ABL kinases promote lung cancer brain metastasis through regulation of transcriptional networks
ABL激酶通过调控转录网络促进肺癌脑转移
基本信息
- 批准号:10064468
- 负责人:
- 金额:$ 3.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:ABL1 geneABL2 geneAccountingBinding SitesBiological MarkersBlood - brain barrier anatomyBrainCancer EtiologyCancer PatientCancer cell lineCell HypoxiaCellsCessation of lifeChromatinClinicalCranial IrradiationDataDiagnosisDrug resistanceEpidermal Growth Factor ReceptorExhibitsFamilyGenesGeneticGenetic TranscriptionHigh PrevalenceHypoxiaHypoxia Inducible FactorImpaired cognitionImpairmentLaboratoriesLinkLuciferasesMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMessenger RNAMetastatic malignant neoplasm to brainModelingMolecularMutationNeoplasm MetastasisOncogenicOutcomePathway interactionsPatientsPharmacologyPhosphotransferasesProtein Tyrosine KinaseProteinsRadiation therapyResistanceRiskRoleSignal TransductionSolid NeoplasmSurvival RateTimeTranscription CoactivatorTranscriptional ActivationTranscriptional RegulationTropismUp-Regulationaxl receptor tyrosine kinasebaseblood-brain barrier permeabilizationcancer cellcancer typechemotherapycomparativedriver mutationdrug developmentgenetic signaturein vitro Assayin vivoin vivo Modelinhibitor/antagonistinsightkinase inhibitorknock-downloss of functionmortalitymouse modelmutantnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsoutcome forecastoverexpressionpatient biomarkerspatient subsetsprogramsresponsetargeted treatmenttherapy resistanttranscription factortranscriptometreatment strategytumorupstream kinase
项目摘要
ABSTRACT
Lung cancer has the highest prevalence of brain metastasis among all other cancer types, occurring in
approximately 40% of patients. The presence of lung cancer brain metastases (LCBM) is associated with
cognitive decline and a median survival of 4-6 months. Currently utilized therapies for treating LCBMs include
whole brain radiation therapy (WBRT), chemotherapies, and targeted therapies aimed at kinases with “driver”
mutations. The use of WBRT increases patient cognitive decline, while targeted therapies have been proven
ineffective due to variable responses and the development of drug resistance. Thus, there is an obvious unmet
clinical need to better understand the molecular mechanisms that promote LCBM and subsequently use these
discoveries to develop new therapeutic strategies. Our laboratory discovered using an in vivo model of brain
metastasis that Abelson tyrosine protein kinase 2 (ABL2) promotes LCBM by propagating a feed-forward loop
consisting of ABL2, AXL receptor tyrosine kinase, and the TAZ transcriptional co-activator. Recently, my
preliminary data revealed an ABL-dependent stabilization and transcriptional activation of hypoxia inducible
factor-1α (HIF-1α) and heatshock factor 1 (HSF1) in this model. Activation of the HIF-1α and HSF1 transcription
networks in cancer is associated with tumor proliferation, metastasis, and therapy resistance. Therefore, my
central hypothesis is that the ABL kinases regulate multiple transcriptional networks that promote lung cancer
brain metastasis and therapy resistance. I will examine this hypothesis through the following two aims: 1) Define
the ABL-regulated HIF-1α transcription network required for lung cancer brain metastasis, and 2) Identify ABL-
dependent HSF1- regulated pathways necessary for lung cancer colonization of the brain. These aims will
evaluate whether increased expression of HIF-1α, HSF1, and TAZ can be used as biomarkers for lung cancer
patients with brain metastasis and whether blood brain barrier permeable ABL kinase inhibitors might be an
effective novel therapy for treating brain metastatic lung cancer.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Benjamin Jacob Mayro其他文献
Benjamin Jacob Mayro的其他文献
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{{ truncateString('Benjamin Jacob Mayro', 18)}}的其他基金
Understanding the impact that tumor representative oxygen tension has on phosphotyrosine-dependent signaling networks in solid tumors
了解肿瘤代表性氧张力对实体瘤中磷酸酪氨酸依赖性信号网络的影响
- 批准号:
10478070 - 财政年份:2021
- 资助金额:
$ 3.75万 - 项目类别:
Understanding the impact that tumor representative oxygen tension has on phosphotyrosine-dependent signaling networks in solid tumors
了解肿瘤代表性氧张力对实体瘤中磷酸酪氨酸依赖性信号网络的影响
- 批准号:
10765139 - 财政年份:2021
- 资助金额:
$ 3.75万 - 项目类别:
Understanding the impact that tumor representative oxygen tension has on phosphotyrosine-dependent signaling networks in solid tumors
了解肿瘤代表性氧张力对实体瘤中磷酸酪氨酸依赖性信号网络的影响
- 批准号:
10303523 - 财政年份:2021
- 资助金额:
$ 3.75万 - 项目类别: