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CN-122012709-A - Use of UXS1 as a biomarker or for detecting UXS1 and pharmaceutical compositions

CN122012709ACN 122012709 ACN122012709 ACN 122012709ACN-122012709-A

Abstract

The invention provides an application of UXS1 as a biomarker or a substance for detecting UXS1 and a pharmaceutical composition, wherein the application is used for preparing and/or screening a product for diagnosing or assisting in diagnosing the sensitivity of metformin therapy of a lung adenocarcinoma patient, an application for preparing and/or screening a product for monitoring the curative effect of the lung adenocarcinoma patient and an application for preparing and/or screening a product for evaluating the resistance of the metformin of the lung adenocarcinoma patient. The technical scheme of the invention has the following advantages that 1, a specific molecular mechanism of relieving allosteric inhibition of metformin through inducing phosphorylation at UGDH S476 is clarified, 2, a metabolic regulation net for initiating UDP-uronic acid toxicity accumulation through UXS1 function inhibition is disclosed, 3, a synergistic treatment scheme for enhancing synthetic lethal effect of UXS inhibitor through metformin pretreatment is provided, and 4, an immune synergistic treatment scheme based on uronic acid metabolism reprogramming is established.

Inventors

  • Sui Qihai
  • ZHAN CHENG
  • Hu zhengyang
  • SHAN GUANGYAO
  • JIN XING
  • CHEN ZHENCONG
  • JIANG WEI

Assignees

  • 复旦大学附属中山医院

Dates

Publication Date
20260512
Application Date
20260123

Claims (10)

  1. 1. Use of UXS1 as a biomarker or a substance to detect UXS1 in at least one of: Use in the manufacture and/or screening of a product for diagnosis or co-diagnosis of metformin therapy sensitivity in patients with lung adenocarcinoma; The application in preparing and/or screening the products for monitoring the curative effect of the lung adenocarcinoma patients; use in the preparation and/or screening of a product for evaluation of metformin resistance in patients with lung adenocarcinoma.
  2. 2. The use according to claim 1, wherein the substance for detecting UXS1 is selected from the group consisting of a substance for detecting UXS protein or mRNA thereof, and wherein the substance for detecting UXS protein or mRNA thereof comprises any reagent required for detecting UXS protein or mRNA expression levels in tumor tissue by immunohistochemistry or qRT-PCR.
  3. 3. Use of UXS1 as a target or UXS1 inhibitor for the manufacture and/or screening of a medicament for the treatment of sensitivity to metformin therapy in a patient suffering from lung adenocarcinoma, said UXS inhibitor comprising a substance which reduces the amount of UXS1 protein expression or UXS protein content or protein activity, or a substance which inhibits UXS gene expression.
  4. 4. The use according to claim 3, wherein the UXS inhibitor is plantain D or a pharmaceutically acceptable salt or a structurally modified derivative thereof.
  5. 5. The use according to claim 4, wherein the structurally modified derivative of UXS inhibitor is an acetylated, glycosylated or sulphonated derivative of plantain.
  6. 6. A method of screening a pharmaceutical composition for the treatment of sensitivity to metformin therapy in a patient suffering from lung adenocarcinoma, said method comprising the steps of: determining a target point based on a molecular mechanism and a regulation and control path, wherein the target point is UXS1; Obtaining candidate compounds through virtual screening and experimental screening of a compound library; The candidate compound is used in combination with metformin to determine the final pharmaceutical composition.
  7. 7. Use of UGDH a sulfation level controlling agent for the preparation and/or screening of a medicament for the treatment of metformin in a lung adenocarcinoma patient, said UGDH sulfation level controlling agent being an agent which reduces the sulfation modification site of UGDHS 476.
  8. 8. A pharmaceutical composition for treating sensitivity to metformin therapy in a patient suffering from lung adenocarcinoma, comprising an effective dose of metformin, the UXS inhibitor of any one of claims 3 to 5 and/or the UGDH sulfation level regulating agent of claim 6.
  9. 9. The pharmaceutical composition of claim 8, wherein the effective dose of metformin is from 0.5 to 2 g/day and the effective dose of the UXS inhibitor plantain D is from 0.1 to 10 mg kg/day.
  10. 10. Use of a pharmaceutical composition according to claim 9 in at least one of the following: Use in the manufacture and/or screening of a product for diagnosis or co-diagnosis of metformin therapy sensitivity in patients with lung adenocarcinoma; The application in preparing and/or screening the products for monitoring the curative effect of the lung adenocarcinoma patients; use in the preparation and/or screening of a product for evaluation of metformin resistance in patients with lung adenocarcinoma.

Description

Use of UXS1 as a biomarker or for detecting UXS1 and pharmaceutical compositions Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of UXS to serving as a biomarker or a substance for detecting UXS1 and a pharmaceutical composition. Background According to Global cancer statistics (Global CANCER STATISTICS 2024) and the report of the incidence and mortality of cancer in China, which is published by the China national cancer center in 2024, the incidence and mortality of lung cancer in China are high, and the public health is seriously threatened. Among them, lung adenocarcinoma is currently the most predominant pathological subtype of lung cancer, and occupies nearly two thirds of all new lung cancer cases each year. Lung adenocarcinoma is active in metabolism, rapid in proliferation and easy to relapse and transfer, so that the treatment effect and prognosis of the existing lung adenocarcinoma patients are still not ideal, and the overall survival rate of 5 years is only about 30%. Therefore, further exploration of the metabolic characteristics of lung adenocarcinoma is of great significance in finding a more accurate and effective treatment scheme of lung adenocarcinoma, reducing recurrence and metastasis and further improving prognosis of patients. The metformin research contradicts that in vitro experiments prove that the metformin can inhibit the proliferation of tumor cells through AMPK/mTOR and other channels, but clinical queue research shows that the metformin has no statistical significance on the improvement of the survival time of patients with lung adenocarcinoma. Recent studies reported UGDH/UXS that "pool model" -UGDH "was used as a" tap "and was abundantly expressed in cancer cells, thus promoting UDPGA production. Excessive UDPGA would destroy the morphology and function of the golgi apparatus and would produce a "poisoning" effect on cancer cells, while UXS is a metabolic enzyme that is localized on the golgi apparatus and acts as a "drain" to convert toxic UDPGA into non-toxic UDP-xylose (UDP-Xyl) thereby avoiding UDPGA accumulation and damage to cells. No targeted small molecule inhibitors of UXS's 1 have been reported. Tumor immunity is an important development direction in the current tumor treatment field, and the body recognizes, responds and kills tumor cells by utilizing immune response. However, during the development of tumors, tumor cells adapt to the changing immune microenvironment in various ways and eventually overcome the immune system's attack, thereby achieving continued growth. The metabolites UDPG, UDPGA, etc. in the uronic acid pathway are reported in the literature to have a close relationship with immunity. UDPG is a natural agonist of the G protein-coupled P2Y14 receptor, present in the immune system, and promotes neutrophil recruitment, resulting in the release of pro-inflammatory chemokines. UDPGA accumulation can significantly alter the function and morphology of the golgi apparatus, ultimately contributing to tumor cell apoptosis. And the antigen released after the tumor cell apoptosis can activate the immune system of the organism and trigger specific immune response. Thus, targeting UXS1 in combination with metformin may have an important impact on the immune microenvironment through the metabolites of the uronic acid pathway. Disclosure of Invention In view of the drawbacks of the prior art, it is an object of the present invention to provide the use of UXS1 as a biomarker or to detect UXS substances as well as pharmaceutical compositions. In order to achieve the above object, the present invention proposes the following technical solutions: in a first aspect, the invention proposes the use of UXS1 as a biomarker or a substance for detecting UXS1 in at least one of: Use in the manufacture and/or screening of a product for diagnosis or co-diagnosis of metformin therapy sensitivity in patients with lung adenocarcinoma; The application in preparing and/or screening the products for monitoring the curative effect of the lung adenocarcinoma patients; use in the preparation and/or screening of a product for evaluation of metformin resistance in patients with lung adenocarcinoma. Preferably, the agent for detecting UXS1 is selected from the group consisting of agents for detecting UXS1 protein or mRNA thereof, and the agent for detecting UXS protein or mRNA thereof includes any agent required for detecting UXS protein or mRNA expression levels in tumor tissue by immunohistochemistry or qRT-PCR. In a second aspect, the invention provides the use of UXS a as a target or UXS a inhibitor in the manufacture and/or screening of a medicament for the treatment of sensitivity to metformin therapy in a patient suffering from lung adenocarcinoma, said UXS a inhibitor comprising a substance which reduces the amount of UXS a protein expression or UXS a protein content or protein activity or a substance wh