FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3083146595> ?p ?o ?g. }

• W3083146595 abstract "Patients with aggressive osteosarcoma (OS) have poor prognosis due in part to copy number variations (CNVs) that contribute to dysregulation of gene expression (GE) and therapeutic resistance. The objective of the present study was to utilize the TARGET database to integrate CNV and corresponding GE with poor prognosis in pediatric OS (n=85) followed by functional validation of prioritized targets. Cox regression analysis indicated that CNVs in 2642 genes correlated with relapse risk in pediatric OS. Furthermore, the top 10 genes with CNVs significantly associated with increased risk for relapse were present on chromosome 8. The MYC and RAD21 copy number gain (MYC-RAD21 CNV+) located on chromosome 8q correlated with increased GE and poor survival in >90% of the relapsed patients. Based on network analysis, the MYC-RAD21 CNV+ was prioritized for development of targeted therapy. MYC, an oncogenic driver of OS growth, can be indirectly inhibited by bromodomain and extra-terminal domain inhibitors (BETi). RAD21 expression has been associated with increased sensitivity to cell cycle checkpoint kinase 1 inhibitors (CHK1i) in melanoma. Additionally, mechanistic links exist between MYC and CHK1, especially during replication stress. Our hypothesis was that the MYC-RAD21 CNV+ serves as a biomarker of poor prognosis and therapeutic response to BETi+CHK1i therapy. Cell growth response to BETi and CHK1i was evaluated in MYC-RAD21 CNV+ pediatric OS cell lines and a patient-derived xenograft (PDX)-derived xenoline (TT2-77). OS lines (G292, MG63, U2OS, and TT2-77) were highly sensitive to single agent BETi/OTX-015, CHK1i/ SRA737 or CHK1i/LY2606368 at clinically relevant concentrations. Combination index and Bliss independence analysis indicated that BETi+CHK1i did not result in synergistic or additive inhibition of growth at clinically relevant concentrations. However, in OS lines Saos2 and Saos2-LM7 BETi+CHK1i resulted in additive to synergistic inhibition of growth at multiple dose-ratios and at clinically relevant concentrations. In the TT2-77 PDX, whole genome sequencing indicated that the original OS biopsy and the TT2-77 PDX generated from a resection sample harbor the MYC-RAD21 CNV+ (4 copies/amplicon). PDX tumor fragments were implanted into the flank of immunodeficient NOD/SCID/IL2Rγ mice. Once tumor volumes reached 100-150 mm3, mice were randomized and treated with four 5-day cycles of BETi/OTX-015 and/or CHK1i/SRA737. BETi+CHK1i significantly decreased TT2-77 growth, increased probability of survival, and was well tolerated. BETi+CHK1i is a promising therapeutic approach for treatment of relapsed pediatric MYC-RAD21 CNV+ OS. It is possible that MYC, BETs, RAD21 and CHK1 protein levels could dictate sensitivity to combination BETi+CHK1i independent of MYC-RAD2 CNV+ status. Studies are in progress to identify responder versus non-responder signatures in OS. Citation Format: Khadijeh Bijangi-Vishehsaraei, Pankita Pandya, Cheng Lijun, Tang Shan, Anthony Sinn, Melissa Trowbridge, Kathy Coy, Courtney Hemenway, Barbara Bailey, Harlan Shannon, Jixin Ding, Erika Dobrota, M. Reza Saadatzadeh, Adily Elmi, Jeremiah Shultz, Mary Murray, Mark Marshall, Michael Ferguson, Todd Bertrand, L. Daniel Wurtz, Sandeep Batra, Lang Li, Jamie Renbarger, Karen Pollok. Systems biology approach provides rationale for dual-targeted inhibition of BET and CHK1 in aggressive pediatric osteosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 450." @default.
• W3083146595 created "2020-09-11" @default.
• W3083146595 creator A5000532556 @default.
• W3083146595 creator A5006404776 @default.
• W3083146595 creator A5014864428 @default.
• W3083146595 creator A5021599737 @default.
• W3083146595 creator A5022327161 @default.
• W3083146595 creator A5027787903 @default.
• W3083146595 creator A5031825011 @default.
• W3083146595 creator A5035509831 @default.
• W3083146595 creator A5041038506 @default.
• W3083146595 creator A5049161723 @default.
• W3083146595 creator A5050941851 @default.
• W3083146595 creator A5052581052 @default.
• W3083146595 creator A5056605480 @default.
• W3083146595 creator A5060412535 @default.
• W3083146595 creator A5063088114 @default.
• W3083146595 creator A5065902063 @default.
• W3083146595 creator A5066992299 @default.
• W3083146595 creator A5070410235 @default.
• W3083146595 creator A5070502683 @default.
• W3083146595 creator A5071864166 @default.
• W3083146595 creator A5073818711 @default.
• W3083146595 creator A5082085477 @default.
• W3083146595 creator A5083657187 @default.
• W3083146595 creator A5089265440 @default.
• W3083146595 date "2020-08-13" @default.
• W3083146595 modified "2023-09-26" @default.
• W3083146595 title "Abstract 450: Systems biology approach provides rationale for dual-targeted inhibition of BET and CHK1 in aggressive pediatric osteosarcoma" @default.
• W3083146595 doi "https://doi.org/10.1158/1538-7445.am2020-450" @default.
• W3083146595 hasPublicationYear "2020" @default.
• W3083146595 type Work @default.
• W3083146595 sameAs 3083146595 @default.
• W3083146595 citedByCount "0" @default.
• W3083146595 crossrefType "proceedings-article" @default.
• W3083146595 hasAuthorship W3083146595A5000532556 @default.
• W3083146595 hasAuthorship W3083146595A5006404776 @default.
• W3083146595 hasAuthorship W3083146595A5014864428 @default.
• W3083146595 hasAuthorship W3083146595A5021599737 @default.
• W3083146595 hasAuthorship W3083146595A5022327161 @default.
• W3083146595 hasAuthorship W3083146595A5027787903 @default.
• W3083146595 hasAuthorship W3083146595A5031825011 @default.
• W3083146595 hasAuthorship W3083146595A5035509831 @default.
• W3083146595 hasAuthorship W3083146595A5041038506 @default.
• W3083146595 hasAuthorship W3083146595A5049161723 @default.
• W3083146595 hasAuthorship W3083146595A5050941851 @default.
• W3083146595 hasAuthorship W3083146595A5052581052 @default.
• W3083146595 hasAuthorship W3083146595A5056605480 @default.
• W3083146595 hasAuthorship W3083146595A5060412535 @default.
• W3083146595 hasAuthorship W3083146595A5063088114 @default.
• W3083146595 hasAuthorship W3083146595A5065902063 @default.
• W3083146595 hasAuthorship W3083146595A5066992299 @default.
• W3083146595 hasAuthorship W3083146595A5070410235 @default.
• W3083146595 hasAuthorship W3083146595A5070502683 @default.
• W3083146595 hasAuthorship W3083146595A5071864166 @default.
• W3083146595 hasAuthorship W3083146595A5073818711 @default.
• W3083146595 hasAuthorship W3083146595A5082085477 @default.
• W3083146595 hasAuthorship W3083146595A5083657187 @default.
• W3083146595 hasAuthorship W3083146595A5089265440 @default.
• W3083146595 hasBestOaLocation W30831465951 @default.
• W3083146595 hasConcept C124952713 @default.
• W3083146595 hasConcept C142362112 @default.
• W3083146595 hasConcept C2777760704 @default.
• W3083146595 hasConcept C2780980858 @default.
• W3083146595 hasConcept C41008148 @default.
• W3083146595 hasConcept C502942594 @default.
• W3083146595 hasConcept C70721500 @default.
• W3083146595 hasConcept C71924100 @default.
• W3083146595 hasConcept C86803240 @default.
• W3083146595 hasConceptScore W3083146595C124952713 @default.
• W3083146595 hasConceptScore W3083146595C142362112 @default.
• W3083146595 hasConceptScore W3083146595C2777760704 @default.
• W3083146595 hasConceptScore W3083146595C2780980858 @default.
• W3083146595 hasConceptScore W3083146595C41008148 @default.
• W3083146595 hasConceptScore W3083146595C502942594 @default.
• W3083146595 hasConceptScore W3083146595C70721500 @default.
• W3083146595 hasConceptScore W3083146595C71924100 @default.
• W3083146595 hasConceptScore W3083146595C86803240 @default.
• W3083146595 hasLocation W30831465951 @default.
• W3083146595 hasOpenAccess W3083146595 @default.
• W3083146595 hasPrimaryLocation W30831465951 @default.
• W3083146595 hasRelatedWork W1942105196 @default.
• W3083146595 hasRelatedWork W2016162236 @default.
• W3083146595 hasRelatedWork W2333442738 @default.
• W3083146595 hasRelatedWork W2343181334 @default.
• W3083146595 hasRelatedWork W2565743403 @default.
• W3083146595 hasRelatedWork W2748952813 @default.
• W3083146595 hasRelatedWork W2899084033 @default.
• W3083146595 hasRelatedWork W2950308704 @default.
• W3083146595 hasRelatedWork W2963272670 @default.
• W3083146595 hasRelatedWork W4292236581 @default.
• W3083146595 isParatext "false" @default.
• W3083146595 isRetracted "false" @default.
• W3083146595 magId "3083146595" @default.
• W3083146595 workType "article" @default.