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Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts
The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP). We compared th...
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| Published in: | PloS one 2016-12, Vol.11 (12), p.e0167272-e0167272 |
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| creator | Lohse, Ines Kumareswaran, Ramya Cao, Pinjiang Pitcher, Bethany Gallinger, Steven Bristow, Robert G Hedley, David W |
| description | The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP).
We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways.
The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone.
While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors. |
| doi_str_mv | 10.1371/journal.pone.0167272 |
| format | article |
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We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways.
The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone.
While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0167272</identifier><identifier>PMID: 28033382</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine diphosphate ; Animals ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Biology and life sciences ; BRCA2 protein ; BRCA2 Protein - genetics ; Breast cancer ; Cancer ; Cancer therapies ; Care and treatment ; Cell cycle ; Cell Proliferation - drug effects ; Cell Proliferation - radiation effects ; Combined Modality Therapy - methods ; Combined treatment ; Comparative analysis ; Damage assessment ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; Health aspects ; Health care networks ; Humans ; Hypoxia ; Inhibition ; Ionizing radiation ; Medical research ; Medicine and Health Sciences ; Mice ; Mice, SCID ; Mutation ; Olaparib ; Ovarian cancer ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - radiotherapy ; Phthalazines - therapeutic use ; Physical Sciences ; Piperazines - therapeutic use ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use ; Prostate cancer ; Radiation ; Radiation, Ionizing ; Radiation-Sensitizing Agents - therapeutic use ; Radiosensitization ; Ribose ; Rodents ; Sensitivity ; Targeted cancer therapy ; Tumors ; Xenograft Model Antitumor Assays - methods ; Xenografts</subject><ispartof>PloS one, 2016-12, Vol.11 (12), p.e0167272-e0167272</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Lohse et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Lohse et al 2016 Lohse et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-21f79e94bf4998929360b8b70fdd3db30d36ce57001a2c48c02bb7a92f1d63353</citedby><cites>FETCH-LOGICAL-c725t-21f79e94bf4998929360b8b70fdd3db30d36ce57001a2c48c02bb7a92f1d63353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1854114160/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1854114160?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25751,27922,27923,37010,37011,44588,53789,53791,74896</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28033382$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chaudhuri, Gautam</contributor><creatorcontrib>Lohse, Ines</creatorcontrib><creatorcontrib>Kumareswaran, Ramya</creatorcontrib><creatorcontrib>Cao, Pinjiang</creatorcontrib><creatorcontrib>Pitcher, Bethany</creatorcontrib><creatorcontrib>Gallinger, Steven</creatorcontrib><creatorcontrib>Bristow, Robert G</creatorcontrib><creatorcontrib>Hedley, David W</creatorcontrib><title>Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP).
We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways.
The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone.
While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors.</description><subject>Adenosine diphosphate</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>Biology and life sciences</subject><subject>BRCA2 protein</subject><subject>BRCA2 Protein - genetics</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Cell cycle</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - radiation effects</subject><subject>Combined Modality Therapy - methods</subject><subject>Combined treatment</subject><subject>Comparative analysis</subject><subject>Damage assessment</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Health aspects</subject><subject>Health care networks</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Inhibition</subject><subject>Ionizing radiation</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Mutation</subject><subject>Olaparib</subject><subject>Ovarian cancer</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - radiotherapy</subject><subject>Phthalazines - therapeutic use</subject><subject>Physical Sciences</subject><subject>Piperazines - therapeutic use</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use</subject><subject>Prostate cancer</subject><subject>Radiation</subject><subject>Radiation, Ionizing</subject><subject>Radiation-Sensitizing Agents - therapeutic use</subject><subject>Radiosensitization</subject><subject>Ribose</subject><subject>Rodents</subject><subject>Sensitivity</subject><subject>Targeted cancer therapy</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays - methods</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tuEzEQhlcIREvhDRBYQkJwkeDT7npvkEIoEKmoVSiHO2vWayeONnawnUJ5GV4Vp02rBvWi8oUt-_v_GY89RfGU4CFhNXmz8OvgoB-uvNNDTKqa1vResU8aRgcVxez-jfVe8SjGBcYlE1X1sNijAjPGBN0v_h4ao1WKyBs09svWOt2h06AhLbVL6JdNczTxzv6xboam0FlI1jsErkNprtHJaHqCJm5uW5t8QMc9rCDYFlmH3k3HI_R5nSDbbPDvts_O56ssyh7ZfPBeB3uWw52AU5uIVqFxXuqAfmjnZwFMio-LBwb6qJ9s54Pi64fD0_GnwdHxx8l4dDRQNS3TgBJTN7rhreFNIxrasAq3oq2x6TrWtQx3rFK6rDEmQBUXCtO2raGhhnQVYyU7KJ5f-q56H-W2tlESUXJCOKlwJiaXROdhIVfBLiGcSw9WXmz4MJMQ8h16LRXjDLgpjYCaG6AgoKKCiJopXemmzV5vt9HW7VJ3KlcjQL9junvi7FzO_JksSdPgi2RebQ2C_7nWMcmljUr3PTjt1xd5N1xQytldUF6RilGR0Rf_obcXYkvNIN_VOuNzimpjKke8LjmmpaCZGt5C5dHppVX5zxqb93cEr3cEmUn6d5rBOkY5-TK9O3v8bZd9eYOda-jTPPp-vfnHcRfkl6AKPsagzfV7ECw3LXdVDblpObltuSx7dvMtr0VXPcb-AdzzJdg</recordid><startdate>20161229</startdate><enddate>20161229</enddate><creator>Lohse, Ines</creator><creator>Kumareswaran, Ramya</creator><creator>Cao, Pinjiang</creator><creator>Pitcher, Bethany</creator><creator>Gallinger, Steven</creator><creator>Bristow, Robert G</creator><creator>Hedley, David W</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20161229</creationdate><title>Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts</title><author>Lohse, Ines ; Kumareswaran, Ramya ; Cao, Pinjiang ; Pitcher, Bethany ; Gallinger, Steven ; Bristow, Robert G ; Hedley, David W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c725t-21f79e94bf4998929360b8b70fdd3db30d36ce57001a2c48c02bb7a92f1d63353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adenosine diphosphate</topic><topic>Animals</topic><topic>Antineoplastic Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lohse, Ines</au><au>Kumareswaran, Ramya</au><au>Cao, Pinjiang</au><au>Pitcher, Bethany</au><au>Gallinger, Steven</au><au>Bristow, Robert G</au><au>Hedley, David W</au><au>Chaudhuri, Gautam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-12-29</date><risdate>2016</risdate><volume>11</volume><issue>12</issue><spage>e0167272</spage><epage>e0167272</epage><pages>e0167272-e0167272</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP).
We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways.
The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone.
While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28033382</pmid><doi>10.1371/journal.pone.0167272</doi><tpages>e0167272</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-12, Vol.11 (12), p.e0167272-e0167272 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1854114160 |
| source | Open Access: PubMed Central; Publicly Available Content Database (Proquest) (PQ_SDU_P3) |
| subjects | Adenosine diphosphate Animals Antineoplastic Agents - therapeutic use Apoptosis Biology and life sciences BRCA2 protein BRCA2 Protein - genetics Breast cancer Cancer Cancer therapies Care and treatment Cell cycle Cell Proliferation - drug effects Cell Proliferation - radiation effects Combined Modality Therapy - methods Combined treatment Comparative analysis Damage assessment Deoxyribonucleic acid DNA DNA damage DNA repair Health aspects Health care networks Humans Hypoxia Inhibition Ionizing radiation Medical research Medicine and Health Sciences Mice Mice, SCID Mutation Olaparib Ovarian cancer Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - radiotherapy Phthalazines - therapeutic use Physical Sciences Piperazines - therapeutic use Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Prostate cancer Radiation Radiation, Ionizing Radiation-Sensitizing Agents - therapeutic use Radiosensitization Ribose Rodents Sensitivity Targeted cancer therapy Tumors Xenograft Model Antitumor Assays - methods Xenografts |
| title | Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-13T14%3A10%3A55IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Effects%20of%20Combined%20Treatment%20with%20Ionizing%20Radiation%20and%20the%20PARP%20Inhibitor%20Olaparib%20in%20BRCA%20Mutant%20and%20Wild%20Type%20Patient-Derived%20Pancreatic%20Cancer%20Xenografts&rft.jtitle=PloS%20one&rft.au=Lohse,%20Ines&rft.date=2016-12-29&rft.volume=11&rft.issue=12&rft.spage=e0167272&rft.epage=e0167272&rft.pages=e0167272-e0167272&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0167272&rft_dat=%3Cgale_plos_%3EA475402582%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c725t-21f79e94bf4998929360b8b70fdd3db30d36ce57001a2c48c02bb7a92f1d63353%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1854114160&rft_id=info:pmid/28033382&rft_galeid=A475402582&rfr_iscdi=true |