Unlock instant, AI-driven research and patent intelligence for your innovation.

Application of Hippo signal channel blocker in preparation of anti-ER + breast tumor medicine

A signaling pathway, breast tumor technology, applied in the field of anti-tumor drugs to achieve the effect of improving drug resistance

Pending Publication Date: 2022-02-01
XINXIANG MEDICAL UNIV
View PDF3 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, resistance to this class of therapeutics remains inevitable in advanced disease

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Application of Hippo signal channel blocker in preparation of anti-ER + breast tumor medicine
  • Application of Hippo signal channel blocker in preparation of anti-ER + breast tumor medicine
  • Application of Hippo signal channel blocker in preparation of anti-ER + breast tumor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Expression and prognosis of YAP in ER+ breast cancer

[0086] 1. Progression-free survival data analysis

[0087] The progression-free survival (PFS) survival data of YAP were obtained from KMPLOT online analysis database (http: / / kmplot.com / analysis / index.php?p=service&cancer=breast). The gene affyID is 224894_at. Select "Automatically Selected Best Cutoff" and "ER Positive" for ER-positive breast cancer analysis. "Auto-selected optimal cutoff" and "ER-negative" were selected for ER-negative breast cancer analysis.

[0088] PFS survival data for TEAD4 in endocrine therapy patients were obtained from the KMPLOT database. The gene affyID is 41037_at. Select "Automatically select best cutoff" and "Endocrine treated patients" for analysis. The PFS survival data of MST1(STK4), MST2(STK3) and TAZ(WWTR1) in endocrine therapy patients were obtained from KMPLOT database. Gene association IDs are 225364(MST1), 204068(MST2) and 202133(TAZ)_at. Select "Automatically select b...

Embodiment 2

[0097] Inhibition of MST1 / 2 or activation of YAP blocks the growth of ER+ breast cancer cells

[0098] To determine whether increasing YAP activity could suppress the growth of ER+ breast cancer cells, we utilized a pharmacological small molecule inhibitor, XMU-MP-1, which specifically inhibits the activity of the kinase MST1 / 2, thereby promoting YAP nuclear localization and activation.

[0099] It was found that XMU-MP-1 inhibited the growth of ER+ breast cancer cell lines including MCF-7 and T47D in a dose-dependent manner ( Figure 7-8 ). Immunostaining or fractionation of MCF-7 cells treated with XMU-MP-1 showed increased nuclear localization of YAP ( Figure 9 ). Furthermore, the inhibitory effect of XMU-MP-1 on the growth of MCF-7 cells was partially reversed by siRNA-mediated YAP knockdown (KD) ( Figure 10 ), indicating that MST1 / 2 inhibition blocks the growth of ER+ breast cancer cells through YAP.

[0100] Consistent with the notion that YAP activation suppresse...

Embodiment 3

[0102] Inhibition of Hippo signaling pathway or activation of YAP inhibits ER+ breast cancer progression in xenograft tumor models

[0103] 1. Daily injection of XMU-MP-1 in estrogen-supplemented female NODscidγ (NSG) mice for 3 weeks significantly inhibited tumor growth compared with control treatment ( Figure 13 ), indicating that MST1 / 2 inhibition can reduce the growth of ER+ breast cancers in vivo.

[0104] 2. We also generated MCF-7 cell lines stably expressing inducible YAP-5SA (Tet-O-YAP-5SA) or its TEAD-binding-deficient form (Tet-O-YAP-5SAS94A), and derived cells carrying these line of xenografts. Mice were injected daily intraperitoneally with Dox (20 mg / kg) in PBS or PBS for the indicated time periods. Dox-induced expression of YAP-5SA significantly reduced tumor growth, whereas expression of YAP-5SAS94A had no effect ( Figure 14 ), indicating that YAP activation suppresses the growth of ER+ breast cancers in vivo and does so by binding to TEAD.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention belongs to the technical field of anti-tumor drugs, and particularly discloses application of a Hippo signal channel blocker in preparation of an anti-ER + breast tumor drug. Experiments prove that the MST1 / 2 kinase inhibitor serving as the Hippo signal channel blocking agent can inhibit the growth of ER + breast tumor cells MCF-7 and T47D by down-regulating the ERalpha protein level in MCF-7 and T47D cells, inhibiting the combination of ERalpha and a target promoter thereof and the like.

Description

technical field [0001] The invention belongs to the technical field of antitumor drugs, and specifically discloses the application of Hippo signaling pathway blockers in the preparation of anti-ER+ breast tumor drugs. Background technique [0002] Cancer, namely malignant tumor, is a major disease that seriously endangers human life. The treatment of cancer has received widespread attention from society. Breast cancer is the most common cancer among women in China, as in most other countries. Currently, breast cancer is the most common cancer among Chinese women. [0003] The Hippo signaling pathway controls tissue growth and organ size by simultaneously limiting cell growth and proliferation and promoting cell death. The core Hippo pathway consists of a kinase cascade: phosphorylation of upstream kinases MST1 / 2 and activation of downstream kinases LATS1 / 2, leading to phosphorylation and inactivation of the retrotranscriptional coactivators YAP / TAZ. When the Hippo signal...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/551A61K31/138A61P35/00
CPCA61K45/00A61K31/551A61K31/138A61P35/00A61K2300/00
Inventor 庄婷朱建杨会洁卓秫李欣
Owner XINXIANG MEDICAL UNIV