Application of combination of paclitaxel and TREM2 inhibitor in preparation of breast cancer treatment medicine

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to application of paclitaxel combined with a TREM2 inhibitor in preparation of a medicine for treating breast cancer. The TREM2 inhibitor product comprises RNA (Ribonucleic Acid) interference molecules aiming at a TREM2 gene, antisense oligonucleotide, a small molecule inhibitor, a substance for implementing lentivirus infection or gene knockout, and a specific antibody aiming at a TREM2 protein. The small molecule inhibitor comprises TREM2 (Trusted Receptor Mode 2)-IN-1. It is found for the first time that the paclitaxel combined with the TREM2 inhibitor can more effectively inhibit breast cancer in-situ growth and pulmonary metastasis. The research result of the invention can provide technical support for prevention and treatment of breast cancer, and has important application value.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to the use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer. Background Art

[0002] Breast cancer is the most common cancer in women worldwide, with metastasis being the leading cause of breast cancer-related death. Neoadjuvant chemotherapy is usually used in most breast cancer patients, but most patients after chemotherapy are prone to tumor recurrence and metastasis due to residual tumors after chemotherapy, tumor-initiating stem cells (TICs), and genetic characteristics of cancer cells. Tumor-promoting host cell secretions such as cytokines, growth factors, extracellular matrix (ECM) proteins, and extracellular vesicles (EVs) have become important regulators of cancer progression after treatment. Preclinical studies have reported that chemotherapy drugs such as paclitaxel (PTX) and doxorubicin (DOX), which are commonly used in the treatment of breast cancer, promote the invasion and metastasis of cancer cells in primary tumors.

[0003] Paclitaxel (PTX) is a commonly used first-line chemotherapy drug for the treatment of various cancers. Although it can be used for breast cancer before surgery (neoadjuvant therapy) or after surgery (adjuvant therapy), it has been reported that paclitaxel has a metastatic effect in mouse models. Summary of the invention

[0004] In order to solve the above technical problems, the present invention first provides the use of paclitaxel combined with TREM2 inhibitor in the preparation of breast cancer treatment drugs.

[0005] In some embodiments of the present invention, although paclitaxel alone can inhibit tumor growth in breast cancer mice, it increases breast cancer lung metastasis. Although TREM2 inhibitors alone can inhibit breast cancer lung metastasis in breast cancer mice, the effect of inhibiting tumor growth is limited. Paclitaxel combined with TREM2 inhibitors to treat breast cancer mice can significantly inhibit tumor growth and significantly inhibit breast cancer lung metastasis, indicating that paclitaxel and TREM2 inhibitors produce a synergistic effect.

[0006] Furthermore, the TREM2 inhibitors include RNA interference molecules, antisense oligonucleotides, small molecule inhibitors targeting the TREM2 gene, substances for implementing lentiviral infection or gene knockout, and antibodies specific to the TREM2 protein.

[0007] Furthermore, the small molecule inhibitor includes TREM2-IN-1.

[0008] Furthermore, the application is the use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for inhibiting the in situ growth and lung metastasis of breast cancer.

[0009] Furthermore, the paclitaxel and the TREM2 inhibitor are administered simultaneously or continuously in any order.

[0010] Furthermore, the paclitaxel, TREM2 inhibitor and carrier or excipient are mixed to prepare a pharmaceutically acceptable dosage form.

[0011] Furthermore, the drug is an oral preparation or an injectable preparation.

[0012] Furthermore, the oral preparation is a tablet, capsule, granule, sustained-release preparation or pill.

[0013] Furthermore, the injection preparation is in the form of a solution or a suspension.

[0014] Secondly, the present invention also provides a drug for treating breast cancer, the active ingredients of which are the paclitaxel and the TREM2 inhibitor; the drug is used to inhibit the in situ growth and lung metastasis of breast cancer.

[0015] The present invention has the following beneficial effects:

[0016] The present invention observed the effects of paclitaxel and TREM2 inhibitor on breast cancer growth and lung metastasis in an in vitro migration experiment and an in vivo transplanted tumor model. The results showed that paclitaxel and TREM2 inhibitor had significant breast cancer treatment effects and could effectively inhibit the growth of in situ breast cancer in mice and inhibit breast cancer lung metastasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The figure shows the effect of each group on the migration of Py8119 breast cancer cells.

[0018] Figure 2 Figure 1 is the effect of each group on the tumor in Py8119 breast cancer transplanted mice. Figure A is a photograph of the tumor in each group, Figure B is a statistical graph of the tumor weight in each group, and each column in each row of Figure A is the result of the parallel experiment of this group.

[0019] Figure 3 The effects of each group on lung metastasis in Py8119 breast cancer tumor-bearing mice. DETAILED DESCRIPTION

[0020] The present invention is described in detail below in conjunction with the accompanying drawings and specific examples, but should not be construed as limiting the present invention. Unless otherwise specified, the technical means used in the following examples are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0021] Example 1: Effect of paclitaxel combined with TREM2 inhibitor on breast cancer cell migration

[0022] The Transwell migration system (Py8119 cells in the upper chamber and drug-containing culture medium in the lower chamber) was divided into 4 groups, including DMSO group (DMSO was purchased from Sigma, 276855, as control), paclitaxel alone group (paclitaxel was purchased from MCE, HY-B0015), TREM2 inhibitor TREM2-IN-1 alone group (TREM2-IN-1 was purchased from MCE, HY-160421), and paclitaxel and TREM2 inhibitor TREM2-IN-1 combined administration group.

[0023] DMSO group: The same concentration as that of the paclitaxel alone group was added to the culture medium of the lower chamber. After 48 hours of culture, the upper chamber was stained with crystal violet and the cells were counted to observe the migration.

[0024] Paclitaxel alone administration group: Paclitaxel was added to the culture medium of the lower chamber at a dose of 20 nM per well. After 48 h of culture, the upper chamber was stained with crystal violet and the cells were counted to observe the migration.

[0025] TREM2 inhibitor TREM2-IN-1 single administration group: TREM2-IN-1 was added to the culture medium of the lower chamber at a dose of 5 nM per well. After 48 hours of culture, the upper chamber was stained with crystal violet and the cells were counted to observe the migration.

[0026] Paclitaxel and TREM2 inhibitor TREM2-IN-1 combined administration group: Paclitaxel was added to the culture medium of the lower chamber at a dose of 20 nM per well and 5 nM per well. After 48 h of culture, the upper chamber was stained with crystal violet and the cells were counted to observe the migration.

[0027] The results are as follows Figure 1 As shown, the number of cells migrating to the upper chamber in the paclitaxel alone administration group and the TREM2 inhibitor TREM2-IN-1 alone administration group was significantly reduced compared with the DMSO group, and the tumor cell migration inhibition in the combined administration group was more significant than that in the DMSO group and the single administration group, indicating that the strategy of combining paclitaxel with a TREM2 inhibitor provided by the present invention can effectively inhibit tumor cell migration.

[0028] Example 2: Effect of paclitaxel combined with TREM2 inhibitor on in situ growth and lung metastasis of breast cancer

[0029] The Py8119 breast cancer tumor-bearing mouse model (Southern Model Organisms Corporation) was randomly divided into 4 groups for intraperitoneal injection of paclitaxel and intratumoral injection of the TREM2 inhibitor TREM2-IN-1. The groups were DMSO group (DMSO was purchased from Sigma, 276855, as control), paclitaxel alone treatment group (paclitaxel was purchased from MCE, HY-B0015), TREM2 inhibitor TREM2-IN-1 alone treatment group (TREM2-IN-1 was purchased from MCE, HY-160421), and paclitaxel and TREM2 inhibitor TREM2-IN-1 combined treatment group.

[0030] DMSO group: DMSO was injected into Py8119 tumor-transplanted mice at the same dose as the paclitaxel alone group, once every two days for a total of five times, after which the tumor and lung were removed for observation;

[0031] Paclitaxel alone treatment group: Paclitaxel was injected into Py8119 tumor-bearing mice at a dose of 8 mg / kg per mouse, once every two days for a total of five times, after which the tumor and lung were removed for observation;

[0032] TREM2 inhibitor TREM2-IN-1 alone treatment group: TREM2-IN-1 was injected into Py8119 tumor-transplanted mice at a dose of 1 mg / kg per mouse, once every two days for a total of five times, after which the tumors and lungs were removed for observation;

[0033] Paclitaxel and TREM2 inhibitor TREM2-IN-1 combined treatment group: Paclitaxel at a dose of 8 mg / kg and TREM2-IN-1 at a dose of 1 mg / kg were injected into Py8119 tumor-transplanted mice once every two days for a total of five times, after which the tumors and lungs were removed for observation;

[0034] The results are as follows Figure 2 and Figure 3 As shown, the tumor weight of Py8119 tumor-transplanted mice in the paclitaxel monotherapy group and the TREM2 inhibitor TREM2-IN-1 monotherapy group was significantly reduced compared with the DMSO group, and the tumor inhibition in the combined treatment group was more significant than that in the control group and the monotherapy group; in addition, compared with the DMSO group, the paclitaxel monotherapy group had increased tumor lung metastasis, compared with the DMSO group, the TREM2 inhibitor TREM2-IN-1 monotherapy group had significantly reduced tumor lung metastasis, compared with the DMSO group and the paclitaxel monotherapy group, the combined treatment group had significantly reduced tumor lung metastasis, and there was no significant difference in breast cancer lung metastasis between the combined treatment group and the TREM2 inhibitor TREM2-IN-1 monotherapy group, indicating that the strategy of paclitaxel combined with TREM2 inhibitor provided by the present invention can effectively inhibit tumor in situ growth and lung metastasis.

[0035] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0036] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. Application of paclitaxel combined with TREM2 inhibitor in the preparation of drugs for the treatment of breast cancer.

2. The use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer according to claim 1, characterized in that: The TREM2 inhibitors include RNA interference molecules, antisense oligonucleotides, small molecule inhibitors targeting the TREM2 gene, substances for implementing lentiviral infection or gene knockout, and antibodies specific to the TREM2 protein.

3. The use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer according to claim 2, characterized in that: The small molecule inhibitors include TREM2-IN-1.

4. The use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer according to claim 1, characterized in that: The application is the use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for inhibiting the in situ growth and lung metastasis of breast cancer.

5. The use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer according to claim 1, characterized in that: The paclitaxel, TREM2 inhibitor and carrier or excipient are mixed to prepare a pharmaceutically acceptable dosage form.

6. The use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer according to claim 5, characterized in that: The medicine is an oral preparation or an injection preparation.

7. The use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer according to claim 6, characterized in that: The oral preparation is a tablet, a capsule, a granule, a sustained-release preparation or a dripping pill.

8. The use of paclitaxel combined with a TREM2 inhibitor in the preparation of a drug for treating breast cancer according to claim 7, characterized in that: The injection preparation is in the form of a solution or a suspension.

9. A drug for treating breast cancer, characterized in that: The active ingredients are paclitaxel and TREM2 inhibitor as described in claim 1; the drug is used to inhibit the in situ growth and lung metastasis of breast cancer.

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