KRAS- and BRAF- Driven Lung Adenocarcinoma
KRAS- and BRAF- Driven Lung Adenocarcinoma
批准号:
8120223
负责人:
NEAL X ROSEN
金额:
$35.87万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至
关键词:
AKT inhibitionAffectAnimalsAntibodiesApoptosisBH3 DomainBRAF geneBad proteinBiological ModelsBreast Cancer TreatmentCancer EtiologyCancer cell lineCatalytic DomainCell LineCellsCessation of lifeClinicClinicalComplexCytostaticsDataDependenceDevelopmentDisabled PersonsDiseaseERBB2 geneElementsEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpithelialEventFeedbackGene MutationGenesGenetic ModelsGoalsGrowthGrowth FactorHumanIn VitroIndividualKRAS2 Gene MutationKRAS2 geneKnowledgeLesionLungLung AdenocarcinomaMAP Kinase GeneMAPK phosphataseMEK inhibitionMEKKsMEKsMaintenanceMalignant neoplasm of lungMediatingModelingMutateMutationNon-Small-Cell Lung CarcinomaOncogene ProteinsOutputPI3K/AKTPIK3CA genePTEN genePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhenocopyPhenotypePhosphotransferasesPlayPre-Clinical ModelPrincipal InvestigatorProliferatingProteinsProto-Oncogene Proteins c-aktRAS inhibitionReagentRefractoryResearch PersonnelResistanceRoleSignal PathwaySignal TransductionStromal NeoplasmSystemTestingTherapeuticTherapeutic AgentsTherapeutic InterventionToxic effectTranslationsTumor Cell LineWestern WorldWorkXenograft Modelangiogenesisbasecancer celldesigngenetic profilinghuman MAP3K1 proteinin vivoinhibitor/antagonistkinase inhibitormouse modelmutantneoplastic cellpatient populationprogramsral Guanine Nucleotide Exchange Factorsmall hairpin RNAtherapeutic developmenttissue culturetreatment strategytumor
中文摘要
在有丝分裂信号通路的四个编码基因中的突变已经被鉴定,
人肺腺癌,包括EGFR、KRAS、HER 2和BRAF。遗传模型表明
KRAS、EGFR和BRAF的激活突变在这些肿瘤的发病机制中起作用。
这些数据表明,抑制这些癌蛋白功能的药物可能是重要的治疗药物。
在这种疾病的代理人。EGFR抑制剂在肿瘤中的临床抗肿瘤活性证实了这一点,
EGFR突变。突变型KRAS是这些病变中最常见的(在25%的腺癌中检测到),
但不幸的是,目前还没有有效抑制这种癌蛋白的药物。这项提案的目的是
是开发抑制KRAS功能的治疗策略。我们假设晚期肺部
具有突变KRAS的腺癌仍然依赖于其功能,并且其作用是由
一种或多种KRAS效应蛋白。这些包括RAF,PI 3 KCA,RAL-GD和其他。我们
初步数据显示,肺腺癌细胞系的一个子集对MEK的抑制敏感,
激酶是RAF的下游靶点。此外,KRAS和PI 3 KCA(编码PI 3 KCA)两者均表达的肿瘤中,
PI 3 K的P110 α催化亚基)突变对MEK或PI 3 K的抑制具有抗性,
对两种靶标的联合抑制敏感。We hypothesize假设lung肺adenocarcinoma腺癌that are KRAS-
突变体和PI 3 KCA野生型将对单独MEK抑制敏感,且额外的肿瘤将
对MEK/MAPK和PI 3 K/AKT途径的联合抑制敏感。我们现在建议,
确定突变型KRAS肺癌细胞系对KRAS及其效应子表达的依赖性,
分子,研究这些肿瘤的MEK和PI 3 K依赖性的机制,
确定单独使用MEK和PI 3 K/AKT抑制剂的生物学和潜在治疗后果,
最终的目标是发展一种治疗肺腺癌的策略,
KRAS依赖性肺腺癌的治疗。
英文摘要
Mutations in four genes that encode components of mitogenic signaling pathways have been identified in
human lung adenocarcinomas,including the EGFR, KRAS, HER2, and BRAF. Genetic models demonstrate
that the activating mutations of KRAS, EGFR, and BRAF play a role in the pathogenesis of these tumors.
These data suggest that agents that inhibit the function of these oncoprpteins could be important therapeutic
agents in this disease. This is borne out by the clinical antitumor activity of EGFR inhibitors in tumors with
EGFR mutation. Mutant KRAS is the most common of these lesions (detected in 25% ofadenocarcinomas),
but unfortunately there is currently no drug that effectively inhibits this oncoprotein. The goal of this proposal
is the development of therapeutic strategies that inhibit KRAS function. We hypothesize that advanced lung
adenocarcinomas with mutant KRAS are still dependent on its function and that its effects are mediated by
one or more of the KRAS effector proteins. These include RAF, PI3KCA, RAL-GDSand others. Our
preliminary data show that a subset of lung adenocarcinomacell lines is sensitive to inhibition of MEK
kinase, the downstreamtarget of RAF. Furthermore, tumors in which both KRAS and PI3KCA (encoding the
P110alpha catalytic subunit of PI3K) are mutated are resistant to inhibition of either MEK or PI3K but
sensitive to combined inhibition of both targets. We hypothesize lung adenocarcinomasthat are KRAS-
mutant and PI3KCA wild type will be sensitive to MEK inhibition alone, and that additional tumors will be
sensitive to combined inhibition of both the MEK/MAPK and PI3K/AKT pathways. We propose now to
determine the dependence of mutant KRAS lung cancer cell lines on expression of KRAS and its effector-
molecules, investigate the mechanisms underlying the MEK and PI3K dependence of these tumors, and
determine the biologic and potential therapeutic consequences of MEK and PI3K/AKT inhibitors, alone and
in combination, in lung adenocarcinomas.The eventual goal is the development of a strategy for the
treatment of KRAS-dependent lungadenocarcinoma.
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KRAS- and BRAF- Driven Lung Adenocarcinoma
-
批准号:7315930
-
项目类别:
-
资助金额:$28.53万
-
财政年份:2007
-
负责人:NEAL X ROSEN
-
依托单位:
DEVELOPMENT OF SIGNAL TRANSDUCTION INHIBITORS FOR THE TREATMENT OF BREAST CANCER
-
批准号:6216536
-
项目类别:
-
资助金额:$32.78万
-
财政年份:1999
-
负责人:NEAL X ROSEN
-
依托单位:
DEVELOPMENT OF SIGNAL TRANSDUCTION INHIBITORS FOR THE TREATMENT OF BREAST CANCER
-
批准号:6203336
-
项目类别:
-
资助金额:$32.78万
-
财政年份:1999
-
负责人:NEAL X ROSEN
-
依托单位:
DEVELOPMENT OF SIGNAL TRANSDUCTION INHIBITORS FOR THE TREATMENT OF BREAST CANCER
-
批准号:6103120
-
项目类别:
-
资助金额:$32.78万
-
财政年份:1998
-
负责人:NEAL X ROSEN
-
依托单位:
WILD TYPE RAS AND FARNESYL TRANSFERASE INHIBITORS IN BREAST CANCER
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批准号:6237603
-
项目类别:
-
资助金额:$30.66万
-
财政年份:1997
-
负责人:NEAL X ROSEN
-
依托单位:
KRAS- and BRAF- Driven Lung Adenocarcinoma
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批准号:8291121
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项目类别:
-
资助金额:$34.57万
-
财政年份:--
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负责人:NEAL X ROSEN
-
依托单位:
WILD TYPE RAS AND FARNESYL TRANSFERASE INHIBITORS IN BREAST CANCER
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批准号:5209471
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项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:NEAL X ROSEN
-
依托单位:--
KRAS- and BRAF- Driven Lung Adenocarcinoma
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批准号:7893052
-
项目类别:
-
资助金额:$35.21万
-
财政年份:--
-
负责人:NEAL X ROSEN
-
依托单位:
海外基金