalling and metabolism. HJC0152 efficiently reduced NSCLC cell proliferation, promoted ROS generation, induced apoptosis, triggered DNA damage and reduced motility in A549 and H460 NSCLC cells. Moreover, HJC0152 significantly inhibited the growth of A549 xenograft tumours in vivo. HJC0152 also affected metabolism, significantly decreasing and perturbating levels of several metabolites in the purine, glutathione and pyrimidine metabolism pathways. Conclusions HJC0152 reduces cellular capacity to scavenge free radicals, leading to ROS generation and accumulation and apoptosis. This study provides a rationale for further developing HJC0152 as a potential therapy for NSCLC and provides insights into the mechanisms by which HJC0152 exerts its anti‐cancer effects.

show abstract

Dianhydrogalactitol induces replication-dependent DNA damage in tumor cells preferentially resolved by homologous recombination

Cited by 13 publications

References 36 publications

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

Dianhydrogalactitol synergizes with topoisomerase poisons to overcome DNA repair activity in tumor cells

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

Contact Info

Product

Resources

About