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Application of FGFR and related signal pathway inhibitor thereof in preparation of medicine for treating FGFR2 mutant tumors

A technology of FGFR2 and signaling pathway, applied in the field of biomedicine, can solve the problem of unclear mechanism of action of breast cancer

Pending Publication Date: 2021-12-03
UNIVERSITY OF MACAU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Fgfr2 fusion genes Fgfr2-dnm3 (Dynamin 3), Fgfr2-tns1 and Fgfr2-zmynd8 were detected in a Brca1 knockout mouse model, so FGFR2 may be involved in mammary tumorigenesis, but its role in Brca1-associated breast cancer mechanism is unclear

Method used

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  • Application of FGFR and related signal pathway inhibitor thereof in preparation of medicine for treating FGFR2 mutant tumors
  • Application of FGFR and related signal pathway inhibitor thereof in preparation of medicine for treating FGFR2 mutant tumors
  • Application of FGFR and related signal pathway inhibitor thereof in preparation of medicine for treating FGFR2 mutant tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Fgfr2 mutation enhances mammary gland branching morphogenesis and promotes mammary gland tumor formation.

[0046] Application of loxp system to specifically activate Fgfr2 in mammary gland tissue, panorama of Fgfr2-S252W mouse mammary gland compared with wild-type (WT) mice, Fgfr2-S252W mouse mammary gland branching is denser ( figure 1 Middle A-C). Tissue sections showed that the number of cells in the mutant mice was relatively more ( figure 1 Middle D). CD29 in mammary epithelial cells revealed by flow cytometry Hi CD24 Med group relative increase ( figure 1 Middle E–F), These characterizations of mammary stem cells suggest that activation of Fgfr2 enhances mammary branching morphology and epithelial cell proliferation, thereby increasing the number of mammary stem cells and promoting tumor formation. Nine months later, mammary tumor development in Fgfr2-S252W mice was observed. During the 22-month period of continuous observation, mammary tumors we...

Embodiment 2

[0047] Example 2: Fgfr2 activation promotes the development of triple negative breast tumors.

[0048] Mammary tumors associated with Fgfr2 mutations were characterized by pathological analysis of mammary tumor tissues from Fgfr2-S252W mice. It was mainly invasive ductal carcinoma (IDC), accounting for 75% (24 / 32), and the rest were invasive lobular carcinoma, lobular carcinoma in situ and ductal carcinoma in situ ( figure 2 Middle A). Immunofluorescence (IF) showed that 65.625% (21 / 32) of breast tumors were basaloid carcinoma, and 34.375% (11 / 32) of other tumors were tubular tumors ( figure 2 Middle B, figure 2 Middle D).

[0049] Molecular subtypes of breast cancer showed that 4 / 32 (12.5%) were Luminal A type (positive estrogen receptor and / or progesterone receptor, HER2 negative, low Ki-67 protein level), 8 / 32 (25%) Luminal B type (estrogen receptor and / or progesterone receptor positive, HER2 positive or HER2 negative, 2 / 32 (6.25%) were HER2-enriched, 18 / 32 (56.25%) ...

Embodiment 3

[0051] Example 3: Fgfr2 activates STAT3-MAPK signal to regulate EMT.

[0052]In order to study the molecular mechanism of Fgfr2-induced tumorigenesis, this example analyzes the transcriptional profiles in mammary glands of WT and Fgfr2-S252W mice at 6 months. 671 differentially expressed genes (DEGs) were identified. Among them, 359 were up-regulated and 312 were down-regulated.

[0053] Bioinformatics analysis revealed that tumorigenesis may be related to epithelial cell differentiation, proliferation, inflammatory response, MAPK cascade reaction, chemokines and other pathways ( image 3 Middle A). protein-protein interaction network image 3 Shown in B. The two groups of genes were positively correlated with inflammatory factors (green boxes) and growth factors / EMT (red boxes), respectively.

[0054] Gene set enrichment analysis (GSEA) revealed that breast cancer pathways and MAPK signaling pathways were highly activated in Fgfr2-S252W mammary glands. Western blot anal...

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Abstract

The invention discloses application of FGFR and a related signal pathway inhibitor thereof in preparation of a medicine for treating FGFR2 mutant tumors, and relates to the field of biological medicine. The invention finds that an FGF / FGFR2 signal drives formation of the triple negative breast cancer and promotes epithelial-mesenchymal transition along with FGFR2-STAT3, and further finds that FGFR2 inhibits BRCA1 through MAPK-YY1 to accelerate formation of tumors. In addition, the FGFR2 also regulates and controls the expression of the PD-L1 through the STAT3-MAPK. Based on the findings above, the invention provides the application of the FGFR and the related signal pathway inhibitor thereof in preparation of the medicine for treating the FGFR2 mutant tumors, and provides a research direction and way for research of an FGFR2 signal pathway and development of related medicines.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of FGFR and its related signaling pathway inhibitors in the preparation of drugs for treating FGFR2 mutant tumors. Background technique [0002] Female breast cancer has now overtaken lung cancer as the most common cancer worldwide. On December 15, 2020, the World Health Organization's International Agency for Research on Cancer (IARC) released the latest global cancer data for 2020, showing that breast cancer is the leading cause of cancer death in women and is expected to cause more than 680,000 deaths by 2020 , so it is imminent to find new treatments for breast cancer. [0003] About 10% of breast cancer and breast cancer-related gene 1 / 2 (BRCA1 / 2), tumor protein P53 (TP53), ATM serine / threonine kinase (ATM) genetic variation are related, but other related genes need to be further identified. Easton DF et al. analyzed 4398 breast cancer cases and 4316 normal tissu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61P35/00
CPCA61K45/06A61P35/00
Inventor 邓初夏雷海鹏
Owner UNIVERSITY OF MACAU
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