权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9910580
负责人：
Rachel Wills
金额：
$ 4.55万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
https://reporter.nih.gov/project-details/9910580
关键词：
1-Phosphatidylinositol 3-Kinase Affinity Automobile Driving Biological Markers Breast Cancer Cell Cell Proliferation Cell membrane Clinical Trials Data Development Enzymes Feedback Genes Goals Homeostasis Knowledge Link Lipids Mammals Maps Measures Mediating Mission Mutation Oncogenic Pathway interactions Patients Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphorylation Phosphotransferases Production Progression-Free Survivals Proteins Proto-Oncogene Proteins c-akt Public Health Regulation Reporting Research Role Scientific Advances and Accomplishments Signal Pathway Signal Transduction Site Testing Yeasts alpelisib anticancer research cancer cell experimental study hormone receptor-positive inhibitor/antagonist malignant breast neoplasm new therapeutic target novel novel marker overexpression phase III trial phosphatidylinositol 3,4,5-triphosphate phosphatidylinositol 4-phosphate phosphatidylinositol 5-phosphate recruit sensor targeted treatment tumor tumor 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.

项目总结