2023
Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
Xu C, Huang K, Law J, Chua J, Sheng T, Flores N, Pizzi M, Okabe A, Tan A, Zhu F, Kumar V, Lu X, Benitez A, Lian B, Ma H, Ho S, Ramnarayanan K, Anene-Nzelu C, Razavi-Mohseni M, Ghani S, Tay S, Ong X, Lee M, Guo Y, Ashktorab H, Smoot D, Li S, Skanderup A, Beer M, Foo R, Wong J, Sanghvi K, Yong W, Sundar R, Kaneda A, Prabhakar S, Mazur P, Ajani J, Yeoh K, So J, Tan P. Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities. Gut 2023, 72: 1651-1663. PMID: 36918265, DOI: 10.1136/gutjnl-2022-328332.Peer-Reviewed Original ResearchMeSH KeywordsCell Cycle ProteinsDNA-Binding ProteinsEpigenomicsHumansMutationNuclear ProteinsStomach NeoplasmsTranscription FactorsTumor MicroenvironmentConceptsGastric cancerMolecular subtypesPromoter activityMutational signaturesProinflammatory tumor microenvironmentTumor microenvironmental changesMutated driver genesSingle-cell transcriptome profilingCTCF occupancyGC molecular subtypesChromatin profilingDistal enhancerRegulatory networksEpigenetic landscapeBRD4 bindingEpigenomic reprogrammingEpigenomic levelsTumor-intrinsicTumor inflammationTumor microenvironmentTherapeutic vulnerabilitiesTranscriptome profilingDriver genesNFkB inhibitorGene expressionClinical relevance of PD-1 positive CD8 T-cells in gastric cancer
Choo J, Kua L, Soe M, Asuncion B, Tan B, Teo C, Tay R, So J, Shabbir A, Guowei K, Tan H, Chan G, Ma H, Ramachandran G, Lum J, Chee C, Sridharan S, Tan P, Sundar R, Yong W. Clinical relevance of PD-1 positive CD8 T-cells in gastric cancer. Gastric Cancer 2023, 26: 393-404. PMID: 36781556, PMCID: PMC10115710, DOI: 10.1007/s10120-023-01364-7.Peer-Reviewed Original ResearchConceptsCD8 T cellsPD-1+CD8+ T cellsT cellsTumor microenvironmentPD-1Overall survivalGastric cancerMultiplex immunohistochemistryT cell-inflamed tumor microenvironmentAssociated with improved OSIncreased PD-1 expressionClinical relevanceGranzyme-B expressionInflamed tumor microenvironmentPD-1 expressionInfluence overall survivalNK cell proportionTreated with immunotherapyPhase 2 trialAssociated with chemotherapyCox proportional hazards modelsProportional hazards modelImproved OSImmunotherapy sensitivityNK cells
2022
Resistance to systemic immune checkpoint inhibition in the peritoneal niche
Chia D, Gwee Y, Sundar R. Resistance to systemic immune checkpoint inhibition in the peritoneal niche. Journal For ImmunoTherapy Of Cancer 2022, 10: e004749. PMID: 35728873, PMCID: PMC9214396, DOI: 10.1136/jitc-2022-004749.Peer-Reviewed Original ResearchMeSH KeywordsAscitesHumansImmune Checkpoint InhibitorsImmunotherapyNeoplasmsPeritoneumTumor MicroenvironmentConceptsImmune checkpoint inhibitionResistance to immune checkpoint inhibitionPeritoneal metastasisCheckpoint inhibitionMetastatic nicheResponse to ICIImmune checkpoint inhibition therapySensitive to immune checkpoint inhibitionIntrinsic tumor factorsPresence of ascitesDeficient mismatch repairPeritoneal microenvironmentTumor factorsMalignant ascitesPrimary resistanceClinical entityTherapeutic optionsMicrosatellite instable tumorsPeritoneal cavityGastrointestinal cancerParacrine factorsAscitesConcurrent ascitesPatientsInstable tumorsIntegration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis
Gwee Y, Chia D, So J, Ceelen W, Yong W, Tan P, Ong C, Sundar R. Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis. Journal Of Clinical Oncology 2022, 40: 2830. PMID: 35649219, PMCID: PMC9390822, DOI: 10.1200/jco.21.02745.Peer-Reviewed Original ResearchMeSH KeywordsGenomicsHumansNeoplasm StagingPeritoneal NeoplasmsPeritoneumStomach NeoplasmsTumor MicroenvironmentConceptsPeritoneal metastasisSystemic therapyClinical trialsGastric cancerTherapeutic strategiesEmergence of novel therapiesSynchronous peritoneal metastasesKnowledge of cancer biologyTraditional systemic therapiesCurrent standard-of-careSite of metastasisGastric cancer peritoneal metastasisAdvanced gastric cancerSurrounding tumor microenvironmentStandard-of-careInternational clinical guidelinesLocoregional therapeutic strategiesDiagnostic laparoscopyDismal prognosisTumor microenvironmentClinical entityNovel therapiesSurgical techniqueDisease stageMolecular profilingSingle-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric CancerSingle-Cell Atlas of Gastric Cancer Subtypes
Kumar V, Ramnarayanan K, Sundar R, Padmanabhan N, Srivastava S, Koiwa M, Yasuda T, Koh V, Huang K, Tay S, Ho S, Tan A, Ishimoto T, Kim G, Shabbir A, Chen Q, Zhang B, Xu S, Lam K, Lum H, Teh M, Yong W, So J, Tan P. Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric CancerSingle-Cell Atlas of Gastric Cancer Subtypes. Cancer Discovery 2022, 12: 670-691. PMID: 34642171, PMCID: PMC9394383, DOI: 10.1158/2159-8290.cd-21-0683.Peer-Reviewed Original ResearchMeSH KeywordsCancer-Associated FibroblastsEcosystemHumansSingle-Cell AnalysisStomach NeoplasmsTranscriptomeTumor MicroenvironmentConceptsPatient-derived organoidsPlasma cell proportionsGastric cancer subtypesLineage statePredictors of poor clinical prognosisCancer subtypesSingle-cell atlasCell proportionCancer-associated fibroblasts' subtypesCell populationsDiffuse-type tumorsPoor clinical prognosisIn vivo modelsComprehensive single-cell atlasPrimary tumorHistological subtypesRNA-sequencing cohortsTumor microenvironmentClinical stageClinical prognosisGastric malignancyTumor ecosystemGastric cancerCancer heterogeneityTumor
2021
Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition
Sundar R, Huang K, Kumar V, Ramnarayanan K, Demircioglu D, Her Z, Ong X, Bin Adam Isa Z, Xing M, Tan A, Tai D, Choo S, Zhai W, Lim J, Thakur M, Molinero L, Cha E, Fasso M, Niger M, Pietrantonio F, Lee J, Jeyasekharan A, Qamra A, Patnala R, Fabritius A, De Simone M, Yeong J, Ng C, Rha S, Narita Y, Muro K, Guo Y, Skanderup A, So J, Yong W, Chen Q, Göke J, Tan P. Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. Gut 2021, 71: 1277-1288. PMID: 34433583, PMCID: PMC9185816, DOI: 10.1136/gutjnl-2021-324420.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEpigenesis, GeneticEpigenomicsGastrointestinal NeoplasmsHumansImmune Checkpoint InhibitorsImmunotherapyMiceStomach NeoplasmsTumor MicroenvironmentConceptsImmune checkpoint inhibitionImmune microenvironmentHuman immune systemCheckpoint inhibitionActive human immune systemGastric cancerHuman T-cell infiltrationT cell cytolytic activityResistance to immune checkpoint inhibitionImmune systemProgression-free survivalImmunotherapy-treated patientsT cell infiltrationTumor immune microenvironmentT cell proportionsImmune-editingImmunotherapy resistanceFunctional in vivo studiesTumor kineticsHumanised miceAlternative promoter useTumor microenvironmentTherapeutic responseCytolytic activityImmune depletion
2017
Combining DNA damaging therapeutics with immunotherapy: more haste, less speed
Brown J, Sundar R, Lopez J. Combining DNA damaging therapeutics with immunotherapy: more haste, less speed. British Journal Of Cancer 2017, 118: 312-324. PMID: 29123260, PMCID: PMC5808021, DOI: 10.1038/bjc.2017.376.Peer-Reviewed Original ResearchConceptsImmunogenic cell deathDNA-damaging therapeuticsPromote immunogenic cell deathPhase I-III trialsDurable response rateDNA-damaging agentsAntitumour immune responseRegimens to patientsProperties of malignant cellsChoice of combinationsCell deathAntitumour immunitySequence of agentsNeoantigen productionTumor microenvironmentMalignant cellsNeoantigen repertoireInflammatory milieuPreclinical workImmune cellsCombination trialsDamaging agentsImmunological memoryMinimal toxicityHypothesis-driven trial