Ink4a/ARF/Ink4b locus in Neurofibromatosis Type 1
1 型神经纤维瘤病中的 Ink4a/ARF/Ink4b 位点
基本信息
- 批准号:10577840
- 负责人:
- 金额:$ 54.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AgeAgreementAnimal ModelAntineoplastic AgentsAutomobile DrivingBenignBiologicalBiological AssayBiologyCDK4 geneCDKN2A geneCause of DeathCell modelCellsClassificationClinicalClustered Regularly Interspaced Short Palindromic RepeatsDevelopmentDiagnosticDiseaseDrug TargetingDrug resistanceEarly DiagnosisEventFrequenciesFutureGenesGeneticHistologicHumanHyperactivityIn VitroLearningLesionLinkLiteratureMEKsMalignant - descriptorMalignant NeoplasmsMediatorModelingMolecularMusNF1 geneNeoplasmsNeurofibromatosis 1NeurofibrosarcomaOncogenicPathogenesisPathway interactionsPatientsPeptidesPharmaceutical PreparationsPhysiologicalPlasmaPlexiform NeurofibromaPreventionProteomicsRAS driven tumorReportingResistanceRoleSamplingSpecimenTestingTherapeutic InterventionTumor BiologyTumor MarkersTumor Suppressor ProteinsUp-RegulationWorkcell transformationchemotherapyclinically significantdrug-sensitivegenetic analysisgenomic locushuman modelimprovedin vivoin vivo Modelindividualized medicineinhibitorinhibitor therapyinnovationinsightliquid biopsymouse modelneurofibromanew combination therapiesoverexpressionpharmacologicpre-clinicalpreclinical studypreemptive interventionpremalignantpreventprognostic assaysprognostic valuereconstitutiontargeted treatmenttherapy resistanttranscriptome sequencingtumortumor DNAtumor progression
项目摘要
Summary/Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with
neurofibromatosis-1 (NF1). MPNSTs arise in NF1 patients from benign plexiform neurofibromas (PNFs) but it is
unclear why only ~30% of PNFs transform into MPNSTs. Recent studies suggest that inactivation of the
INK4a/ARF/INK4b locus (called CDKN2A for INK4a and ARF; CDKN2B for INK4b) generates a pre-malignant
lesion called an atypical neurofibromatous neoplasm of uncertain biology (ANNUBP). ANNUBPs are the newly
recognized precursor to MPNSTs, but mechanisms that drive and classify this transitional intermediate are poorly
defined. INK4a/ARF/INK4b disruption is the main alteration currently linked to ANNUBPs, besides NF1 loss and
RABL6A upregulation. In MPNSTs, the locus is altered at one, two or all three genes, with worse patient survival
associated with loss of all three. Each gene (INK4a, ARF, and INK4b) encodes a tumor suppressor, but their
separate contributions and cooperativity with other factors in driving cancer remain incompletely understood.
Given their prominent role, a better understanding of INK4a, ARF, and INK4b in MPNST development is needed,
as drugs targeting the locus are either approved or showing promise in other cancers.
Our central hypothesis is p16Ink4a, ARF and p15Ink4b act cooperatively in multiple pathways to
suppress the transformation of benign PNFs and ANNUBPs to MPNSTs. Aim 1 will define significant genetic
and proteomic events coinciding with INK4a, ARF and INK4b inactivation in human ANNUBPs and MPNSTs by
genetic, molecular and histologic analyses. Results will be correlated to clinical variables such as survival. The
prognostic value of a newly developed liquid biopsy assay evaluating locus status and other tumor markers will
be determined in NF1 patients. Aim 2 employs CRISPR editing of p16Ink4a, ARF and/or p15Ink4b in human
PNF-derived cells to determine their roles in PNF-ANNUBP-MPNST transformation. Directed analyses of
suspected MPNST driver genes in cells and mouse models will identify genes that selectively cooperate with
INK4a, ARF, or INK4b loss to drive ANNUBP-MPNST transformation in vitro and in vivo. Aim 3 establishes the
biological significance of drugs targeting Ink4a/Arf/Ink4b relevant pathways in PNF-ANNUBP-MPNST therapy
and prevention. Predicted mediators of acquired resistance to therapy will be verified using molecular and
pharmacologic approaches. Studies will determine the value of targeted therapy against pre-MPNST models to
prevent malignant progression. Impact: Studies will provide new insights into INK4a/ARF/INK4b, one of the most
frequently inactivated loci in human cancers. Innovative animal models of PNF-ANNUBP-MPNST progression
will be generated and mechanisms of transformation leading to MPNST will be defined. Preclinical studies will
assess a new combination therapy targeting Ink4a/Arf/Ink4b pathways in preventing malignant progression.
Results will advance our understanding of events driving MPNST development, facilitating earlier diagnosis and
pre-emptive interventions targeting ANNUBPs.
摘要/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Benjamin Will Darbro其他文献
Benjamin Will Darbro的其他文献
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{{ truncateString('Benjamin Will Darbro', 18)}}的其他基金
Ink4a/ARF/Ink4b locus in Neurofibromatosis Type 1
1 型神经纤维瘤病中的 Ink4a/ARF/Ink4b 位点
- 批准号:
10453098 - 财政年份:2022
- 资助金额:
$ 54.49万 - 项目类别:
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