Baclofen boosts immunotherapy use in triple-negative breast cancer
By combining baclofen with PD-L1 antibodies, the PD-L1 protein level in breast cancer cells was enhanced, and the problem of limited treatment for triple-negative breast cancer was solved, the effect of immunotherapy was significantly improved, and effective inhibition of triple-negative breast cancer cells was achieved.
Patent Information
- Application Number
- CN202310046483.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-01-31
- Publication Date
- 2025-05-06
- Estimated Expiration
- 2043-01-31
AI Technical Summary
The treatment strategies for triple-negative breast cancer are very limited, and the existing immunotherapy is not effective, and it is urgent to find effective therapeutic drugs.
Baclofen and PD-L1 antibody are used to enhance the PD-L1 protein level in breast cancer cells, thereby preparing drugs for the treatment of triple-negative breast cancer, significantly improving the effectiveness of immunotherapy.
In mice, baclofen and PD-L1 antibody were used in combination to significantly inhibit the growth of triple-negative breast cancer cells, improved the efficacy of immunotherapy, and was simple to operate and inexpensive.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of tumor treatment, and specifically relates to the use of baclofen in promoting immunotherapy of triple-negative breast cancer. Background Art
[0002] Breast cancer is the most common type of cancer in women, and most early, non-metastatic breast cancers (70-80%) are curable. Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers and is characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) molecular markers. It has the worst prognosis within 3 to 5 years of initial diagnosis and the highest risk of distant recurrence. The treatment strategies for TNBC are very limited, and until 2019, TNBC treatment was still limited to chemotherapy. In the past two years, immunotherapy combined with chemotherapy has also been used to treat TNBC, showing good application prospects, but there are still a large number of TNBC patients who do not respond to immunotherapy. Therefore, the treatment of TNBC is still a difficult problem to be solved clinically, and there is an urgent need to find effective therapeutic drugs. Summary of the invention
[0003] The purpose of the present invention is to provide a new strategy for the treatment of triple negative breast cancer (TNBC), and it is found that the combination of baclofen and PD-L1 antibody has a significant inhibitory effect on mouse TNBC and can promote the efficacy of TNBC immunotherapy. The method is simple to operate and low in cost.
[0004] The first aspect of the present invention discloses the use of baclofen in the preparation of an immunological drug for treating triple-negative breast cancer.
[0005] In some embodiments, experiments have found that baclofen can enhance the protein level of PD-L1 in breast cancer cells. Therefore, baclofen can be used to prepare PD-L1 enhancer drugs for immunotherapy of triple-negative breast cancer.
[0006] The second aspect of the present invention discloses the use of baclofen in combination with PD-L1 antibody in the preparation of a drug for treating triple-negative breast cancer.
[0007] In some embodiments, in vitro experiments found that baclofen used alone did not affect the proliferation of triple-negative breast cancer cells; in animal experiments, baclofen used alone had no inhibitory effect on triple-negative breast cancer cells in the animal model, while when baclofen was used in combination with PD-L1 antibodies, it was found that compared with the use of PD-L1 antibodies alone, the inhibitory effect on triple-negative breast cancer cells in the animal model was better.
[0008] Preferably, the pharmaceutical composition for treating triple-negative breast cancer comprises baclofen, PD-L1 antibody and a pharmaceutically acceptable carrier.
[0009] The dosage form of the above-mentioned pharmaceutical composition can be tablets, capsules, powders, granules or oral liquids; all of which can play a good inhibitory effect on triple-negative breast cancer cells.
[0010] Compared with the prior art, the present invention has the following advantages:
[0011] 1) Promote immunotherapy for triple-negative breast cancer: In mice, the use of PD-L1 antibodies alone inhibited the growth of tumor cells compared with the control group or baclofen alone, but the combination of baclofen and PD-L1 antibodies significantly enhanced the effect of PD-L1 antibody treatment.
[0012] 2) Baclofen is a clinical drug. This study found that it has new functions and is low in price, which is an “old drug with new uses.” BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Figure 1 This is a diagram showing the effect of baclofen on enhancing the protein level of PD-L1 in triple-negative breast cancer cells.
[0014] Figure 2 This is a diagram showing the proliferation effect of triple-negative breast cancer cells when baclofen is used alone.
[0015] Figure 3 This is a diagram showing how baclofen enhances the immunotherapy effect of triple-negative breast cancer in mice. This is a diagram showing how the combined use of baclofen and PD-L1 antibody promotes the effect of PD-L1 antibody immunotherapy. DETAILED DESCRIPTION
[0016] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.
[0017] The PD-L1 antibody described in the embodiment is InVivoMAb anti-mouse PD-L1 (CD274), which is a commonly used PD-L1 antibody in the art. Those skilled in the art may also select other PD-L1 antibodies for use in combination with baclofen according to clinical or experimental needs.
[0018] Example 1 Baclofen enhances PD-L1 protein levels in triple-negative breast cancer cells
[0019] The human breast cancer MDA-MB-231 cells were treated with baclofen-containing cell culture medium at concentrations of 0 μM, 25 μM, 50 μM, 100 μM, 200 μM and 300 μM, and the protein level of PD-L1 in the cells was detected by Western blot at 48 hours. Figure 1 As shown in A.
[0020] Human breast cancer MDA-MB-231 cells were treated with cell culture medium containing 100 μM baclofen at a time gradient of 0 h, 3 h, 6 h, 12 h, and 24 h, and the protein level of PD-L1 in the cells was detected by Western blot. Figure 1 As shown in B.
[0021] Example 2 Proliferation of triple-negative breast cancer cells when baclofen is used alone.
[0022] Human breast cancer MDA-MB-231 cells were treated with cell culture medium containing 100 μM baclofen. After 15 days, cell proliferation was detected by clone formation assay. It was found that baclofen did not affect cell proliferation in vitro. The results are as follows Figure 2 shown.
[0023] Example 3 The combination of baclofen and PD-L1 effectively inhibits the growth of triple-negative breast cancer in mice.
[0024] a) Construction of triple-negative breast cancer model in mice. 5 4T1 mouse triple-negative breast cancer cells were injected into the mammary fat pad of female BALB / c mice, and solid breast tumors grew after about 7 days.
[0025] b) The experimental mice were divided into four groups: control group, baclofen alone group, PD-L1 antibody alone group, and baclofen and PD-L1 antibody combination group;
[0026] c) Administration: Baclofen was intraperitoneally injected at a dose of 25 mg / kg per day, and PD-L1 antibody was intraperitoneally injected once every three days per mouse at a dose of 100 μg;
[0027] d) Tumor volume detection: Starting from the inoculation of the tumor, every three days, the length and width of the tumor in the mammary gland of the mouse were measured with a vernier caliper, and the volume was calculated;
[0028] e) Tumor size of tumor-bearing mice, tumor volume graph, mouse tumor growth curve graph, tumor mass statistics graph and tumor tissue immunohistochemistry graph Figure 3 shown.
[0029] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.
Claims
1. Application of baclofen combined with PD-L1 antibody in the preparation of immune drugs for the treatment of triple-negative breast cancer; The baclofen described herein is used as a PD-L1 enhancer in the drug.