Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

Venere, Monica; Hamerlik, Petra; Wu, Qiulian; Rasmussen, Rikke; Song, Lee Ann; Vasanji, Amit; Tenley, Nathan; Flavahan, William; Hjelmeland, Anita B.; Bártek, Jiří; Rich, Jeremy

doi:10.1038/cdd.2013.136

Cited by 154 publications

(143 citation statements)

References 53 publications

(72 reference statements)

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“…Several preclinical studies have successfully used DDRi to increase chemoand radiosensitivity in glioblastoma models, but these results were not substantiated in the treatment-resistant GSC population (30)(31)(32)(33)(34). More recently, we have shown the ATM inhibitor KU55933 to be a potent radiosensitizer of GSC (27), and inhibition of PARP has also been shown to overcome radioresistance of GSCs (35). These findings corroborate and extend the landmark study by Bao and colleagues in which inhibition of CHK1 and CHK2 was shown to enhance the radiosensitivity of GSCs (10).…”

Section: Introductionsupporting

confidence: 80%

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells

et al. 2015

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Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G 2 -M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G 2 -M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC. Cancer Res; 75(20); 4416-28. Ó2015 AACR.

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Section: Introductionsupporting

confidence: 80%

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells

et al. 2015

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“…In fact, inhibition of Notch signaling significantly reduces GBM growth in vitro and in vivo, 12 likely by reducing the size or functionality of the cancer stem cell population. 33 This and other 17,34 innovative strategies indicate that translational therapies targeting GCSCs could significantly improve the prognosis of patients with GBM.…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

et al. 2015

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Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (GCSCs), a subpopulation of GBM cells that can give rise to recurrent tumors. GBMs express human cytomegalovirus (HCMV) proteins, and previously we found that the level of expression of HCMV immediate-early (IE) protein in GBMs is a prognostic factor for poor patient survival. In this study, we investigated the relation between HCMV infection of GBM cells and the presence of GCSCs. Primary GBMs were characterized by their expression of HCMV-IE and GCSCs marker CD133 and by patient survival. The extent to which HCMV infection of primary GBM cells induced a GCSC phenotype was evaluated in vitro. In primary GBMs, a large fraction of CD133-positive cells expressed HCMV-IE, and higher co-expression of these two proteins predicted poor patient survival. Infection of GBM cells with HCMV led to upregulation of CD133 and other GSCS markers (Notch1, Sox2, Oct4, Nestin). HCMV infection also promoted the growth of GBM cells as neurospheres, a behavior typically displayed by GCSCs, and this phenotype was prevented by either chemical inhibition of the Notch1 pathway or by treatment with the anti-viral drug ganciclovir. GBM cells that maintained expression of HCMV-IE failed to differentiate into neuronal or astrocytic phenotypes. Our findings imply that HCMV infection induces phenotypic plasticity of GBM cells to promote GCSC features and may thereby increase the aggressiveness of this tumor. GBM is the most prevalent and the most aggressive primary malignancy of the central nervous system in adults. It is a highly vascularized and infiltrating tumor, rarely cured and prone to recurrence. The median duration of survival after diagnosis is less than 15 months, despite aggressive therapy consisting of surgical resection and concomitant radiotherapy and chemotherapy. 1 Surgical resection of GBMs is typically incomplete, as they are located in the brain and are highly infiltrative. Postoperative radiotherapy and chemotherapy fail to eradicate all remaining GBM cells. Thus, a breakthrough in identifying a new treatment option leading to a cure of this disease is still lacking.GBMs contain a subpopulation of highly tumorigenic cells with unlimited capacity for self-renewal that are commonly resistant to standard therapy. Phenotypically and functionally, these cells resemble neural stem cells and, when implanted in immunodeficient mice, can generate new tumors. As a result, they are referred to as glioma cancer initiating cells or glioma cancer stem cells (GCSCs) (reviewed in Lima et al. 2 ).Because of their apparent pivotal role in gliomagenesis and tumor recurrence after therapy, GCSCs are a major focus of research whose ultimate goal is to identify more effective therapies for GBM patients.GCSCs were first identified by their surface expression of CD133, based on the findings that these cells grow as neurospheres under nonadher...

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“…For example, a specific inhibitor of the checkpoint kinases debromohymenialdisine (DBH) has been demonstrated to reverse the radio-resistance of GSCs defined as CD133+ [3] . PARP inhibitor (olaparib) was also able to sensitize GICs to radiation [37] . In addition, NSCLC-stem cell survival can be dramatically reduced by Chk1 inhibitors (SB218078 and AZD7762) in combination with chemotherapy [43] .…”

Section: Targeting the Ddr To Facilitate Eradication Of Cscsmentioning

confidence: 99%

“…Glioblastomainitiating cells (GICs) also exhibit enhanced basal activation of SSB repair due to enhanced activation of the key SSB repair player PARP1. The growth, selfrenewal, and DNA damage repair capacity of GICs can be inhibited by PARP inhibition, leading to an enhanced sensitization of GICs to radiation [37] . In addition,…”

Section: Ddr In Cscsmentioning

confidence: 99%

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

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The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.

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Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

Cited by 154 publications

References 53 publications

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

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