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... SCIENCE TIMES of time, and can be a safe and poten- these double stranded breaks fail to trigger glioma by determining correlation between tially more effective treatment modality for a DNA damage response. expression levels of these genes and overall GBM. Glioblastoma multiforme (GBM) repre- survival in GBM patients. In their dataset, sents an aggressive primary brain cancer they found that patients with high levels of with high levels of DNA replication. These BRCA1 had a median survival of 230 days Muhammad Babar Khan, MD high levels of DNA replication expose compared to those with low BRCA1 levels Shamik Chakraborty, MD GBMs to significant replication stress and or negative for BRCA1 whose survival at John Andrew Boockvar, MD DNA errors causing cell-cycle arrest. While the completion of their study could not be Brain Tumor Center BRCA1 is customarily viewed as a tumor determined as more than 50% were still Department of Neurosurgery suppressor gene, the work of Rasmussen living. Similarly, RRM2 positive (median Lenox Hill Hospital et al demonstrates that in GBMs, BRCA1 of 1%) patients had shorter survival times Hofstra-Northwell School of Medicine helps to minimize replication stress and (median survival 222 days) compared to New York, New York improve GBM cell survival. RRM2 negative patients (median survival Rasmussen et al begin by demon- not yet reached by end of study). Overall, REFERENCES strating that BRCA1 expression is directly elevated BRCA1 and RRM2 expression 1. Batlevi CL, Matsuki E, Brentjens RJ, Younes A. correlated with GBM cell viability and proved to be negative prognostic markers Novel immunotherapies in lymphoid malignancies. tumor growth in a GBM xenograft model. (hazard ratio = 7.772, 95% confidence Nat Rev Clin Oncol. 2016;13(1):25-40. 2. Maus MV, Grupp SA, Porter DL, June Not only did they note decreased GBM interval [2.98-19.97] and hazard ratio = CH. Antibody-modified T cells: CARs take the cell survival in BRCA1 knockdowns, but 3.14, 95% confidence interval [1.82-5.42], front seat for hematologic malignancies. Blood. they also noted an absence of the same respectively). 2014;123(17):2625-2635. 3. Brown CE, Alizadeh D, Starr R, et al. Regression of effect in other cancer cell lines. Mecha- The investigators provide a novel and Glioblastoma after Chimeric Antigen Receptor T-Cell nistically, Rasmussen and his group were unexpected relationship between normal Therapy. NEnglJMed. 2016;375(26):2561-2569. able to show that BRCA1 protects GBM tumor suppressor gene function and GBM 4. Ahmed N, Brawley V, Hegde M, et al. Autol- cells against endogenous replication stress- pathophysiology. First, they provide a ogous HER2 CMV bispecific CAR T cells are safe and demonstrate clinical benefit for glioblastoma in induced DNA damage causing DNA rationale for the clinical application of aphase Itrial. J Immunother Cancer. 2015;3(Suppl double strand breaks through its upstream existing chemotherapeutics such as triapine 2):O11. regulation of RRM2 expression. They were (an RRM2 inhibitor) in combination 5. O’Rourke DM, Nasrallah M, Morrissette JJ, et al. Pilot study of T cells redirected to EGFRvIII with a also able to demonstrate that this same with other agents. Second, their findings chimeric antigen receptor in patients with EGFRvIII+ BRCA1–RRM2 relationship was present in offer a new testable predictive biomarker. glioblastoma. J Clin Oncol. 2016;34:2067-2067. normal human astrocytes, but not present While further study is warranted to inves- in the non-GBM cancer cell lines studied. tigate the full clinical implications of the In order to determine the clinical BRCA1–RRM2 signaling axis, this work BRCA1-Regulated significance of the BRCA1–RRM2 opens new avenues for chemotherapeutic signaling pathway in malignant gliomas, interventions in malignant gliomas. RRM2 Expression they analyzed 145 gliomas and 10 non- Protects Glioblastoma neoplastic adult brain samples and found W. Christopher Newman, MD increased BRCA1 expression in 5.92% Cells from Endogenous Wi Jin Kim, BA of WHO grade II, 39.85% of WHO Nduka M. Amankulor, MD grade III, and 41.6% of WHO grade Replication Stress and Department of Neurological Surgery IV gliomas, with WHO grade III and University of Pittsburgh Medical Center Promotes IV gliomas having significantly higher Pittsburgh, Pennsylvania BRCA1 expression than normal brain Tumorigenicity University of Pittsburgh School of Medicine (P < .0001). Similarly, RRM2 positivity Pittsburgh, Pennsylvania utations in BRCA1 represent was significantly higher in WHO grade a major cause of inheritable III and grade IV gliomas (4.15% and malignancies. Traditionally, the 9.3%, respectively; P = .0134). They REFERENCES BRCA1 gene is known as a potent tumor then utilized the Repository for Molecular 1. Bartkova J, Rezaei N, Liontos M, Karakaidos P, suppressor whose function is mediated by Brain Neoplasia Data (REMBRANDT) Kletsas D, et al. Oncogene-induced senescence is part stabilizing deoxyribonucleic acid (DNA) glioma dataset to validate their finding of of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-637. replication forks and allowing error-free the correlation between high grade gliomas 2. Rasmussen RD, Gajjar MK, Tuckova L, et al. replication of DNA. In general, BRCA1 and BRCA1 and RRM2 positivity. BRCA1-regulated RRM2 expression protects loss can result in replication fork collapse The investigators then sought to glioblastoma cells from endogenous replication and DNA double strand breaks, which can determine the clinical implications of stress and promotes tumorigenicity. Nat Commun. 2016;7:13398. doi: 10.1038/ncomms13398. contribute to malignant transformation if elevated BRCA1 and RRM2 expression in N34 | VOLUME 80 | NUMBER 5 | MAY 2017 www.neurosurgery-online.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

BRCA1-Regulated RRM2 Expression Protects Glioblastoma Cells from Endogenous Replication Stress and Promotes Tumorigenicity

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Congress of Neurological Surgeons
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Copyright © 2017 by the Congress of Neurological Surgeons
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0148-396X
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1524-4040
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10.1093/neuros/nyx106
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Abstract

SCIENCE TIMES of time, and can be a safe and poten- these double stranded breaks fail to trigger glioma by determining correlation between tially more effective treatment modality for a DNA damage response. expression levels of these genes and overall GBM. Glioblastoma multiforme (GBM) repre- survival in GBM patients. In their dataset, sents an aggressive primary brain cancer they found that patients with high levels of with high levels of DNA replication. These BRCA1 had a median survival of 230 days Muhammad Babar Khan, MD high levels of DNA replication expose compared to those with low BRCA1 levels Shamik Chakraborty, MD GBMs to significant replication stress and or negative for BRCA1 whose survival at John Andrew Boockvar, MD DNA errors causing cell-cycle arrest. While the completion of their study could not be Brain Tumor Center BRCA1 is customarily viewed as a tumor determined as more than 50% were still Department of Neurosurgery suppressor gene, the work of Rasmussen living. Similarly, RRM2 positive (median Lenox Hill Hospital et al demonstrates that in GBMs, BRCA1 of 1%) patients had shorter survival times Hofstra-Northwell School of Medicine helps to minimize replication stress and (median survival 222 days) compared to New York, New York improve GBM cell survival. RRM2 negative patients (median survival Rasmussen et al begin by demon- not yet reached by end of study). Overall, REFERENCES strating that BRCA1 expression is directly elevated BRCA1 and RRM2 expression 1. Batlevi CL, Matsuki E, Brentjens RJ, Younes A. correlated with GBM cell viability and proved to be negative prognostic markers Novel immunotherapies in lymphoid malignancies. tumor growth in a GBM xenograft model. (hazard ratio = 7.772, 95% confidence Nat Rev Clin Oncol. 2016;13(1):25-40. 2. Maus MV, Grupp SA, Porter DL, June Not only did they note decreased GBM interval [2.98-19.97] and hazard ratio = CH. Antibody-modified T cells: CARs take the cell survival in BRCA1 knockdowns, but 3.14, 95% confidence interval [1.82-5.42], front seat for hematologic malignancies. Blood. they also noted an absence of the same respectively). 2014;123(17):2625-2635. 3. Brown CE, Alizadeh D, Starr R, et al. Regression of effect in other cancer cell lines. Mecha- The investigators provide a novel and Glioblastoma after Chimeric Antigen Receptor T-Cell nistically, Rasmussen and his group were unexpected relationship between normal Therapy. NEnglJMed. 2016;375(26):2561-2569. able to show that BRCA1 protects GBM tumor suppressor gene function and GBM 4. Ahmed N, Brawley V, Hegde M, et al. Autol- cells against endogenous replication stress- pathophysiology. First, they provide a ogous HER2 CMV bispecific CAR T cells are safe and demonstrate clinical benefit for glioblastoma in induced DNA damage causing DNA rationale for the clinical application of aphase Itrial. J Immunother Cancer. 2015;3(Suppl double strand breaks through its upstream existing chemotherapeutics such as triapine 2):O11. regulation of RRM2 expression. They were (an RRM2 inhibitor) in combination 5. O’Rourke DM, Nasrallah M, Morrissette JJ, et al. Pilot study of T cells redirected to EGFRvIII with a also able to demonstrate that this same with other agents. Second, their findings chimeric antigen receptor in patients with EGFRvIII+ BRCA1–RRM2 relationship was present in offer a new testable predictive biomarker. glioblastoma. J Clin Oncol. 2016;34:2067-2067. normal human astrocytes, but not present While further study is warranted to inves- in the non-GBM cancer cell lines studied. tigate the full clinical implications of the In order to determine the clinical BRCA1–RRM2 signaling axis, this work BRCA1-Regulated significance of the BRCA1–RRM2 opens new avenues for chemotherapeutic signaling pathway in malignant gliomas, interventions in malignant gliomas. RRM2 Expression they analyzed 145 gliomas and 10 non- Protects Glioblastoma neoplastic adult brain samples and found W. Christopher Newman, MD increased BRCA1 expression in 5.92% Cells from Endogenous Wi Jin Kim, BA of WHO grade II, 39.85% of WHO Nduka M. Amankulor, MD grade III, and 41.6% of WHO grade Replication Stress and Department of Neurological Surgery IV gliomas, with WHO grade III and University of Pittsburgh Medical Center Promotes IV gliomas having significantly higher Pittsburgh, Pennsylvania BRCA1 expression than normal brain Tumorigenicity University of Pittsburgh School of Medicine (P < .0001). Similarly, RRM2 positivity Pittsburgh, Pennsylvania utations in BRCA1 represent was significantly higher in WHO grade a major cause of inheritable III and grade IV gliomas (4.15% and malignancies. Traditionally, the 9.3%, respectively; P = .0134). They REFERENCES BRCA1 gene is known as a potent tumor then utilized the Repository for Molecular 1. Bartkova J, Rezaei N, Liontos M, Karakaidos P, suppressor whose function is mediated by Brain Neoplasia Data (REMBRANDT) Kletsas D, et al. Oncogene-induced senescence is part stabilizing deoxyribonucleic acid (DNA) glioma dataset to validate their finding of of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-637. replication forks and allowing error-free the correlation between high grade gliomas 2. Rasmussen RD, Gajjar MK, Tuckova L, et al. replication of DNA. In general, BRCA1 and BRCA1 and RRM2 positivity. BRCA1-regulated RRM2 expression protects loss can result in replication fork collapse The investigators then sought to glioblastoma cells from endogenous replication and DNA double strand breaks, which can determine the clinical implications of stress and promotes tumorigenicity. Nat Commun. 2016;7:13398. doi: 10.1038/ncomms13398. contribute to malignant transformation if elevated BRCA1 and RRM2 expression in N34 | VOLUME 80 | NUMBER 5 | MAY 2017 www.neurosurgery-online.com

Journal

NeurosurgeryOxford University Press

Published: May 1, 2017

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