Targeting the PI3 pathway in Gliomas with PI3 inhibitors and rational combination
Targeting the PI3 pathway in Gliomas with PI3 inhibitors and rational combination
批准号:
7450203
负责人:
W K ALFRED Yung
金额:
$19.09万
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-09-01 至 2013-08-31
关键词:
AEE 788Animal ModelAutomobile DrivingBAY 54-9085CaringCellsCharacteristicsClinicClinicalClinical ProtocolsClinical TrialsCombined Modality TherapyCultured CellsDataDevelopmentDimensionsDose-LimitingDrug CombinationsDrug Delivery SystemsEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorErlotinibFingerprintGefitinibGlioblastomaGliomaGlycolysisGrowth FactorHumanImageIndividualKnowledgeLeadMalignant - descriptorMalignant GliomaMalignant neoplasm of brainModelingMolecularMolecular TargetMutationPTEN genePathway interactionsPharmaceutical PreparationsPhasePre-Clinical ModelRadiationReceptor Protein-Tyrosine KinasesRecurrenceRefractoryResearchScreening procedureSignal PathwaySignal TransductionSignal Transduction InhibitorSirolimusSmall Interfering RNAStagingStandards of Weights and MeasuresTestingTimeToxic effectTumor Suppressor GenesTumor Suppressor ProteinsValidationVascular Endothelial Growth FactorsXenograft procedureanalogbasecancer stem celldrug testingimprovedin vivoinhibitor/antagonistmTOR Inhibitorneovascularizationnovelpre-clinicalprogramsresearch clinical testingsmall hairpin RNAsmall moleculesuccesstemozolomidetumorwortmannin
中文摘要
胶质母细胞瘤的分子改变特征包括EGFR的扩增和EGFR的缺失
英文摘要
Molecular alterations characteristic of glioblastoma include the amplification of EGFR and the loss of the
PTEN tumor suppressor, which lead to the constitutive activation of the PI3K/Akt pathway and provides the
rationale for our focus in this Project on a unique PI3K inhibitor, PX-866 (ProIX). This wortmannin analog
offers three key improvements: 1) it is biologically stable; 2) it is a more potent inhibitor of the p110-a
subunit of PI3K and 3) it is a weaker inhibitor of p110-p, and so shows much reduced dose limiting ontarget
toxicity common to all PI3K inhibitors. We plan to test the hypothesis that the PI3K inhibitor PX-
866 is an effective therapy for glioma by evaluating it in preclinical models and in the clinic in early phase
clinical trials for glioblastoma. However, the limited success of signal transduction inhibitors used as single
agents, which is most likely due to compensatory or collateral pathways, is a strong rationale for exploring
combination therapies. Some combinations can be suggested on the basis of current knowledge of
signaling pathways, and we propose to test the most compelling in our models and the clinic. At the same
time we plan to identify additional molecular target(s) or pathway(s) that would, once they are blocked by
another drug, confer synergy to a PI3K inhibitor, based on siRNA synthetic lethality screening. Together
these efforts will test the hypothesis that combination therapies based on PI3K inhibitors are
effective in the treatment of glioma. Our Specific Aims are 1) To study PX-866 and rational combinations
in improved preclinical culture and animal models of glioma, using xenografts of human glioma cells that
retain the molecular hallmarks of the parental tumors and on brain cancer stem cells. Rational
combinations include PX-866 and the small molecule drugs Tarceva, Sorafenib and rapamycin/RADOOl as
well as the standard of care - radiation and temozolomide; 2) To initiate clinical trials of PX-866 and rational
combinations, based on the data obtained in Aim 1; and 3) To identify novel synergistic targets for rational
drug combinations with PX-866 using siRNA synthetic lethality screening. By completing these Aims we will
pursue, in parallel, the clinical deployment of a promising PI3K inhibitor and the development of
combination therapies based on it. Both rational (Aim 1) and newly discovered (Aim 3) co-targets/therapies
will be developed, allowing both near-term and mid-term combination therapies to follow the individual lead
compound (Aim 2) into clinical evaluation. Therefore this project emphasizes the translational dimension of
our signal transduction research program with the hope of accelerating promising new treatment to the
bedside.
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会议论文
SPORE in Brain Cancer
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批准号:8332730
-
项目类别:
-
资助金额:$230.0万
-
财政年份:2008
-
负责人:W K ALFRED Yung
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依托单位:
Targeting the PI3K Pathway in Malignant Glioma
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批准号:8753977
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项目类别:
-
资助金额:$22.24万
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财政年份:2008
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负责人:W K ALFRED Yung
-
依托单位:
SPORE in Brain Cancer
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批准号:8138385
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项目类别:
-
资助金额:$218.5万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
SPORE in Brain Cancer
-
批准号:7432340
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项目类别:
-
资助金额:$230.0万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
Career Development Program
-
批准号:7450249
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项目类别:
-
资助金额:$9.81万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
SPORE in Brain Cancer
-
批准号:7681537
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项目类别:
-
资助金额:$230.0万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
SPORE in Brain Cancer
-
批准号:7921427
-
项目类别:
-
资助金额:$230.0万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
Targeting the PI3K Pathway in Malignant Glioma
-
批准号:8588568
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项目类别:
-
资助金额:$22.52万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
Targeting the PI3K Pathway in Malignant Glioma
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批准号:8918451
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项目类别:
-
资助金额:$23.3万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
Targeting the PI3K Pathway in Malignant Glioma
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批准号:9339981
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项目类别:
-
资助金额:$24.25万
-
财政年份:2008
-
负责人:W K ALFRED Yung
-
依托单位:
Deciphering synergistic combinatorial targets in glioma
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批准号:7139264
-
项目类别:
-
资助金额:$27.34万
-
财政年份:2006
-
负责人:W K ALFRED Yung
-
依托单位:
Deciphering synergistic combinatorial targets in glioma
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批准号:7667519
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项目类别:
-
资助金额:$26.54万
-
财政年份:2006
-
负责人:W K ALFRED Yung
-
依托单位:
Deciphering synergistic combinatorial targets in glioma
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批准号:7484276
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项目类别:
-
资助金额:$26.54万
-
财政年份:2006
-
负责人:W K ALFRED Yung
-
依托单位:
Deciphering synergistic combinatorial targets in glioma
-
批准号:7285209
-
项目类别:
-
资助金额:$26.54万
-
财政年份:2006
-
负责人:W K ALFRED Yung
-
依托单位:
Deciphering synergistic combinatorial targets in glioma
-
批准号:7893667
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项目类别:
-
资助金额:$26.54万
-
财政年份:2006
-
负责人:W K ALFRED Yung
-
依托单位:
Triple Anti-Angiogenic Therapy for Brain Tumors
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批准号:7107964
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项目类别:
-
资助金额:$19.63万
-
财政年份:2000
-
负责人:W K ALFRED Yung
-
依托单位:
Triple Anti-Angiogenic Therapy for Brain Tumors
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批准号:6952023
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项目类别:
-
资助金额:$25.1万
-
财政年份:2000
-
负责人:W K ALFRED Yung
-
依托单位:
TRIPLE ANTI ANGIOGENIC THERAPY FOR BRIAN TUMORS
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批准号:6130433
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项目类别:
-
资助金额:$20.39万
-
财政年份:2000
-
负责人:W K ALFRED Yung
-
依托单位:
TRIPLE ANTI ANGIOGENIC THERAPY FOR BRIAN TUMORS
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批准号:6514180
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项目类别:
-
资助金额:$20.39万
-
财政年份:2000
-
负责人:W K ALFRED Yung
-
依托单位:
MOLECULAR REGULATION OF ANGIOGENIC PHENOTYPE
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批准号:6300396
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项目类别:
-
资助金额:$14.15万
-
财政年份:2000
-
负责人:W K ALFRED Yung
-
依托单位:
海外基金