2024
Spatially resolved niche and tumor microenvironmental alterations in gastric cancer peritoneal metastases
Zhao J, Ong C, Srivastava S, Chia D, Ma H, Huang K, Sheng T, Ramnarayanan K, Ong X, Tay S, Hagihara T, Tan A, Teo M, Tan Q, Ng G, Tan J, Ng M, Gwee Y, Walsh R, Law J, Shabbir A, Kim G, Tay Y, Her Z, Leoncini G, Teh B, Hong J, Tay R, Teo C, Dings M, Bijlsma M, Lum J, Mathur S, Pietrantonio F, Blum S, van Laarhoven H, Klempner S, Yong W, So J, Chen Q, Tan P, Sundar R. Spatially resolved niche and tumor microenvironmental alterations in gastric cancer peritoneal metastases. Gastroenterology 2024 PMID: 39147169, DOI: 10.1053/j.gastro.2024.08.007.Peer-Reviewed Original ResearchPeritoneal metastasisTumor microenvironmentPrimary tumorTranscoelomic metastasisGastric cancerExpression of therapeutic targetsAssociated with poor prognosisGastric cancer peritoneal metastasisAssociated with increased riskHumanized mouse modelTherapeutic targetComprehensive multi-omics analysisTumor microenvironment signaturesTumor microenvironment alterationsDigital spatial profilingInvestigate molecular alterationsWhole-exome sequencingMatched normal tissuesStromal infiltrationComprehensive molecular characterizationLiver metastasesImmune compositionFGFR2b expressionImprove patient outcomesPredictive markerA phase Ib/II study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients (pts) with solid tumors harboring the 1q21.3 copy number amplification (CNA).
Lim J, Aau M, Yeong J, Goh B, Yong W, Soo R, Wong A, Tan D, Chee C, Sundar R, Jeyasekharan A, Wong C, Chen P, Liu H, Yu Q, Tam W, Lee S. A phase Ib/II study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients (pts) with solid tumors harboring the 1q21.3 copy number amplification (CNA). Journal Of Clinical Oncology 2024, 42: 43-43. DOI: 10.1200/jco.2024.42.23_suppl.43.Peer-Reviewed Original ResearchProgression-free survivalT cell populationsCD8+ T cell populationsCopy number amplificationInterleukin-1 receptor-associated kinase 1Solid tumorsTumor microenvironmentCell populationsDose levelsCD4+ T cell populationRecommended phase II dosePlasma cell-free DNAPeripheral blood mononuclear cells analysisSystemic immune modulationPhase II doseRefractory solid tumorsPhase Ib/II clinical trialDose-expansion cohortDendritic cell populationsMyeloid cell populationsTumor biopsy samplesImmune cell populationsDecreased tumor growthModulated immune cell populationsPreclinical animal modelsAbstract P28: 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. Abstract P28: Comprehensive Molecular Phenotyping of ARID1A -deficient Gastric Cancer Reveals Pervasive Epigenomic Reprogramming and Therapeutic Opportunities. Cancer Research 2024, 84: p28-p28. DOI: 10.1158/1538-7445.fcs2023-p28.Peer-Reviewed Original ResearchGastric cancerMolecular subtypesARID1A lossPro-inflammatory tumor microenvironmentTherapeutic opportunitiesARID1A inactivationTumor microenvironmental changesEpigenomic reprogrammingMutational signaturesPromoter activityGastric cell linesARID1A depletionTumor-intrinsicTumor inflammationTumor microenvironmentSingle-cell transcriptome profilingMutated driver genesTherapeutic vulnerabilitiesGC molecular subtypesNFkB inhibitorARID1ATherapeutic strategiesPharmacological inhibitionGC patientsSingapore cohortAbstract P37: Establishment of Gastric Organoids Biobank and Its Usage
Hagihara T, Huang K, Sundar R, Uchihara T, Ng C, Tay S, Tan A, So J, Tan P. Abstract P37: Establishment of Gastric Organoids Biobank and Its Usage. Cancer Research 2024, 84: p37-p37. DOI: 10.1158/1538-7445.fcs2023-p37.Peer-Reviewed Original Research
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 ResearchConceptsGastric 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
Integration 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 ResearchConceptsPeritoneal 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 ResearchConceptsPatient-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 heterogeneityTumorCiprofloxacin plus gemcitabine-based chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma: A pilot study of microbiome manipulation.
Cheo S, Lee J, Walsh R, Sundar R, Choo J, Chan G, Yong W, Meah W, Khor C, Chee C. Ciprofloxacin plus gemcitabine-based chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma: A pilot study of microbiome manipulation. Journal Of Clinical Oncology 2022, 40: 570-570. DOI: 10.1200/jco.2022.40.4_suppl.570.Peer-Reviewed Original ResearchMetastatic pancreatic ductal adenocarcinomaGemcitabine-based chemotherapyProgression free survivalPancreatic ductal adenocarcinomaResistance to chemotherapyProgressive diseaseOverall survivalDuctal adenocarcinomaTreated with nab-paclitaxelMedian progression free survivalPancreatic ductal adenocarcinoma tumor microenvironmentGrade 1/2 rashSafety of ciprofloxacinResistance to gemcitabinePost-treatment stool samplesMicrobiome changesNab-paclitaxelOral ciprofloxacinFebrile neutropeniaFree survivalMedian agePrimary endpointSecondary endpointsTumor microenvironmentGut microbiome changes
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 ResearchConceptsImmune 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