PIP5K1A Enhances Phosphoinositide Signaling to Drive Breast Cancer
PIP5K1A 增强磷酸肌醇信号传导以驱动乳腺癌
基本信息
- 批准号:10116158
- 负责人:
- 金额:$ 4.6万
- 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:2020-06-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAffinityAutomobile DrivingBiological MarkersBreast Cancer CellCell ProliferationCell membraneClinical TrialsDataDevelopmentEnzymesFeedbackGenesGoalsHomeostasisKnowledgeLinkLipidsMammalsMapsMeasuresMediatingMissionMutationOncogenicPathway interactionsPatientsPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPhosphorylationPhosphotransferasesProductionProgression-Free SurvivalsProteinsProto-Oncogene Proteins c-aktPublic HealthRegulationReportingResearchRoleScientific Advances and AccomplishmentsSignal PathwaySignal TransductionSiteTestingYeastsalpelisibanticancer researchcancer cellexperimental studyhormone receptor-positiveinhibitor/antagonistmalignant breast neoplasmnew therapeutic targetnovelnovel markeroverexpressionphase III trialphosphatidylinositol 3,4,5-triphosphatephosphatidylinositol 4-phosphatephosphatidylinositol 5-phosphaterecruitsensortargeted treatmenttumortumor growth
项目摘要
PROJECT SUMMARY
The class I phosphoinositide-3 kinase α (PI3Kα), which produces the signaling lipid phosphatidylinositol 3,4,5-
trisphosphate (PIP3), is overactive in over 40% of breast cancer cases. Results from recent clinical trials have
shown that targeted inhibition of PI3Kα is effective in prolonging survival in these patients. PI3Ks produce PIP3
by phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2), which is synthesized by phosphatidylinositol
4-phosphate 5-kinases (PIP5Ks). PIP5K1A has been implicated as a driver in breast cancer and is found
amplified in over 18% of tumors, though often with inactivating mutations. This amplification is found independent
of PI3Kα mutations in half of these cases. However, it is not yet understood whether amplification of PIP5K1A
and elevated PIP2 levels will drive tumor growth by increasing PIP3 production. The objective in this particular
application is to determine the mechanism by which increased PIP5K1A expression disrupts PIP2 homeostasis,
and how subsequently elevated PIP2 levels drive PI3K signaling. The central hypothesis is that amplification of
PIP5K1A saturates a negative regulator, leading to elevated PIP2 and increased PI3K signaling, regardless of
PIP5K catalytic activity. The rationale for the proposed research is that this will reveal how amplified PIP5K1A
drives PI3K signaling in breast cancer. Guided by strong preliminary data, this hypothesis will be tested using
two specific aims: 1) Identify the mechanism of PIP2 homeostasis at the plasma membrane; and 2) Define the
role of altered PIP2 homeostasis in driving PI3K signaling, and its effects breast cancer cell proliferation. Under
the first aim, the interaction between PIP5K and a negative regulator will be determined and the effects on
catalytic activity will be identified. Under the second aim, the effect of PIP5K1A over-expression and elevated
PIP2 levels on PI3K signaling and breast cancer cell proliferation will be determined. The proposed research is
significant because it will identify PIP5K1A as a novel biomarker of breast cancer sensitivity to PI3Kα inhibitors.
This will be a critical first step in establishing treatment options for ~10% of breast cancer cases without activation
of PI3Kα.
项目摘要
I类磷脂酰肌醇-3激酶α(PI 3 K α)产生信号脂质磷脂酰肌醇3,4,5-
三磷酸盐(PIP 3)在超过40%的乳腺癌病例中过度活跃。最近的临床试验结果表明,
表明靶向抑制PI 3 K α可有效延长这些患者的生存期。PI 3 K产生PIP 3
通过磷脂酰肌醇4,5-二磷酸(PIP 2)的磷酸化,PIP 2由磷脂酰肌醇合成,
4-磷酸5-激酶(PIP 5 Ks)。PIP 5 K1 A被认为是乳腺癌的驱动因素,
在超过18%的肿瘤中扩增,尽管通常具有失活突变。发现这种放大独立于
PI 3 K α基因突变。然而,目前还不清楚PIP 5 K1 A的扩增是否
并且升高的PIP 2水平将通过增加PIP 3产生来驱动肿瘤生长。在这个特殊的目标,
本申请的目的是确定增加的PIP 5 K1 A表达破坏PIP 2体内平衡的机制,
以及随后升高的PIP 2水平如何驱动PI 3 K信号传导。核心假设是,
PIP 5 K1 A使负调节子饱和,导致升高的PIP 2和增加的PI 3 K信号传导,无论
PIP 5 K催化活性。这项研究的基本原理是,这将揭示放大的PIP 5 K1 A
在乳腺癌中驱动PI 3 K信号。在强有力的初步数据的指导下,这一假设将使用
两个具体的目标:1)确定PIP 2在质膜上的稳态机制;和2)定义PIP 2在质膜上的稳态机制。
改变的PIP 2稳态在驱动PI 3 K信号传导中的作用及其对乳腺癌细胞增殖的影响。下
第一个目标,将确定PIP 5 K和负调节因子之间的相互作用,
将鉴定催化活性。在第二个目标下,PIP 5 K1 A过表达和升高的作用是通过抑制PIP 5 K1 A的表达来实现的。
将测定PIP 2水平对PI 3 K信号传导和乳腺癌细胞增殖的影响。拟议的研究是
这是因为它将识别PIP 5 K1 A作为乳腺癌对PI 3 K α抑制剂敏感性的新生物标志物。
这将是为约10%的乳腺癌病例建立治疗方案的关键第一步,
PI3Kα
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane.
- DOI:10.1242/jcs.261494
- 发表时间:2023-08-15
- 期刊:
- 影响因子:4
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{{ truncateString('Rachel Wills', 18)}}的其他基金
PIP5K1A Enhances Phosphoinositide Signaling to Drive Breast Cancer
PIP5K1A 增强磷酸肌醇信号传导以驱动乳腺癌
- 批准号:
9910580 - 财政年份:2020
- 资助金额:
$ 4.6万 - 项目类别:
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