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CN-121987789-A - EGR1+Pharmaceutical use of neutrophil inhibitors

CN121987789ACN 121987789 ACN121987789 ACN 121987789ACN-121987789-A

Abstract

The invention belongs to the technical field of biological medicines, and relates to a pharmaceutical application of an EGR1 + neutrophil inhibitor. The invention discloses that KIAA1199 is highly expressed, and the signal axis of KIAA 1199-PPARgamma/SAA 2-FPR2-EGR1 induces EGR1 + neutrophils, so that angiogenesis is promoted, and liver metastasis is accelerated. The invention adopts FPR2 antagonist, PPARgamma agonist, PI3K inhibitor or EGR1 inhibitor to block the axis and inhibit liver metastasis formation, thus providing a new target and strategy for preventing and treating colorectal cancer liver metastasis.

Inventors

  • ZHANG DEJUN
  • ZHANG TAO
  • ZHAO LEI
  • LI LISHA
  • CAO KUI
  • LIN ZHENYU

Assignees

  • 华中科技大学同济医学院附属协和医院

Dates

Publication Date
20260508
Application Date
20260119

Claims (10)

  1. Use of an egr1 + neutrophil inhibitor in the manufacture of a medicament for the prevention or treatment of a disease driven by high expression of KIAA 1199.
  2. 2. The method of claim 1, wherein the inhibitor of neutrophils in EGR1 + is a substance that inhibits the production of a subset of neutrophils in EGR1 + or inhibits neutrophil function in EGR1 + .
  3. 3. The method of claim 1, wherein the inhibitor of neutrophils in EGR1 + is one or more of an FPR2 antagonist, a PPARgamma agonist, an EGR1 inhibitor, and a PI3K inhibitor.
  4. 4. A use according to claim 3, characterized in that: The FPR2 antagonist is WRW4 or a pharmaceutically acceptable derivative thereof, and/or, The PPARgamma agonist is rosiglitazone or a pharmaceutically acceptable derivative thereof, and/or, The EGR1 inhibitor is a substance that inhibits EGR1 expression or activity, and/or, The PI3K inhibitor is Wortmannin or a pharmaceutically acceptable derivative thereof.
  5. 5. The use of claim 1, wherein the high expression of KIAA1199 is indicative of significantly higher levels of KIAA1199 protein or mRNA than healthy levels in the lesion.
  6. 6. The use according to claim 1, wherein the disease driven by high expression of KIAA1199 is colorectal cancer liver metastasis.
  7. 7. The use according to claim 6, wherein the physiological characteristics of colorectal cancer liver metastasis include one or more of the following: 1) Liver microenvironment changes; 2) The survival time of the patient is obviously shortened; 3) Progressive exacerbation of liver metastasis burden; 4) Significant pathological angiogenesis.
  8. 8. A pharmaceutical composition for preventing and treating colorectal cancer liver metastasis is characterized by comprising at least two EGR1 + neutrophil inhibitors selected from the group consisting of FPR2 antagonists, PPARgamma agonists, EGR1 inhibitors and PI3K inhibitors.
  9. 9. The pharmaceutical composition for preventing and treating colorectal cancer liver metastasis according to claim 8, wherein: The FPR2 antagonist is WRW4 or a pharmaceutically acceptable derivative thereof, and/or, The PPARgamma agonist is rosiglitazone or a pharmaceutically acceptable derivative thereof, and/or, The EGR1 inhibitor is a substance that inhibits EGR1 expression or activity, and/or, The PI3K inhibitor is Wortmannin or a pharmaceutically acceptable derivative thereof.
  10. 10. The use according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 or 9, wherein the medicament or the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, and the preparation is in the form of an injection, a tablet or a capsule.

Description

Pharmaceutical application of EGR1 + neutrophil inhibitor Technical Field The invention belongs to the technical field of biological medicines, and relates to a pharmaceutical application of an EGR1 + neutrophil inhibitor. Background Colorectal cancer (Colorectal Cancer, CRC) is one of the most common malignant tumors worldwide, with both morbidity and mortality residing in the prostate. The leading cause of death in colorectal cancer patients is not the primary tumor itself, but rather distant metastasis, with the liver being the predominant metastatic target organ. Colorectal cancer liver metastasis (Colorectal CANCER LIVER METASTASES, CRLM) is a key factor affecting the prognosis of patients, and despite the continuous progress of comprehensive treatment means such as surgery, chemotherapy, targeted therapy and the like, the survival rate of CRLM patients in 5 years is still low and is only 12% -30%. Therefore, the molecular cell mechanism of CRLM is deeply elucidated, and the searching of effective early intervention targets and new therapeutic strategies are important challenges for the current clinic. Successful metastatic fixation is a complex multi-step process. In recent years, studies have shown that primary tumors are able to remotely regulate the microenvironment of distant organs prior to tumor cell dissemination, creating a so-called "Pre-metastatic microenvironment" (Pre-METASTATIC NICHE, PMN) that provides a suitable "soil" for upcoming circulating tumor cells. PMN formation involves a variety of biological processes including immunosuppression, angiogenesis, extracellular matrix remodeling, and the like. Among them, angiogenesis (Angiogenesis) is a critical event in the early phase of PMN formation, and the new blood vessels not only provide nutrients for metastases, but also promote the exudation and colonization of tumor cells. Among the various cellular components that make up PMNs, myeloid immune cells, particularly neutrophils, have proven to be a key coordinator. Conventionally, neutrophils are considered as terminally differentiated effector cells of short life. However, recent studies revealed a high degree of heterogeneity and plasticity in neutrophils, where "Tumor-associated neutrophils" (Tumor-Associated Neutrophils, TANs) were able to significantly promote Tumor progression and metastasis by secreting matrix metalloproteinases (e.g., MMP-9), vascular Endothelial Growth Factor (VEGF), and forming Neutrophil Extracellular Traps (NETs), among other means. However, the upstream signaling and precise mechanisms driving neutrophil differentiation towards a metastasis phenotype, especially in the specific context of colorectal liver metastasis, remain unclear. In summary, the prior art is still deficient in the mechanism of colorectal cancer liver metastasis, and particularly lacks a clear molecular pathway pattern in the remote communication of primary tumors with distant organ microenvironments. This greatly limits the ability to early alert CRLM and effectively intervene. Accordingly, there is a strong need in the art to disclose a new, complete signal transduction pathway and based thereon develop new methods for predicting, preventing or treating CRLM. Disclosure of Invention The invention provides a pharmaceutical application of an EGR1 + neutrophil inhibitor, which aims to solve the problem that the prior art lacks effective intervention of a critical immune cell subset in a transfer microenvironment before colorectal cancer liver transfer. The inventor finds that colorectal cancer cells with high expression of KIAA1199 can inhibit PPARgamma signal channels in liver cells by remotely regulating liver microenvironment, so that inhibition of SAA2 gene transcription is relieved, SAA2 protein expression and secretion are obviously up-regulated, SAA2 activates PI3K/AKT signal channels in neutrophils by combining with a receptor FPR2 thereof, formation of an EGR1 + neutrophil subgroup is induced, and the specialized EGR1 + neutrophils promote angiogenesis by secreting VEGFA, so that colorectal cancer liver metastasis is accelerated. The intervention of one or more of FPR2 antagonist, PPAR gamma agonist, PI3K inhibitor and EGR1 inhibitor can effectively block the signal axis and inhibit liver metastasis formation. Based on the findings, the invention provides the following technical scheme: in a first aspect, the invention provides the use of an EGR1 + neutrophil inhibitor in the manufacture of a medicament for the prevention or treatment of a KIAA 1199-high expression-driven disease. With reference to the first aspect, in some embodiments, the EGR1 + neutrophil inhibitor is a substance that inhibits EGR1 + neutrophil subpopulation generation or inhibits EGR1 + neutrophil function. With reference to the first aspect, in some embodiments, the EGR1 + neutrophil inhibitor is one or more of an FPR2 antagonist, a ppary agonist, an EGR1 inhibitor, a PI3K inhibitor. Further, the FPR2 antagon