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dc.contributor.authorNazareth, Deborah
dc.contributor.authorJones, Mathew JK
dc.contributor.authorGabrielli, Brian
dc.date.accessioned2019-11-25T02:41:46Z
dc.date.available2019-11-25T02:41:46Z
dc.date.issued2019
dc.identifier.issn2072-6694
dc.identifier.doi10.3390/cancers11091320
dc.identifier.urihttp://hdl.handle.net/10072/389227
dc.description.abstractThe poor selectivity of standard cytotoxic chemotherapy regimens causes severe side-effects in patients and reduces the quality of life during treatment. Targeting cancer-specific vulnerabilities can improve response rates, increase overall survival and limit toxic side effects in patients. Oncogene-induced replication stress serves as a tumour specific vulnerability and rationale for the clinical development of inhibitors targeting the DNA damage response (DDR) kinases (CHK1, ATR, ATM and WEE1). CHK1 inhibitors (CHK1i) have served as the pilot compounds in this class and their efficacy in clinical trials as single agents has been disappointing. Initial attempts to combine CHK1i with chemotherapies agents that enhance replication stress (such as gemcitabine) were reported to be excessively toxic. More recently, it has emerged that combining CHK1i with subclinical doses of replication stress inducers is more effective, better tolerated and more compatible with immunotherapies. Here we focus on the lessons learned during the clinical development of CHK1i with the goal of improving the design of future clinical trials utilizing DDR inhibitors to target replication stress in cancer.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)
dc.publisher.placeSwitzerland
dc.relation.ispartofpagefrom1320: 1
dc.relation.ispartofpageto1320: 12
dc.relation.ispartofissue9
dc.relation.ispartofjournalCancers
dc.relation.ispartofvolume11
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchcode3211
dc.subject.keywordsATR
dc.subject.keywordsGEMCITABINE
dc.subject.keywordsACTIVATION
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.titleEverything in Moderation: Lessons Learned by Exploiting Moderate Replication Stress in Cancer
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationNazareth, D; Jones, MJK; Gabrielli, B, Everything in Moderation: Lessons Learned by Exploiting Moderate Replication Stress in Cancer, Cancers, 2019, 11 (9), pp. 1320: 1-1320: 12
dcterms.dateAccepted2019-09-04
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/
dc.date.updated2019-11-22T03:35:38Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorGabrielli, Brian


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