2023
FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner.
Pifer P, Yang L, Kumar M, Xie T, Frederick M, Hefner A, Beadle B, Molkentine D, Molkentine J, Dhawan A, Abdelhakiem M, Osman A, Leibowitz B, Myers J, Pickering C, Sandulache V, Heymach J, Skinner H. FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner. Clinical Cancer Research 2023, 30: 187-197. PMID: 37819945, PMCID: PMC10767302, DOI: 10.1158/1078-0432.ccr-23-0964.Peer-Reviewed Original ResearchConceptsHPV-negative headHPV-negative HNSCC tumorsWorse disease-free survivalNeck squamous cell carcinomaMutant TP53HPV-negative HNSCC cell linesBackbone of therapyDisease-free survivalPlatinum-based chemotherapySquamous cell carcinomaHPV-negative HNSCCHNSCC cell linesCell linesWild-type TP53Cisplatin-resistant cell linesCell carcinomaHNSCC cohortNeck cancerHNSCC tumorsVivo shRNA screenWorse outcomes
2021
Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
Kumar M, Molkentine D, Molkentine J, Bridges K, Xie T, Yang L, Hefner A, Gao M, Bahri R, Dhawan A, Frederick MJ, Seth S, Abdelhakiem M, Beadle BM, Johnson F, Wang J, Shen L, Heffernan T, Sheth A, Ferris RL, Myers JN, Pickering CR, Skinner HD. Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function. Nature Communications 2021, 12: 6340. PMID: 34732714, PMCID: PMC8566594, DOI: 10.1038/s41467-021-26570-8.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsApoptosisBiomarkers, TumorBRCA1 ProteinCell Line, TumorCREB-Binding ProteinE1A-Associated p300 ProteinGain of Function MutationHistone AcetyltransferasesHomologous RecombinationHumansMaleMice, NudeMutationNeoplasmsProtein DomainsSquamous Cell Carcinoma of Head and NeckXenograft Model Antitumor AssaysBiology of the Radio- and Chemo-Responsiveness in HPV Malignancies
Spiotto MT, Taniguchi CM, Klopp AH, Colbert LE, Lin SH, Wang L, Frederick MJ, Osman AA, Pickering CR, Frank SJ. Biology of the Radio- and Chemo-Responsiveness in HPV Malignancies. Seminars In Radiation Oncology 2021, 31: 274-285. PMID: 34455983, PMCID: PMC8689584, DOI: 10.1016/j.semradonc.2021.02.009.Peer-Reviewed Original ResearchConceptsHPV-positive cancersPotential biological mechanismsHPV-positive cancer cellsHPV-negative cancersCancer cellsImproved clinical outcomesCancer stem cell subpopulationMultiple anatomic sitesHPV-negative cellsG2/M arrestBiological mechanismsHPV MalignanciesLocoregional controlOverall survivalClinical outcomesPreclinical observationsAnatomic sitesHypoxic tumor microenvironmentStem cell subpopulationCancerTumor microenvironmentCell subpopulationsRadiosensitive phaseImpaired DNA damage responseOxidative stressLow doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu‐opioid receptor
Gorur A, Patiño M, Shi T, Corrales G, Takahashi H, Rangel R, Gleber‐Netto F, Pickering C, Myers JN, Cata JP. Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu‐opioid receptor. Journal Of Cellular Physiology 2021, 236: 7698-7710. PMID: 34038587, DOI: 10.1002/jcp.30421.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Line, TumorCell MovementCell ProliferationEpithelial-Mesenchymal TransitionHead and Neck NeoplasmsHumansMaleMice, Inbred C57BLMice, NudeNaltrexoneNarcotic AntagonistsNeoplasm InvasivenessQuaternary Ammonium CompoundsReceptors, Opioid, muSignal TransductionSquamous Cell Carcinoma of Head and NeckTumor BurdenXenograft Model Antitumor AssaysConceptsMu-opioid receptorsEffects of methylnaltrexoneHNSCC cell linesTumor growthCell linesNeck squamous cell carcinoma growthNeck squamous cell carcinomaDifferent HNSCC cell linesClonogenic activitySquamous cell carcinoma growthSquamous cell carcinomaLung cancer cell linesCyclic adenosine monophosphate levelsTumor-bearing miceAggressive cell behaviorEpithelial-mesenchymal transitionAdenosine monophosphate levelsCancer cell linesCell carcinomaMethylnaltrexoneCarcinoma growthTherapeutic targetLow dosesFaDu cellsMetastasis formationMu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma
Gorur A, Patiño M, Takahashi H, Corrales G, Pickering CR, Gleber-Netto FO, Myers JN, Cata JP. Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma. Life Sciences 2021, 278: 119541. PMID: 33930368, DOI: 10.1016/j.lfs.2021.119541.Peer-Reviewed Original ResearchConceptsMu-opioid receptorsMOR activationTumor growthSelective MOR agonist DAMGOMu-opioid receptor activationNeck squamous cell carcinomaSquamous cell carcinoma progressionNeck squamous cell carcinoma progressionMOR agonist DAMGOSquamous cell carcinomaTumorigenesis of HNSCCPotential therapeutic targetVivo tumor growthAgonist DAMGOCell carcinomaSaline 0.9MOR agonistsTherapeutic targetCarcinoma progressionReceptor activationHNSCCVivo studiesColony formationCell linesMe-PheTargeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis
Knitz MW, Bickett TE, Darragh LB, Oweida AJ, Bhatia S, Van Court B, Bhuvane S, Piper M, Gadwa J, Mueller AC, Nguyen D, Nangia V, Osborne DG, Bai X, Ferrara SE, Boss MK, Goodspeed A, Burchill MA, Tamburini BAJ, Chan ED, Pickering CR, Clambey ET, Karam SD. Targeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis. Journal For ImmunoTherapy Of Cancer 2021, 9: e001955. PMID: 33883256, PMCID: PMC8061827, DOI: 10.1136/jitc-2020-001955.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, ImmunologicalBasic-Leucine Zipper Transcription FactorsCell Line, TumorCombined Modality TherapyDendritic CellsDrug Resistance, NeoplasmHead and Neck NeoplasmsImmune Checkpoint InhibitorsImmunotherapyInterleukin-2 Receptor alpha SubunitLymphocyte DepletionMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutPhenotypeRadiation Dose HypofractionationRadiation ToleranceRepressor ProteinsSquamous Cell Carcinoma of Head and NeckT-Lymphocytes, RegulatoryTumor BurdenTumor MicroenvironmentTumor Necrosis Factor Receptor Superfamily, Member 9ConceptsCombination radiation therapyRadiation therapyDendritic cellsLymph nodesMouse modelRadioresistant tumorsRegulatory T-cell depletionT cell effector responsesTumor-draining lymph nodesNeck squamous cell carcinomaOral squamous cell carcinoma tumorsT cell-dependent responsesSquamous cell carcinoma tumorsAnti-CD137 treatmentDC activation statusGy x 5Higher Treg numbersPlasticity of TregsAdoptive transfer studiesT-cell depletionSquamous cell carcinomaCell-dependent responsesOrthotopic mouse modelTumor necrosis factorαNew therapeutic opportunities
2020
Caspase 8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic induced necroptosis
Uzunparmak B, Gao M, Lindemann A, Erikson K, Wang L, Lin E, Frank SJ, Gleber-Netto FO, Zhao M, Skinner HD, Newton JM, Sikora AG, Myers JN, Pickering CR. Caspase 8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic induced necroptosis. JCI Insight 2020, 5: e139837. PMID: 33108350, PMCID: PMC7714407, DOI: 10.1172/jci.insight.139837.Peer-Reviewed Original ResearchConceptsReceptor-interacting serine/threonine-protein kinase 3Caspase-8Serine/threonine-protein kinase 3Regulated cell death mechanismsPan-caspase inhibitor z-VADSecond mitochondria-derived activatorProtein kinase 3Cell death mechanismsRIP3 functionSmac mimeticsZ-VADKinase 3Death mechanismsMolecular underpinningsNecroptosis pathwayHNSCC cell linesNecroptosisRIP3 expressionCancer cellsCell linesBirinapantNeck squamous cell carcinomaCASP8 mutationsSquamous cell carcinomaSyngeneic mouse modelTargeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints
Molkentine JM, Molkentine DP, Bridges KA, Xie T, Yang L, Sheth A, Heffernan TP, Clump DA, Faust AZ, Ferris RL, Myers JN, Frederick MJ, Mason KA, Meyn RE, Pickering CR, Skinner HD. Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints. International Journal Of Radiation Biology 2020, 97: 1121-1128. PMID: 32073931, PMCID: PMC7483862, DOI: 10.1080/09553002.2020.1730014.Peer-Reviewed Original ResearchConceptsHPV statusHPV(-) cellsNeck cancerPARP inhibitionPCR arrayDNA repair genesSignificant radiosensitizationBeneficial treatment optionPARP inhibitor niraparibEffective treatment strategiesHNSCC cell linesNormal tissue toxicityRepair genesShRNA screenRole of p16HPV- tumorsHNSCC xenograftsTreatment optionsTreatment modalitiesTreatment strategiesTherapeutic ratioLimited progressionHPVP16 expressionNiraparib
2019
PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition
Sambandam V, Frederick MJ, Shen L, Tong P, Rao X, Peng S, Singh R, Mazumdar T, Huang C, Li Q, Pickering CR, Myers JN, Wang J, Johnson FM. PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition. Clinical Cancer Research 2019, 25: 3329-3340. PMID: 30770351, PMCID: PMC6548600, DOI: 10.1158/1078-0432.ccr-18-3276.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell Line, TumorCell ProliferationCRISPR-Cas SystemsDisease Models, AnimalDose-Response Relationship, DrugGene EditingGene ExpressionGene Knockdown TechniquesHumansLoss of Function MutationMicePhosphatidylinositol 3-KinasesProtein Kinase InhibitorsPyruvate Dehydrogenase Acetyl-Transferring KinaseReceptor, Notch1Signal TransductionSquamous Cell Carcinoma of Head and NeckTOR Serine-Threonine KinasesConceptsPI3K/mTOR inhibitorPI3K/mTOR inhibitionPI3K/mTOR pathway inhibitorsMTOR pathway inhibitorsHNSCC cell linesMTOR inhibitorsMTOR inhibitionCell linesPathway inhibitorNeck squamous cell carcinomaDrug-sensitive cell linesClinical response ratePI3K/mTOR pathwaySquamous cell carcinomaBiomarkers of responseOrthotopic xenograft modelCell carcinomaTumor sizeXenograft modelHNSCCSingle agentPDK1 overexpressionResponse rateMolecular vulnerabilitiesPharmacogenomic approach
2018
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
Campbell JD, Yau C, Bowlby R, Liu Y, Brennan K, Fan H, Taylor AM, Wang C, Walter V, Akbani R, Byers LA, Creighton CJ, Coarfa C, Shih J, Cherniack AD, Gevaert O, Prunello M, Shen H, Anur P, Chen J, Cheng H, Hayes DN, Bullman S, Pedamallu CS, Ojesina AI, Sadeghi S, Mungall KL, Robertson AG, Benz C, Schultz A, Kanchi RS, Gay CM, Hegde A, Diao L, Wang J, Ma W, Sumazin P, Chiu HS, Chen TW, Gunaratne P, Donehower L, Rader JS, Zuna R, Al-Ahmadie H, Lazar AJ, Flores ER, Tsai KY, Zhou JH, Rustgi AK, Drill E, Shen R, Wong CK, Network T, Caesar-Johnson S, Demchok J, Felau I, Kasapi M, Ferguson M, Hutter C, Sofia H, Tarnuzzer R, Wang Z, Yang L, Zenklusen J, Zhang J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Cho J, DeFreitas T, Frazer S, Gehlenborg N, Getz G, Heiman D, Kim J, Lawrence M, Lin P, Meier S, Noble M, Saksena G, Voet D, Zhang H, Bernard B, Chambwe N, Dhankani V, Knijnenburg T, Kramer R, Leinonen K, Liu Y, Miller M, Reynolds S, Shmulevich I, Thorsson V, Zhang W, Akbani R, Broom B, Hegde A, Ju Z, Kanchi R, Korkut A, Li J, Liang H, Ling S, Liu W, Lu Y, Mills G, Ng K, Rao A, Ryan M, Wang J, Weinstein J, Zhang J, Abeshouse A, Armenia J, Chakravarty D, Chatila W, de Bruijn I, Gao J, Gross B, Heins Z, Kundra R, La K, Ladanyi M, Luna A, Nissan M, Ochoa A, Phillips S, Reznik E, Sanchez-Vega F, Sander C, Schultz N, Sheridan R, Sumer S, Sun Y, Taylor B, Wang J, Zhang H, Anur P, Peto M, Spellman P, Benz C, Stuart J, Wong C, Yau C, Hayes D, Parker J, Wilkerson M, Ally A, Balasundaram M, Bowlby R, Brooks D, Carlsen R, Chuah E, Dhalla N, Holt R, Jones S, Kasaian K, Lee D, Ma Y, Marra M, Mayo M, Moore R, Mungall A, Mungall K, Robertson A, Sadeghi S, Schein J, Sipahimalani P, Tam A, Thiessen N, Tse K, Wong T, Berger A, Beroukhim R, Cherniack A, Cibulskis C, Gabriel S, Gao G, Ha G, Meyerson M, Schumacher S, Shih J, Kucherlapati M, Kucherlapati R, Baylin S, Cope L, Danilova L, Bootwalla M, Lai P, Maglinte D, Van Den Berg D, Weisenberger D, Auman J, Balu S, Bodenheimer T, Fan C, Hoadley K, Hoyle A, Jefferys S, Jones C, Meng S, Mieczkowski P, Mose L, Perou A, Perou C, Roach J, Shi Y, Simons J, Skelly T, Soloway M, Tan D, Veluvolu U, Fan H, Hinoue T, Laird P, Shen H, Zhou W, Bellair M, Chang K, Covington K, Creighton C, Dinh H, Doddapaneni H, Donehower L, Drummond J, Gibbs R, Glenn R, Hale W, Han Y, Hu J, Korchina V, Lee S, Lewis L, Li W, Liu X, Morgan M, Morton D, Muzny D, Santibanez J, Sheth M, Shinbrot E, Wang L, Wang M, Wheeler D, Xi L, Zhao F, Hess J, Appelbaum E, Bailey M, Cordes M, Ding L, Fronick C, Fulton L, Fulton R, Kandoth C, Mardis E, McLellan M, Miller C, Schmidt H, Wilson R, Crain D, Curley E, Gardner J, Lau K, Mallery D, Morris S, Paulauskis J, Penny R, Shelton C, Shelton T, Sherman M, Thompson E, Yena P, Bowen J, Gastier-Foster J, Gerken M, Leraas K, Lichtenberg T, Ramirez N, Wise L, Zmuda E, Corcoran N, Costello T, Hovens C, Carvalho A, de Carvalho A, Fregnani J, Longatto-Filho A, Reis R, Scapulatempo-Neto C, Silveira H, Vidal D, Burnette A, Eschbacher J, Hermes B, Noss A, Singh R, Anderson M, Castro P, Ittmann M, Huntsman D, Kohl B, Le X, Thorp R, Andry C, Duffy E, Lyadov V, Paklina O, Setdikova G, Shabunin A, Tavobilov M, McPherson C, Warnick R, Berkowitz R, Cramer D, Feltmate C, Horowitz N, Kibel A, Muto M, Raut C, Malykh A, Barnholtz-Sloan J, Barrett W, Devine K, Fulop J, Ostrom Q, Shimmel K, Wolinsky Y, Sloan A, De Rose A, Giuliante F, Goodman M, Karlan B, Hagedorn C, Eckman J, Harr J, Myers J, Tucker K, Zach L, Deyarmin B, Hu H, Kvecher L, Larson C, Mural R, Somiari S, Vicha A, Zelinka T, Bennett J, Iacocca M, Rabeno B, Swanson P, Latour M, Lacombe L, Têtu B, Bergeron A, McGraw M, Staugaitis S, Chabot J, Hibshoosh H, Sepulveda A, Su T, Wang T, Potapova O, Voronina O, Desjardins L, Mariani O, Roman-Roman S, Sastre X, Stern M, Cheng F, Signoretti S, Berchuck A, Bigner D, Lipp E, Marks J, McCall S, McLendon R, Secord A, Sharp A, Behera M, Brat D, Chen A, Delman K, Force S, Khuri F, Magliocca K, Maithel S, Olson J, Owonikoko T, Pickens A, Ramalingam S, Shin D, Sica G, Van Meir E, Zhang H, Eijckenboom W, Gillis A, Korpershoek E, Looijenga L, Oosterhuis W, Stoop H, van Kessel K, Zwarthoff E, Calatozzolo C, Cuppini L, Cuzzubbo S, DiMeco F, Finocchiaro G, Mattei L, Perin A, Pollo B, Chen C, Houck J, Lohavanichbutr P, Hartmann A, Stoehr C, Stoehr R, Taubert H, Wach S, Wullich B, Kycler W, Murawa D, Wiznerowicz M, Chung K, Edenfield W, Martin J, Baudin E, Bubley G, Bueno R, De Rienzo A, Richards W, Kalkanis S, Mikkelsen T, Noushmehr H, Scarpace L, Girard N, Aymerich M, Campo E, Giné E, Guillermo A, Van Bang N, Hanh P, Phu B, Tang Y, Colman H, Evason K, Dottino P, Martignetti J, Gabra H, Juhl H, Akeredolu T, Stepa S, Hoon D, Ahn K, Kang K, Beuschlein F, Breggia A, Birrer M, Bell D, Borad M, Bryce A, Castle E, Chandan V, Cheville J, Copland J, Farnell M, Flotte T, Giama N, Ho T, Kendrick M, Kocher J, Kopp K, Moser C, Nagorney D, O’Brien D, O’Neill B, Patel T, Petersen G, Que F, Rivera M, Roberts L, Smallridge R, Smyrk T, Stanton M, Thompson R, Torbenson M, Yang J, Zhang L, Brimo F, Ajani J, Gonzalez A, Behrens C, Bondaruk J, Broaddus R, Czerniak B, Esmaeli B, Fujimoto J, Gershenwald J, Guo C, Lazar A, Logothetis C, Meric-Bernstam F, Moran C, Ramondetta L, Rice D, Sood A, Tamboli P, Thompson T, Troncoso P, Tsao A, Wistuba I, Carter C, Haydu L, Hersey P, Jakrot V, Kakavand H, Kefford R, Lee K, Long G, Mann G, Quinn M, Saw R, Scolyer R, Shannon K, Spillane A, Stretch O, Synott M, Thompson J, Wilmott J, Al-Ahmadie H, Chan T, Ghossein R, Gopalan A, Levine D, Reuter V, Singer S, Singh B, Tien N, Broudy T, Mirsaidi C, Nair P, Drwiega P, Miller J, Smith J, Zaren H, Park J, Hung N, Kebebew E, Linehan W, Metwalli A, Pacak K, Pinto P, Schiffman M, Schmidt L, Vocke C, Wentzensen N, Worrell R, Yang H, Moncrieff M, Goparaju C, Melamed J, Pass H, Botnariuc N, Caraman I, Cernat M, Chemencedji I, Clipca A, Doruc S, Gorincioi G, Mura S, Pirtac M, Stancul I, Tcaciuc D, Albert M, Alexopoulou I, Arnaout A, Bartlett J, Engel J, Gilbert S, Parfitt J, Sekhon H, Thomas G, Rassl D, Rintoul R, Bifulco C, Tamakawa R, Urba W, Hayward N, Timmers H, Antenucci A, Facciolo F, Grazi G, Marino M, Merola R, de Krijger R, Gimenez-Roqueplo A, Piché A, Chevalier S, McKercher G, Birsoy K, Barnett G, Brewer C, Farver C, Naska T, Pennell N, Raymond D, Schilero C, Smolenski K, Williams F, Morrison C, Borgia J, Liptay M, Pool M, Seder C, Junker K, Omberg L, Dinkin M, Manikhas G, Alvaro D, Bragazzi M, Cardinale V, Carpino G, Gaudio E, Chesla D, Cottingham S, Dubina M, Moiseenko F, Dhanasekaran R, Becker K, Janssen K, Slotta-Huspenina J, Abdel-Rahman M, Aziz D, Bell S, Cebulla C, Davis A, Duell R, Elder J, Hilty J, Kumar B, Lang J, Lehman N, Mandt R, Nguyen P, Pilarski R, Rai K, Schoenfield L, Senecal K, Wakely P, Hansen P, Lechan R, Powers J, Tischler A, Grizzle W, Sexton K, Kastl A, Henderson J, Porten S, Waldmann J, Fassnacht M, L. S, Schadendorf D, Couce M, Graefen M, Huland H, Sauter G, Schlomm T, Simon R, Tennstedt P, Olabode O, Nelson M, Bathe O, Carroll P, Chan J, Disaia P, Glenn P, Kelley R, Landen C, Phillips J, Prados M, Simko J, Smith-McCune K, VandenBerg S, Roggin K, Fehrenbach A, Kendler A, Sifri S, Steele R, Jimeno A, Carey F, Forgie I, Mannelli M, Carney M, Hernandez B, Campos B, Herold-Mende C, Jungk C, Unterberg A, von Deimling A, Bossler A, Galbraith J, Jacobus L, Knudson M, Knutson T, Ma D, Milhem M, Sigmund R, Godwin A, Madan R, Rosenthal H, Adebamowo C, Adebamowo S, Boussioutas A, Beer D, Giordano T, Mes-Masson A, Saad F, Bocklage T, Landrum L, Mannel R, Moore K, Moxley K, Postier R, Walker J, Zuna R, Feldman M, Valdivieso F, Dhir R, Luketich J, Pinero E, Quintero-Aguilo M, Carlotti C, Dos Santos J, Kemp R, Sankarankuty A, Tirapelli D, Catto J, Agnew K, Swisher E, Creaney J, Robinson B, Shelley C, Godwin E, Kendall S, Shipman C, Bradford C, Carey T, Haddad A, Moyer J, Peterson L, Prince M, Rozek L, Wolf G, Bowman R, Fong K, Yang I, Korst R, Rathmell W, Fantacone-Campbell J, Hooke J, Kovatich A, Shriver C, DiPersio J, Drake B, Govindan R, Heath S, Ley T, Van Tine B, Westervelt P, Rubin M, Lee J, Aredes N, Mariamidze A, Stuart J, Laird P, Hoadley K, Weinstein J, Peto M, Pickering C, Chen Z, Van Waes C. Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. Cell Reports 2018, 23: 194-212.e6. PMID: 29617660, PMCID: PMC6002769, DOI: 10.1016/j.celrep.2018.03.063.Peer-Reviewed Original ResearchConceptsChromosomal copy number alterationsSquamous cell carcinomaRAS-MAPK pathwayChromatin modifiersGenomic integrityCopy number alterationsAlternative promotersHuman papillomavirusDNA mutationsPathway networkAberrant methylationCell stemnessHarbor mutationsOxidative damageAtlas studyMesenchymal differentiationCell signatureMutationsMolecular featuresImmune checkpointsImmune therapySquamous carcinomaCell carcinomaImmunoregulatory moleculesTherapeutic approaches
2017
Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation
Tanaka N, Patel AA, Tang L, Silver NL, Lindemann A, Takahashi H, Jaksik R, Rao X, Kalu NN, Chen TC, Wang J, Frederick MJ, Johnson F, Gleber-Netto FO, Fu S, Kimmel M, Wang J, Hittelman WN, Pickering CR, Myers JN, Osman AA. Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation. Clinical Cancer Research 2017, 23: 6541-6554. PMID: 28790110, PMCID: PMC5724758, DOI: 10.1158/1078-0432.ccr-17-0947.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCarcinoma, Squamous CellCell Cycle ProteinsCell Line, TumorCell ProliferationDNA DamageDNA ReplicationDrug SynergismFemaleHead and Neck NeoplasmsHistone Deacetylase InhibitorsHumansHydroxamic AcidsMiceMutationNuclear ProteinsPhosphorylationProtein-Tyrosine KinasesPyrazolesPyrimidinesPyrimidinonesRisk FactorsS PhaseSquamous Cell Carcinoma of Head and NeckTumor Suppressor Protein p53VorinostatConceptsOrthotopic mouse modelHNSCC cellsOral cancerMouse modelNeck squamous cell carcinomaSquamous cell carcinomaCombination of vorinostatProlongs animal survivalHNSCC cell linesClin Cancer ResClonogenic survival assaysAdvanced HNSCCAdvanced headStandard therapyCell carcinomaCure rateEffective therapyClinical investigationCell cycleP53 mutationsTumor growthVorinostatAnimal survivalAZD1775Cancer ResIntegrative Analysis Identifies a Novel AXL–PI3 Kinase–PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer
Skinner HD, Giri U, Yang LP, Kumar M, Liu Y, Story MD, Pickering CR, Byers LA, Williams MD, Wang J, Shen L, Yoo SY, Fan YH, Molkentine DP, Beadle BM, Meyn RE, Myers JN, Heymach JV. Integrative Analysis Identifies a Novel AXL–PI3 Kinase–PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer. Clinical Cancer Research 2017, 23: 2713-2722. PMID: 28476872, PMCID: PMC5457365, DOI: 10.1158/1078-0432.ccr-16-2586.Peer-Reviewed Original ResearchMeSH KeywordsAgedAxl Receptor Tyrosine KinaseB7-H1 AntigenBiomarkers, TumorCarcinoma, Squamous CellCell Line, TumorFemaleGene Expression Regulation, NeoplasticHead and Neck NeoplasmsHumansLymphocytes, Tumor-InfiltratingMaleMiddle AgedPapillomaviridaePhosphatidylinositol 3-KinasesProteomicsProto-Oncogene ProteinsRadiation ToleranceReceptor Protein-Tyrosine KinasesRNA, MessengerSignal TransductionConceptsPD-L1HPV-negative HNSCC tumorsNeck squamous cell carcinomaCell linesHPV-negative HNSCC cell linesLocal failureLocal treatment failurePD-L1 axisPD-L1 expressionTumor-infiltrating lymphocytesSquamous cell carcinomaHuman papilloma virusLow expression groupActivation of AxlHNSCC cell linesClin Cancer ResNegative cell linesTreatment failureCell carcinomaPapilloma virusHNSCC tumorsExpression groupMultivariate analysisMRNA expression analysisPI3-kinaseMutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors
Zhang M, Singh R, Peng S, Mazumdar T, Sambandam V, Shen L, Tong P, Li L, Kalu NN, Pickering CR, Frederick M, Myers JN, Wang J, Johnson FM. Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors. Cancer Letters 2017, 392: 71-82. PMID: 28126323, PMCID: PMC5404895, DOI: 10.1016/j.canlet.2017.01.024.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsApoptosisCarcinoma, Squamous CellCell Cycle ProteinsCell Line, TumorCell ProliferationCheckpoint Kinase 1Checkpoint Kinase 2Dose-Response Relationship, DrugG2 Phase Cell Cycle CheckpointsGenotypeHead and Neck NeoplasmsHumansLIM Domain ProteinsMice, NudeMolecular Targeted TherapyMutationNuclear ProteinsPhenotypeProtein Kinase InhibitorsProtein Serine-Threonine KinasesProtein-Tyrosine KinasesProto-Oncogene ProteinsPteridinesPyrazolesPyrimidinesPyrimidinonesRas ProteinsRNA InterferenceSignal TransductionSmad4 ProteinSquamous Cell Carcinoma of Head and NeckThiophenesTime FactorsTransfectionTumor BurdenUreaXenograft Model Antitumor AssaysConceptsPolo-like kinase 1Cell linesLIM protein AjubaHNSCC cell linesInhibitor-induced apoptosisProtein expressionCell cycle inhibitorsCell cycle arrestKnockdown of PLK1Neck squamous cell carcinomaAjubaExogenous expressionNeck squamous cell carcinoma (HNSCC) tumorsSquamous cell carcinoma tumorsKinase 1HNSCC mouse modelSquamous cell carcinomaSubstrate inhibitionHigher drug dosesPotential candidate biomarkersGenomic alterationsMitotic inhibitorsPLK1 inhibitionSensitive cell linesMutations
2016
Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer
Skinner HD, Giri U, Yang L, Woo SH, Story MD, Pickering CR, Byers LA, Williams MD, El-Naggar A, Wang J, Diao L, Shen L, Fan YH, Molkentine DP, Beadle BM, Meyn RE, Myers JN, Heymach JV. Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer. Clinical Cancer Research 2016, 22: 4643-4650. PMID: 27036135, PMCID: PMC5061056, DOI: 10.1158/1078-0432.ccr-15-2785.Peer-Reviewed Original ResearchConceptsHPV-negative HNSCC cell linesHPV-negative HNSCCHNSCC cell linesTargetable biomarkersHuman papillomavirusIndependent cohortCandidate biomarkersPoor disease-free survivalNeck squamous cell carcinomaBiomarker of radioresistanceDisease-free survivalSquamous cell carcinomaDisease-related mortalityMerit further evaluationCell linesFAK inhibitionG2-M arrestFocal adhesion kinaseAdvanced HNSCCWorse DFSCancer Genome AtlasCell carcinomaPharmacologic blockadeCancer subgroupsFAK overexpressionHuman epidermal growth factor receptor 2/neu as a novel therapeutic target in sinonasal undifferentiated carcinoma
Takahashi Y, Lee J, Pickering C, Bell D, Jiffar TW, Myers JN, Hanna EY, Kupferman ME. Human epidermal growth factor receptor 2/neu as a novel therapeutic target in sinonasal undifferentiated carcinoma. Head & Neck 2016, 38: e1926-e1934. PMID: 26752332, PMCID: PMC6453572, DOI: 10.1002/hed.24350.Peer-Reviewed Original ResearchConceptsHuman epidermal growth factor receptor 2Sinonasal undifferentiated carcinomaEpidermal growth factor receptor 2Growth factor receptor 2Potential therapeutic targetFactor receptor 2Cell linesGrowth inhibitionProtein expression levelsCell growth inhibitionMethylthiazol tetrazoliumMultimodal therapyHER2 inhibitionUndifferentiated carcinomaNovel therapiesAggressive cancerNew therapiesReceptor 2Therapeutic targetFlank modelClonogenic assayWestern blottingWhole-genome single nucleotide polymorphism (SNP) analysisTherapyERBB2 gene
2015
Down‐regulation of malic enzyme 1 and 2: Sensitizing head and neck squamous cell carcinoma cells to therapy‐induced senescence
Woo SH, Yang LP, Chuang HC, Fitzgerald A, Lee HY, Pickering C, Myers JN, Skinner HD. Down‐regulation of malic enzyme 1 and 2: Sensitizing head and neck squamous cell carcinoma cells to therapy‐induced senescence. Head & Neck 2015, 38: e934-e940. PMID: 25994759, DOI: 10.1002/hed.24129.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Squamous CellCell Line, TumorCellular SenescenceCyclin-Dependent Kinase Inhibitor p21Down-RegulationGene Expression Regulation, NeoplasticGene Knockdown TechniquesHead and Neck NeoplasmsHumansMalate DehydrogenaseMetforminRadiation, IonizingReactive Oxygen SpeciesTumor Suppressor Protein p53ConceptsTherapy-induced senescenceOverall survivalReactive oxygen speciesNeck squamous cell carcinomaSquamous cell carcinomaPoor overall survivalPotential therapeutic benefitHNSCC cell linesAntioxidant N-acetyl cysteineN-acetyl cysteinePoor outcomeCell carcinomaPatient outcomesHNSCC cellsGeneration of ROSTherapeutic benefitME2 expressionInduction of senescenceHNSCCP53 statusHigh expressionEnzyme expressionCell linesOxygen speciesOutcomesEvolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer
Neskey DM, Osman AA, Ow TJ, Katsonis P, McDonald T, Hicks SC, Hsu TK, Pickering CR, Ward A, Patel A, Yordy JS, Skinner HD, Giri U, Sano D, Story MD, Beadle BM, El-Naggar AK, Kies MS, William WN, Caulin C, Frederick M, Kimmel M, Myers JN, Lichtarge O. Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer. Cancer Research 2015, 75: 1527-1536. PMID: 25634208, PMCID: PMC4383697, DOI: 10.1158/0008-5472.can-14-2735.Peer-Reviewed Original ResearchConceptsTP53 mutationsDistant metastasisP53 mutationsNeck squamous cell carcinomaSquamous cell carcinomaPoor survival outcomesAggressive tumor behaviorEvolutionary action scoreHigh-risk mutationsLung metastasesPrognostic significanceSurvival outcomesCell carcinomaNeck cancerClinical prognosisHigh incidenceLower riskTumor behaviorDecreased survivalKey cellular pathwaysTumor cellsMetastasisRisk mutationsPatientsTumorsEvolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients
Osman AA, Neskey DM, Katsonis P, Patel AA, Ward AM, Hsu TK, Hicks SC, McDonald TO, Ow TJ, Alves MO, Pickering CR, Skinner HD, Zhao M, Sturgis EM, Kies MS, El-Naggar A, Perrone F, Licitra L, Bossi P, Kimmel M, Frederick MJ, Lichtarge O, Myers JN. Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients. Cancer Research 2015, 75: 1205-1215. PMID: 25691460, PMCID: PMC4615655, DOI: 10.1158/0008-5472.can-14-2729.Peer-Reviewed Original ResearchConceptsNeck cancer patientsEvolutionary action scoreCancer patientsTP53 mutationsNeck squamous cell carcinomaSquamous cell carcinomaCisplatin-based therapyPlatinum-based therapySubset of headThird of casesNovel scoring systemSurvival benefitProspective evaluationCell carcinomaPlatinum responsePreclinical modelsTreatment selectionAction scoresScoring systemPatientsHNSCCTherapyCoding variantPredictive responseScores
2014
Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer
Guerrero-Preston R, Michailidi C, Marchionni L, Pickering CR, Frederick MJ, Myers JN, Yegnasubramanian S, Hadar T, Noordhuis MG, Zizkova V, Fertig E, Agrawal N, Westra W, Koch W, Califano J, Velculescu VE, Sidransky D. Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer. Epigenetics 2014, 9: 1031-1046. PMID: 24786473, PMCID: PMC4143405, DOI: 10.4161/epi.29025.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Squamous CellCell Line, TumorCohort StudiesCpG IslandsDNA MethylationFemaleGene SilencingGenes, Tumor SuppressorHead and Neck NeoplasmsHumansMaleMutationPaired Box Transcription FactorsPAX5 Transcription FactorPromoter Regions, GeneticReceptor, Notch1Tumor Suppressor Protein p53ConceptsKey tumor suppressor genesTumor suppressor geneSuppressor geneRecent high-throughput genomic studiesSomatic mutationsPromoter methylationWhole genome gene expression arraysHigh-throughput genomic studiesPax gene familyNovel tumor suppressor geneIntegrated molecular analysisSpecific promoter methylationK methylation arrayGene expression arraysGenome maintenanceEpigenomic levelsGene familyCell fateGenomic studiesDownregulated genesTranscription factorsCanonical NotchEpigenomic alterationsDomain sequencingMethylation arraysHRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells
Hah JH, Zhao M, Pickering CR, Frederick MJ, Andrews GA, Jasser SA, Fooshee DR, Milas ZL, Galer C, Sano D, William WN, Kim E, Heymach J, Byers LA, Papadimitrakopoulou V, Myers JN. HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells. Head & Neck 2014, 36: 1547-1554. PMID: 24123531, PMCID: PMC4010580, DOI: 10.1002/hed.23499.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCarcinoma, Squamous CellCell Line, TumorCell ProliferationDown-RegulationDrug Resistance, NeoplasmErlotinib HydrochlorideHead and Neck NeoplasmsHumansMiceMolecular Targeted TherapyMutationProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)QuinazolinesSensitivity and SpecificitySignal TransductionSquamous Cell Carcinoma of Head and NeckTransfectionConceptsShort hairpin RNACell linesHRAS expressionErlotinib sensitivityErlotinib-sensitive cell linesErlotinib-resistant cell linesErlotinib resistanceHRAS mutationsNeck squamous cell carcinoma cellsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinibNeck squamous cell carcinoma cell linesSquamous cell carcinoma cellsTyrosine kinase inhibitor erlotinibPanel of headReceptor tyrosine kinase inhibitorsHairpin RNAHNSCC cell linesSquamous cell carcinoma cell linesCell carcinoma cell linesCarcinoma cell linesKinase inhibitor erlotinibTyrosine kinase inhibitorsMutations