Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma

Rasmussen, Rikke; Gajjar, Madhavsai K.; Jensen, Knud; Hamerlik, Petra

doi:10.1016/j.molonc.2015.12.014

Cited by 65 publications

(51 citation statements)

References 44 publications

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“…This was concordant with our previous work showing that induction of ROS and oxidative DNA lesions renders GBM cells dependent on functional PARP (ref. 38). …”

Section: Resultsmentioning

confidence: 99%

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

et al. 2016

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Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM.

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“…This was concordant with our previous work showing that induction of ROS and oxidative DNA lesions renders GBM cells dependent on functional PARP (ref. 38). …”

Section: Resultsmentioning

confidence: 99%

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

et al. 2016

Self Cite

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“…Singh and colleagues reported that an FDA-approved HDAC inhibitor vorinostat in combination with tranylcypromine, can reduce GBM stem cell viability in a GBM xenograft model and lead to changes in apoptosis-regulatory genes such as TP53 and TP73 [ 141 ]. HDAC inhibitor SAHA shows strong effects in destabilizing mut-p53 by dissociating HDAC6 from functional interaction with Hsp90 and thereby inhibits GBM growth and resistance to chemotherapy [ 142 , 143 , 144 , 145 , 146 ]. However, SAHA was recently found to also down regulate wt-p53 [ 147 ], suggesting that it should be applied only to homozygous mut-p53 tumors.…”

Section: P53-targeted Therapiesmentioning

confidence: 99%

The p53 Pathway in Glioblastoma

Zhang

Dube

Gibert

et al. 2018

Cancers

291

235

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The tumor suppressor and transcription factor p53 plays critical roles in tumor prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance of genomic stability, inhibition of angiogenesis, and regulation of cell metabolism and tumor microenvironment. TP53 is one of the most commonly deregulated genes in cancer. The p53-ARF-MDM2 pathway is deregulated in 84% of glioblastoma (GBM) patients and 94% of GBM cell lines. Deregulated p53 pathway components have been implicated in GBM cell invasion, migration, proliferation, evasion of apoptosis, and cancer cell stemness. These pathway components are also regulated by various microRNAs and long non-coding RNAs. TP53 mutations in GBM are mostly point mutations that lead to a high expression of a gain of function (GOF) oncogenic variants of the p53 protein. These relatively understudied GOF p53 mutants promote GBM malignancy, possibly by acting as transcription factors on a set of genes other than those regulated by wild type p53. Their expression correlates with worse prognosis, highlighting their potential importance as markers and targets for GBM therapy. Understanding mutant p53 functions led to the development of novel approaches to restore p53 activity or promote mutant p53 degradation for future GBM therapies.

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“…Olaparib, is a poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) inhibitor, capable of suppressing activities of PARP1 in single-strand break (SSB) repair [27]. PARP inhibitors have been shown in several studies to control glioblastoma growth in combination with different agents [28,29] and are currently being evaluated in six different clinical trials. Importantly, the catalytic subunit of ribonucleotide reductase M2 (RRM2) which we determined to be regulated by Msi1, protects GBM cells from replication stress, DNA damage and apoptosis.…”

Section: Luteolin Sensitizes Glioblastoma Cells To Radiation and Parpmentioning

confidence: 99%

Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells

Li²,

Ivanov

et al. 2018

RNA Biology

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RNA binding proteins have emerged as critical oncogenic factors and potential targets in cancer therapy. In this study, we evaluated Musashi1 (Msi1) targeting as a strategy to treat glioblastoma (GBM); the most aggressive brain tumor type. Msi1 expression levels are often high in GBMs and other tumor types and correlate with poor clinical outcome. Moreover, Msi1 has been implicated in chemo-and radio-resistance. Msi1 modulates a range of cancer relevant processes and pathways and regulates the expression of stem cell markers and oncogenic factors via mRNA translation/stability. To identify Msi1 inhibitors capable of blocking its RNA binding function, we performed a~25,000 compound fluorescence polarization screen. NMR and LSPR were used to confirm direct interaction between Msi1 and luteolin, the leading compound. Luteolin displayed strong interaction with Msi1 RNA binding domain 1 (RBD1). As a likely consequence of this interaction, we observed via western and luciferase assays that luteolin treatment diminished Msi1 positive impact on the expression of pro-oncogenic target genes. We tested the effect of luteolin treatment on GBM cells and showed that it reduced proliferation, cell viability, colony formation, migration and invasion of U251 and U343 GBM cells. Luteolin also decreased the proliferation of patient-derived glioma initiating cells (GICs) and tumor-organoids but did not affect normal astrocytes. Finally, we demonstrated the value of combined treatments with luteolin and olaparib (PARP inhibitor) or ionizing radiation (IR). Our results show that luteolin functions as an inhibitor of Msi1 and demonstrates its potential use in GBM therapy.

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Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma

Cited by 65 publications

References 44 publications

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

The p53 Pathway in Glioblastoma

Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells

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