A New Mechanism for Castration Resistant Prostate Cancer
去势抵抗性前列腺癌的新机制
基本信息
- 批准号:9233878
- 负责人:
- 金额:$ 36.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcetatesAddressAndrogen ReceptorAndrogensAnimalsAttenuatedBiochemicalBiologicalBiological TestingCYP17A1 geneCancer PatientCastrationCellsClinicalDataDevelopmentDisease ProgressionFutureGene ExpressionGenesGenetic TranscriptionGrowthHGF geneHormonesLeadMalignant Epithelial CellMalignant neoplasm of prostateModelingMolecularMorphogenesisNeoplasm MetastasisOutcomePathway interactionsPatientsPharmaceutical PreparationsPhenotypePlayPrincipal InvestigatorPromoter RegionsProstatic NeoplasmsProto-Oncogene Protein c-metReceptor Protein-Tyrosine KinasesRefractoryReportingRepressionResistanceRoleSamplingSignal TransductionSystemTechnologyTestingThe SunTimeTranscription CoactivatorTransgenic MiceTranslatingWorkabirateroneandrogen independent prostate cancerangiogenesisbasecastration resistant prostate cancercell growth regulationcell motilityclinical applicationdeprivationeffective therapyhormone therapyimprovedinhibitor/antagonistmeetingsmenmouse modelneoplastic cellnovelnovel therapeutic interventionnovel therapeuticsoutcome forecastoverexpressionparacrinepreventprogramsprostate cancer cellprotein complexpublic health relevancereceptorresponsesingle walled carbon nanotubetherapeutic targettumortumor growthtumor progression
项目摘要
Principal Investigator/Program Director (Last, first, middle): Sun, Zijie
Project Summary
It has been almost 60 years since Charles Huggins and Clarence Hodges invented androgen
deprivation therapy for the treatment of prostate cancer. Many different medications have been developed and
applied to patients to achieve androgen reduction or androgen receptor (AR) suppression since then, but the
fundamental premise behind androgen deprivation has remained almost unchanged. Most patients develop
hormone refractory tumor, also known as castration resistant prostate cancer (CRPC) within two to three years
following initiation of therapy, for which there is no effective treatment.
The hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that plays a
critical role in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. HGF/SF exerts its
effects through its receptor, c-Met, a transmembrane receptor tyrosine kinase (RTK). The aberrant expression
of HGF/SF and c-Met often correlates with poor prognosis in cancer patients. A paracrine mechanism for
HGF/SF stimulation of c-Met has been largely implicated in the progression of prostate cancer. It has been
shown that HGF significantly increases the proliferation, motility, and invasion of malignant epithelial cells
through the c-Met protein. Interestingly, an inverse correlation between the expression of the AR and c-Met
has been observed in prostate cancer cells. An increase in c-Met expression was reported in castrated
animals 8, 14, and in metastatic prostate tumor samples. These data suggest a critical role for c-Met in
promoting disease progression, castration resistance, and metastasis.
Previously, our group and others have demonstrated that the AR represses c-Met expression in prostate
cancer cells. Specifically, we identified that the AR interrupts Sp1-induced activation of c-Met transcription.
These findings suggest a dual regulatory role for the AR as both a transcriptional activator and a repressor in
prostate cancer cells, and imply a novel molecular mechanism for prostate cancer progression. While
androgen ablation therapy suppresses activation of the growth promoting gene expression induced by the AR,
it also attenuates the repressive role of the AR on c-Met expression and increases the c-Met in tumor cells.
Since overexpression of c-Met directly correlates with more aggressive tumor phenotypes, adding c-Met
inhibitors to standard androgen ablation therapy may significantly improve the clinical outcome and delay time
to CRPC. Thus, in this RO1 application we propose three unique but integrated specific aims to further test
our central hypothesis: Inhibition of AR activity through concurrent androgen ablation therapy increases c-Met
expression thereby inducing androgen-insensitivity and more aggressive phenotypes of prostate cancer, and
co-inhibition of AR and c-Met pathways can prevent or delay CRPC development. The major objective is to
use biologically relevant systems to translate our bench work to the bedside, which will lead to a novel
therapeutic strategy for treating advanced prostate cancer. Three specific aims are 1) we will directly assess
the role of c-Met in prostate cancer formation and progression, 2) as proof-in-principle, we will directly
determine the combined effects of c-Met inhibition and androgen ablation on prostate tumor growth and
progression, and 3) we will further explore the molecular mechanism for AR repression of c-Met expression to
discover future therapeutic targets in the AR and c-Met pathways.
Project Description Page 6
首席研究员/项目主任(后、一、中):孙子杰
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(2)
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ZIJIE SUN其他文献
ZIJIE SUN的其他文献
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{{ truncateString('ZIJIE SUN', 18)}}的其他基金
Androgen Signaling in prostate cancer progression and CRPC development
前列腺癌进展和 CRPC 发展中的雄激素信号传导
- 批准号:
9233875 - 财政年份:2016
- 资助金额:
$ 36.9万 - 项目类别:
Androgen Signaling in prostate cancer progression and CRPC development
前列腺癌进展和 CRPC 发展中的雄激素信号传导
- 批准号:
9197890 - 财政年份:2016
- 资助金额:
$ 36.9万 - 项目类别:
A new regulator for Wnt/beta-catenin signaling and prostate tumorigenesis
Wnt/β-连环蛋白信号传导和前列腺肿瘤发生的新调节因子
- 批准号:
9233879 - 财政年份:2016
- 资助金额:
$ 36.9万 - 项目类别:
Androgen Signaling in Prostatic Sonic Hedgehog Responsive Cells
前列腺 Sonic Hedgehog 反应细胞中的雄激素信号传导
- 批准号:
10630343 - 财政年份:2015
- 资助金额:
$ 36.9万 - 项目类别:
Androgen Signaling in Prostatic Sonic Hedgehog Responsive Cells
前列腺 Sonic Hedgehog 反应细胞中的雄激素信号传导
- 批准号:
10451616 - 财政年份:2015
- 资助金额:
$ 36.9万 - 项目类别:
Androgen Signaling in Prostatic Sonic Hedgehog Responsive Cells
前列腺 Sonic Hedgehog 反应细胞中的雄激素信号传导
- 批准号:
10295736 - 财政年份:2015
- 资助金额:
$ 36.9万 - 项目类别:
Cellular And Molecular Properties Of PINs In Prostate Tumorigenesis
前列腺肿瘤发生中 PIN 的细胞和分子特性
- 批准号:
8791506 - 财政年份:2014
- 资助金额:
$ 36.9万 - 项目类别:
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