FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4382395513> ?p ?o ?g. }

• W4382395513 abstract "<div>Purpose:<p>O⁶-methylguanine DNA methyltransferase (<i>MGMT</i>)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has <i>MGMT</i> silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer.</p>Experimental Design:<p>Patients with advanced colorectal cancer were screened for <i>MGMT</i> promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m² days 1–7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers.</p>Results:<p><i>MGMT</i> promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8⁺ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 <i>KRAS</i> and 1 <i>ERBB2</i>). Flow cytometry identified peripheral expansion of effector T cells.</p>Conclusions:<p>Our results indicate discordance between <i>MGMT</i> promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8⁺ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations.</p>Significance:<p>TMZ and PARP inhibitors synergize <i>in vitro</i> and <i>in vivo</i> in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.</p></div>" @default.
• W4382395513 created "2023-06-29" @default.
• W4382395513 creator A5012563381 @default.
• W4382395513 creator A5012787104 @default.
• W4382395513 creator A5015339168 @default.
• W4382395513 creator A5023884031 @default.
• W4382395513 creator A5039115208 @default.
• W4382395513 creator A5040738951 @default.
• W4382395513 creator A5046170235 @default.
• W4382395513 creator A5052643581 @default.
• W4382395513 creator A5055159334 @default.
• W4382395513 creator A5056682593 @default.
• W4382395513 creator A5059401787 @default.
• W4382395513 creator A5064953304 @default.
• W4382395513 creator A5069279240 @default.
• W4382395513 creator A5069423306 @default.
• W4382395513 creator A5073006325 @default.
• W4382395513 creator A5092350372 @default.
• W4382395513 date "2023-06-28" @default.
• W4382395513 modified "2023-09-23" @default.
• W4382395513 title "Data from Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer" @default.
• W4382395513 doi "https://doi.org/10.1158/2767-9764.c.6717656" @default.
• W4382395513 hasPublicationYear "2023" @default.
• W4382395513 type Work @default.
• W4382395513 citedByCount "0" @default.
• W4382395513 crossrefType "posted-content" @default.
• W4382395513 hasAuthorship W4382395513A5012563381 @default.
• W4382395513 hasAuthorship W4382395513A5012787104 @default.
• W4382395513 hasAuthorship W4382395513A5015339168 @default.
• W4382395513 hasAuthorship W4382395513A5023884031 @default.
• W4382395513 hasAuthorship W4382395513A5039115208 @default.
• W4382395513 hasAuthorship W4382395513A5040738951 @default.
• W4382395513 hasAuthorship W4382395513A5046170235 @default.
• W4382395513 hasAuthorship W4382395513A5052643581 @default.
• W4382395513 hasAuthorship W4382395513A5055159334 @default.
• W4382395513 hasAuthorship W4382395513A5056682593 @default.
• W4382395513 hasAuthorship W4382395513A5059401787 @default.
• W4382395513 hasAuthorship W4382395513A5064953304 @default.
• W4382395513 hasAuthorship W4382395513A5069279240 @default.
• W4382395513 hasAuthorship W4382395513A5069423306 @default.
• W4382395513 hasAuthorship W4382395513A5073006325 @default.
• W4382395513 hasAuthorship W4382395513A5092350372 @default.
• W4382395513 hasConcept C104317684 @default.
• W4382395513 hasConcept C121608353 @default.
• W4382395513 hasConcept C126322002 @default.
• W4382395513 hasConcept C143998085 @default.
• W4382395513 hasConcept C182979987 @default.
• W4382395513 hasConcept C2777389519 @default.
• W4382395513 hasConcept C2778227246 @default.
• W4382395513 hasConcept C2779138821 @default.
• W4382395513 hasConcept C2779962180 @default.
• W4382395513 hasConcept C502942594 @default.
• W4382395513 hasConcept C526805850 @default.
• W4382395513 hasConcept C55493867 @default.
• W4382395513 hasConcept C71924100 @default.
• W4382395513 hasConcept C82381507 @default.
• W4382395513 hasConcept C86803240 @default.
• W4382395513 hasConceptScore W4382395513C104317684 @default.
• W4382395513 hasConceptScore W4382395513C121608353 @default.
• W4382395513 hasConceptScore W4382395513C126322002 @default.
• W4382395513 hasConceptScore W4382395513C143998085 @default.
• W4382395513 hasConceptScore W4382395513C182979987 @default.
• W4382395513 hasConceptScore W4382395513C2777389519 @default.
• W4382395513 hasConceptScore W4382395513C2778227246 @default.
• W4382395513 hasConceptScore W4382395513C2779138821 @default.
• W4382395513 hasConceptScore W4382395513C2779962180 @default.
• W4382395513 hasConceptScore W4382395513C502942594 @default.
• W4382395513 hasConceptScore W4382395513C526805850 @default.
• W4382395513 hasConceptScore W4382395513C55493867 @default.
• W4382395513 hasConceptScore W4382395513C71924100 @default.
• W4382395513 hasConceptScore W4382395513C82381507 @default.
• W4382395513 hasConceptScore W4382395513C86803240 @default.
• W4382395513 hasLocation W43823955131 @default.
• W4382395513 hasOpenAccess W4382395513 @default.
• W4382395513 hasPrimaryLocation W43823955131 @default.
• W4382395513 hasRelatedWork W1876426852 @default.
• W4382395513 hasRelatedWork W2741839613 @default.
• W4382395513 hasRelatedWork W2928359858 @default.
• W4382395513 hasRelatedWork W3001769037 @default.
• W4382395513 hasRelatedWork W3023457002 @default.
• W4382395513 hasRelatedWork W3113016627 @default.
• W4382395513 hasRelatedWork W3175416687 @default.
• W4382395513 hasRelatedWork W3208048504 @default.
• W4382395513 hasRelatedWork W4286296881 @default.
• W4382395513 hasRelatedWork W4362566480 @default.
• W4382395513 isParatext "false" @default.
• W4382395513 isRetracted "false" @default.
• W4382395513 workType "article" @default.