Characterizing ALCAM as an oncoprotein and immunotherapeutic target in neuroblastoma
Characterizing ALCAM as an oncoprotein and immunotherapeutic target in neuroblastoma
批准号:
10452634
负责人:
Jarrett Lindsay
金额:
$3.42万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-01 至 2023-07-31
关键词:
ALCAM geneAdultAntibodiesAntibody-drug conjugatesAntigensBindingBioinformaticsBiological AssayCRISPR interferenceCell AdhesionCell Adhesion MoleculesCell LineCell Surface ProteinsCell SurvivalCell surfaceChIP-seqChildChildhoodClinicalClinical TrialsColorectal CancerCredentialingDNA sequencingDataData SetDefectDevelopmentDiagnosisDiseaseDopamine-beta-monooxygenaseDown-RegulationEffectivenessFaceGanglioside GD2GenesGenetic TranscriptionGrowthImmunotherapeutic agentImmunotherapyIn VitroInterventionLesionMAP Kinase GeneMalignant Childhood NeoplasmMalignant NeoplasmsMalignant neoplasm of prostateMasksMediatingMetalloproteasesMigration AssayModelingMolecular BiologyMonoclonal AntibodiesMonoclonal Antibody TherapyMutationNeoplasm MetastasisNeural CrestNeuritesNeuroblastomaNeurosecretory SystemsNociceptorsOncogenicOncoproteinsOntologyOperative Surgical ProceduresPathway interactionsPatientsPeptide HydrolasesPeptidesPharmaceutical PreparationsPhase I/II Clinical TrialPhenotypePrimary NeoplasmProcessPrognostic MarkerProstatePublic HealthRadiationRefractoryRegulationRelapseResearchRetinal Ganglion CellsRoleSamplingScientistSolidSurvival RateSympathetic Nervous SystemTherapeuticTissuesToxic effectTranslational ResearchTumor AntigensTyrosine 3-MonooxygenaseUnresectableXenograft procedurebonecancer stem cellcell growthcell motilitychemotherapychromatin modificationdefined contributiondifferential expressiongenomic locushigh riskimprovedin vivoknock-downlung small cell carcinomamortality riskneuroblastoma cellneurotransmissionnoradrenergicnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpreclinical developmentprogenitorprotein expressionresearch clinical testingresistance mechanismskillssmall hairpin RNAstem cell biomarkerstargeted treatmenttherapeutic developmenttranscription factortranscriptome sequencingtumortumor growthtumorigenesis
中文摘要
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英文摘要
Project Summary
Neuroblastoma is a pediatric extracranial solid malignancy that arises from the developing sympathetic nervous
system. Patients with high risk neuroblastoma face five-year survival rates of only 50%, despite intensive
intervention with chemotherapy, surgery, radiation, and immunotherapy. Development of new therapies for
neuroblastoma has been challenging due to the paucity of targetable oncogenic mutations. However, recent
approval of monoclonal antibody therapy targeting GD2 has credentialed immunotherapy as a new avenue of
therapeutic development in neuroblastoma. Conversely anti-GD2 therapy causes significant on-target, off-tumor
toxicity due to the presence of GD2 on nociceptive neurons, and relapse due to loss of GD2 expression remains
common. To subvert antigen downregulation as a mechanism of resistance, our lab focuses on development of
immunotherapy targets that are both differentially expressed and necessary for tumor survival. We recently
identified the cell adhesion molecule ALCAM as a potential target for immunotherapy development. ALCAM is a
cellular adhesion molecule involved in retinal ganglion development, and high ALCAM expression is a negative
prognostic marker in a variety of cancers. Our RNA-sequencing data shows ALCAM is highly expressed in most
patient neuroblastomas. Furthermore, an ALCAM-targeted antibody-drug conjugate, CX-2009, is currently in
clinical trials for advanced metastatic or locally unresectable adult cancers. This project aims to discover the
mechanism of ALCAM overexpression in neuroblastoma, as well as define the contribution of ALCAM
overexpression to tumor growth and metastasis. Preliminary data suggests shRNA-mediated ALCAM
knockdown induces neurite formation in vitro, a phenotype associated with differentiation. Additionally, ChIP-
sequencing data from two neuroblastoma cell lines shows expression ALCAM may be regulated by a network of
transcription factors termed the core regulatory circuit (CRC). The CRC is a feed-forward transcriptional
regulatory circuit in which each transcription factor regulates the expression of itself and the others, together
defining a noradrenergic phenotype characterized by expression of proteins such as tyrosine hydroxylase and
dopamine beta hydroxylase. By integrating bioinformatics and molecular biology approaches, we will uncover
the mechanism of ALCAM overexpression in neuroblastoma. More broadly, this project will credential ALCAM
as a viable target of immunotherapy, as well as an oncoprotein necessary for tumor survival.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1158/1078-0432.ccr-20-4221
发表时间:
2021-05-15
期刊:
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子:
--
作者:
[Kendsersky NM, Lindsay J, Kolb EA, Smith MA, Teicher BA, Erickson SW, Earley EJ, Mosse YP, Martinez D, Pogoriler J, Krytska K, Patel K, Groff D, Tsang M, Ghilu S, Wang Y, Seaman S, Feng Y, Croix BS, Gorlick R, Kurmasheva R, Houghton PJ, Maris JM]
通讯作者:
Maris JM
海外基金