RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells

King, Henry; Brend, Tim; Payne, Helen L.; Wright, Alexander; Ward, Thomas A.; Patel, Karan; Egnuni, Teklu; Stead, Lucy F.; Patel, Anjana; Wurdak, Heiko; Short, Susan

doi:10.1016/j.stemcr.2016.12.005

Cited by 102 publications

(104 citation statements)

References 48 publications

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“…The latter were generated from an established patient-derived GBM cell model (GBM1) which is characterized by stem cell-like features, including NESTIN/SOX2 co-expression as well as clonal growth, and in vivo tumorigenicity/invasion capacity. 17,19 Homogenous GBM spheroids were generated by aggregation of 500 GBM1 cells stably expressing green fluorescent protein (GFP). To maximize experimental throughput, we used a short mESCs differentiation period (12 days) that suffices to induce neural tissue identity in eCOs 18 prior to the co-culture assay ( Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion

et al. 2018

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Organoid methodology provides a platform for the ex vivo investigation of the cellular and molecular mechanisms underlying brain development and disease. High-grade brain tumor glioblastoma multiforme (GBM) is considered a cancer of unmet clinical need, in part due to GBM cell infiltration into healthy brain parenchyma making complete surgical resection improbable. Modelling the process of GBM invasion in real time is challenging as it requires both tumor and neural tissue compartments. Here, we demonstrate that human GBM spheroids possess the ability to spontaneously infiltrate earlystage cerebral organoids (eCO). The resulting formation of hybrid organoids demonstrated an invasive tumor phenotype that was distinct from non-cancerous adult neural progenitor (NP) spheroid incorporation into eCOs. These findings provide a basis for the modelling and quantification of the GBM infiltration process using a stem cell-based organoid approach, and may be used for the identification of anti-GBM invasion strategies.

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Section: Resultsmentioning

confidence: 99%

Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion

et al. 2018

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“…Consequently, active DNA repair mechanisms can promote therapy resistance and recurrence in various tumour types. For instance, DNA repair protein RAD51 homolog 1 (RAD51) overexpression in breast and brain cancer cells can lead to increased HDR activity, resulting in resistance to chemoradiotherapy (6)(7)(8). Fortunately, small-molecule modulators of DNA repair mechanisms have since been reported to increase the efficacy of DNA-targeting therapeutics against cancers (4), and genome editing tools are being actively investigated for therapeutic and precision diagnostic applications.…”

Section: Introductionmentioning

confidence: 99%

A multiplexed bioluminescent reporter for sensitive and non-invasive tracking of DNA double strand break repair dynamics in vitro and in vivo

Chien

Tabet

Pinkham

et al. 2020

Preprint

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Tracking DNA double strand break (DSB) repair is paramount for the understanding and therapeutic development of various diseases including cancers. Herein, we describe a multiplexed bioluminescent repair reporter (BLRR) for non-invasive monitoring of DSB repair pathways in living cells and animals. The BLRR approach employs secreted Gaussia and Vargula luciferases to simultaneously detect homology-directed repair (HDR) and non-homologous end joining (NHEJ), respectively. BLRR data are consistent with next-generation sequencing results for reporting HDR (R2 = 0.9722) and NHEJ (R2 = 0.919) events. Moreover, BLRR analysis allows longitudinal tracking of HDR and NHEJ activities in cells, and enables detection of DSB repairs in xenografted tumours in vivo. Using the BLRR system, we observed a significant difference in the efficiency of CRISPR/Cas9-mediated editing with guide RNAs only 1-10 bp apart. Moreover, BLRR analysis detected altered dynamics for DSB repair induced by small-molecule modulators. Finally, we discovered HDR-suppressing functions of anticancer cardiac glycosides in human glioblastomas and glioma cancer stem-like cells via inhibition of DNA repair protein RAD51 homolog 1 (RAD51). The BLRR method provides a highly sensitive platform to simultaneously and longitudinally track HDR and NHEJ dynamics that is sufficiently versatile for elucidating the physiology and therapeutic development of DSB repair.

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“…Prevention of DNA strand break (DSB) repair post radiation treatment by targeted disruption of DSB repair protein activity in the gliomas can be also used to treat the disease. Some of the protein specifically targeted for such therapeutics are the disruption of RAD51 (King, Brend et al 2017), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia-telangiectasia mutated (ATM) (Gil del Alcazar, Hardebeck et al 2014) and EGFRvIII (Mukherjee, McEllin et al 2009) protein.…”

Section: Radiationmentioning

confidence: 99%

Brain Tumor Treatment: 2017 Update

Chakraborty¹,

Han²,

Faltas³

et al. 2018

CCO

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Malignant brain tumors are a heterogeneous group of diseases arising from different cell types that affect both adults and children. The high recurrence rate of malignant brain tumors typically is due to reappearance of focal masses, indicating that a sub population of tumor cells are insensitive to current therapies and may be responsible for reinitiating tumor growth. It is generally agreed that the resistant tumor cells are comprised of cancer stem cells or tumor-initiating cells. While brain tumor stem cells (BTSCs) were first isolated within the last decade, much of the early research has been focused on identifying the BTSC markers and therapeutic targets. The challenge however, is to translate this knowledge to therapeutics. In the current review, we survey the remedial strategies to target BTSCs, which includes diagnostic, pharmacologic, immunologic, viral, and post-transcriptional approaches.

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RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells

Cited by 102 publications

References 48 publications

Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion

Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion

A multiplexed bioluminescent reporter for sensitive and non-invasive tracking of DNA double strand break repair dynamics in vitro and in vivo

Brain Tumor Treatment: 2017 Update

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