Use of an EZH2 inhibitor in the manufacture of a medicament for preventing and / or treating lymphedema

Abstract

The present application relates to the use of an EZH2 inhibitor in the preparation of a drug for preventing and / or treating lymphedema. The present application first discovers and proves by experiments that the EZH2 inhibitor can significantly inhibit the skin fibrosis symptoms of a lymphedema subject, thereby effectively retarding the progression of lymphedema, and further achieving the purpose of alleviating, relieving and / or improving lymphedema and its related symptoms. In addition, the inventors have also found that the EZH2 inhibitor has good drug safety. Therefore, the EZH2 inhibitor is expected to become a candidate therapeutic drug for lymphedema, and has great clinical application prospects and value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the use of EZH2 inhibitors in the preparation of medicaments for the prevention and / or treatment of lymphedema. Background Technology

[0002] Lymphedema is a chronic, progressive, and incurable disease caused by dysfunction of the lymphatic system. It is classified into primary and secondary lymphedema. Primary lymphedema is relatively rare, while lymphedema following cancer treatment is a major cause of secondary lymphedema. Lymphedema severely affects the shape and function of the limbs, significantly reducing patients' quality of life and easily triggering psychological problems such as anxiety and depression. Early-stage lymphedema mainly manifests as edema; as the disease progresses, late-stage lymphedema is characterized by chronic inflammation, fat deposition, and tissue fibrosis. Because lymph fluid is rich in macromolecules such as proteins and hyaluronic acid, it stimulates fibroblasts to synthesize collagen. When excessive collagen fibers are deposited, the skin tissue hardens and thickens, leading to increased limb size and deformities. This not only further weakens the transport capacity of the lymphatic system but also makes the skin and lymphatic vessels more susceptible to infection. Recurrent cellulitis can, in turn, worsen lymphedema, creating a vicious cycle. Therefore, antifibrotic therapy is crucial throughout the entire treatment process for lymphedema.

[0003] In the treatment of lymphedema, early-stage patients can undergo conservative treatment, namely, comprehensive anti-edema therapy, which includes postural drainage, pressure bandaging, massage, etc. However, this therapy has significant drawbacks. It requires patients to adhere to daily care, demanding a high degree of patient compliance, and its treatment effect is limited. In particular, for patients with moderate to severe or chronic edema, the effect is difficult to sustain, and it is not very effective in inhibiting tissue fibrosis.

[0004] Drug therapy is also a common treatment for lymphedema. For example, antibiotics can relieve acute inflammation, but lack long-term efficacy; diuretics can alleviate acute edema symptoms, but they carry the risk of side effects, and long-term use may cause electrolyte imbalances. More importantly, existing drug treatments do not target the tissue fibrosis process, and there are currently no available anti-lymphedema fibrosis drugs on the market.

[0005] Lymphedema can also be treated with physical therapy methods, including baking therapy, soaking, wet compresses, and intermittent barotherapy. However, the effectiveness of these methods is highly dependent on continuous treatment; once interrupted, the condition is very likely to relapse, and the treatment effect is poor for patients with severe skin fibrosis or in the late stage of the disease.

[0006] Surgical treatment is also an option for treating lymphedema, such as lymphangiovenous anastomosis and tissue resection. Among them, lymphangiovenous anastomosis requires ultra-microsurgical equipment and experienced doctors, which limits the widespread application of this technique; while tissue resection can remove hyperplastic fibrous and fatty tissue, it may damage normal tissue during the operation, and the probability of postoperative recurrence or infection is relatively high.

[0007] Therefore, current treatments for lymphedema have certain limitations, and there is an urgent need to develop new and effective treatments to improve the condition of patients with lymphedema.

[0008] Histone methyltransferase EZH2 (Enhancer of zeste homolog 2) is a core subunit of the polycomb repressive complex 2 (PRC2). PRC2 can trimethylate the lysine 27th residue (H3K27) of histone H3 in the promoter region of target genes, thereby repressing the transcription of the target genes. Currently, two EZH2 inhibitors designed targeting the active site of the EZH2 enzyme—EPZ6438 and GSK126—have been developed, both of which can specifically inhibit the methyl transfer function of EZH2. EPZ6438 (Tazemetostat) is the world's first approved EZH2 inhibitor and has been used to treat epithelioid sarcoma and follicular lymphoma; GSK126 has also shown significant inhibitory effects on lung cancer cell proliferation and apoptosis in preclinical studies. Summary of the Invention

[0009] Purpose of the invention

[0010] In view of the needs or deficiencies existing in the prior art, the purpose of this invention is to provide the use of EZH2 inhibitors in the preparation of medicaments for the prevention and / or treatment of lymphedema.

[0011] Solution

[0012] To achieve the above objectives, the present invention adopts the following technical solution:

[0013] In a first aspect, the present invention provides the use of EZH2 inhibitors in the preparation of medicaments for the prevention and / or treatment of lymphedema.

[0014] In a feasible implementation, the EZH2 inhibitor is selected from any one or more of the following: EPZ6438, GSK126, and their pharmaceutically acceptable salts.

[0015] In a feasible implementation, the lymphedema is primary lymphedema and / or secondary lymphedema.

[0016] Preferably, the lymphedema is secondary lymphedema following cancer surgery.

[0017] In a feasible implementation, the treatment of lymphedema includes reducing, alleviating, and / or improving lymphedema or its symptoms.

[0018] Preferably, the symptoms of lymphedema that are relieved, alleviated, and / or improved are those of skin fibrosis.

[0019] In feasible implementation schemes, the subjects are mammals;

[0020] And / or, in the medicament for preventing and / or treating lymphedema, the EZH2 inhibitor is the sole active ingredient or one of the active ingredients;

[0021] And / or, the drug may also include a pharmaceutically acceptable carrier and / or excipient.

[0022] In feasible implementation schemes, the subjects are humans;

[0023] And / or, for human subjects, the preventive effective dose of the EZH2 inhibitor is 1-3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutic effective dose is 3-5 mg / kg body weight, preferably 4 mg / kg body weight. For example, in a feasible embodiment, for lymphedema in human subjects, the preventive effective dose of EPZ6438 or GSK126 is 1-3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutic effective dose is 3-5 mg / kg body weight, preferably 4 mg / kg body weight.

[0024] In a feasible implementation, the drug is selected from the following dosage forms: oral dosage form, injectable dosage form, implantable dosage form and / or transdermal dosage form.

[0025] Preferably, the oral dosage form is selected from: tablets, capsules, granules, oral liquids, pills, powders, tinctures, and syrups;

[0026] Preferably, the dosage form for injection is an injection solution or a powder for injection;

[0027] Preferably, the implantable drug delivery dosage form is selected from: implantable tablets, implantable rods, implantable microspheres and / or implantable nanoparticles;

[0028] Preferably, the transdermal dosage form is selected from ointments, creams, gels, patches, and / or aerosols.

[0029] In a second aspect, the present invention provides a method for preventing and / or treating lymphedema, the method comprising: administering a preventive and / or therapeutically effective amount of an EZH2 inhibitor to a subject in need.

[0030] In a feasible implementation, the EZH2 inhibitor is selected from any one or more of the following: EPZ6438, GSK126, and their pharmaceutically acceptable salts.

[0031] In a feasible implementation, the lymphedema is primary lymphedema and / or secondary lymphedema.

[0032] Preferably, the lymphedema is secondary lymphedema following cancer surgery.

[0033] In a feasible implementation, the treatment of lymphedema includes reducing, alleviating, and / or improving lymphedema or its symptoms.

[0034] Preferably, the symptoms of lymphedema that are relieved, alleviated, and / or improved are those of skin fibrosis.

[0035] In a feasible implementation, the EZH2 inhibitor is provided in the form of a pharmaceutical formulation in which the EZH2 inhibitor is the sole active ingredient or one of the active ingredients; in addition to the EZH2 inhibitor, the pharmaceutical formulation also includes a pharmaceutically acceptable carrier and / or excipient.

[0036] In a feasible implementation, the pharmaceutical formulation is selected from the following dosage forms: oral dosage form, injectable dosage form, implantable dosage form, and / or transdermal dosage form.

[0037] Preferably, the oral dosage form is selected from: tablets, capsules, granules, oral liquids, pills, powders, tinctures, and syrups;

[0038] Preferably, the dosage form for injection is an injection solution or a powder for injection;

[0039] Preferably, the implantable drug delivery dosage form is selected from: implantable tablets, implantable rods, implantable microspheres and / or implantable nanoparticles;

[0040] Preferably, the transdermal dosage form is selected from ointments, creams, gels, patches, and / or aerosols.

[0041] In a feasible implementation, the subject is a human;

[0042] For human subjects, preferably, the preventive effective dose of the EZH2 inhibitor is 1-3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutic effective dose is 3-5 mg / kg body weight, preferably 4 mg / kg body weight. For example, in a feasible embodiment, for lymphedema in human subjects, the preventive effective dose of EPZ6438 or GSK126 is 1-3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutic effective dose is 3-5 mg / kg body weight, preferably 4 mg / kg body weight.

[0043] The term "effective amount" refers to the quantity or dose of an active ingredient administered to a subject, whether once or multiple times, to provide the intended effect for the prevention or treatment of that subject. The effective amount can be determined by a diagnostic physician skilled in the art based on known techniques and observations in similar circumstances. In determining the effective amount or dose of the administered active ingredient, the participating diagnostic physician should consider a variety of factors, including but not limited to: the species of mammal; size, age, and general health; the specific disease involved; the extent or severity of the disease; the individual patient's response; the specific compound administered; the administration method; the bioavailability of the administered formulation; the chosen dosing regimen; the use of concomitant drug therapies; and other relevant circumstances.

[0044] Beneficial effects

[0045] This invention provides the use of EZH2 inhibitors in the preparation of medicaments for the prevention and / or treatment of lymphedema. The inventors have experimentally demonstrated that EZH2 inhibitors can significantly inhibit the degree of skin fibrosis in patients with lymphedema, manifested in: a significant reduction in skin thickness, epidermal thickness, and fibroadipose tissue thickness, and a significant reduction in the degree of fibrosis. This effective inhibition of skin fibrosis can effectively halt the progression of lymphedema in patients, thereby achieving the goal of reducing, alleviating, and / or improving lymphedema and its related symptoms.

[0046] Furthermore, safety is a key consideration in drug application. The research in this invention found that treating mice with lymphedema using EZH2 inhibitors did not produce any significant side effects on their internal organs, which fully demonstrates that EZH2 inhibitors have good safety profiles.

[0047] In summary, given the significant efficacy and excellent safety profile of EZH2 inhibitors in inhibiting lymphedema and skin fibrosis, they have great potential and broad application prospects as a treatment for lymphedema, making them highly promising candidate drugs. Attached Figure Description

[0048] One or more embodiments are illustrated by way of example with reference to the accompanying drawings, and these illustrative examples are not intended to limit the embodiments. The term "illustrative" as used herein means "serving as an example, embodiment, or illustration." Any embodiment illustrated herein as "illustrative" is not necessarily to be construed as superior to or better than other embodiments.

[0049] Figure 1 The staining results of affected skin tissue from patients with lymphedema versus healthy controls are shown. Figure A shows the hematoxylin-eosin staining results, Figure B shows the Sirius red staining results, and Figure C shows the Masson staining results.

[0050] Figure 2 The results show the detection of EZH2 and H3K27me3 expression levels in skin tissues of patients with lymphedema versus healthy controls using immunofluorescence assay. Figure A shows the results of immunofluorescence staining using an antibody against EZH2; Figure B is a bar chart summarizing the results of Figure A; Figure C shows the results of immunofluorescence staining using an antibody against H3K27me3; and Figure D is a bar chart summarizing the results of Figure C. * indicates P < 0.05 compared to the control.

[0051] Figure 3 This is a schematic diagram of the process of treating a mouse model of lower limb lymphedema with an EZH2 inhibitor, as described in Example 2.

[0052] Figure 4 The staining results of skin tissues from mice in each experimental group in Example 2 are shown. Figure A shows the hematoxylin-eosin staining results, Figure B shows the Sirius red staining results, and Figure C shows the Masson staining results.

[0053] Figure 5 The results of skin thickness (A), epidermal thickness (B), fibrofat thickness (C), and quantitative fibrosis (D) of mice in each experimental group in Example 2 are shown; where * indicates that P < 0.05 between the two specified groups; ** indicates that P < 0.01 between the two specified groups; *** indicates that P < 0.001 between the two specified groups.

[0054] Figure 6 The results of hematoxylin-eosin staining of the heart (A), liver (B), spleen (C), lung (D), kidney (E), and small intestine (F) of mice in each experimental group in Example 3 are shown. Detailed Implementation

[0055] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with embodiments. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0056] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, materials, elements, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0057] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0058] The present invention will be further described in detail below through examples.

[0059] Unless otherwise specified, the materials, animals, reagents, etc. used in the following embodiments are commercially available.

[0060] Example 1: Structural characterization of skin tissue and expression of EZH2 and H3K27me3 proteins in patients with lymphedema

[0061] 1) The tissue structure and fibrosis of the skin in patients with lymphedema

[0062] Discarded skin tissue samples were collected from patients with secondary lymphedema following cancer surgery (i.e., skin tissue affected by lymphedema) as the experimental group. Discarded skin tissue samples were collected from healthy subjects after plastic surgery (i.e., healthy control skin tissue) as the control group. The collected skin tissues from both the experimental and control groups were fixed in 4% paraformaldehyde for 48 hours, followed by dehydration using graded ethanol solutions. After dehydration, the tissues were embedded in paraffin and sectioned. Subsequently, the tissue sections were stained using a hematoxylin-eosin staining kit, a modified Sirius red staining kit, and a Masson's trichrome staining kit (all purchased from Beijing Solarbio Science & Technology Co., Ltd., catalog numbers G1120, G1473, and G1340, respectively), according to the instructions of their respective kits, to assess changes in tissue structure and fibrosis.

[0063] The results of hematoxylin-eosin, Sirius red, and Masson staining are as follows: Figure 1Figures A, B, and C show that a large amount of fibrotic tissue is visible in the affected skin tissue of patients with lymphedema; in contrast, there is very little fibrotic tissue in the skin tissue of healthy controls.

[0064] 2) Expression of EZH2 and H3K27me3 in the skin tissue of patients with lymphedema

[0065] According to the standard immunofluorescence staining procedure, the affected skin tissues of lymphedema patients and healthy control skin tissues collected in 1) above were subjected to immunofluorescence staining using antibodies against EZH2 (Cell Signaling Technology, #5246, 1:200) and H3K27me3 (Cell Signaling Technology, #9733, 1:200), respectively.

[0066] Immunofluorescence staining results of antibodies against EZH2 are as follows: Figure 2 As shown in Figure A, the statistical results are as follows: Figure 2 As shown in Figure B. (From...) Figure 2 As shown in Figures A and B, compared with healthy control skin tissue, the expression level of EZH2 in the affected skin tissue of patients with lymphedema was significantly increased, by about 62 times.

[0067] Immunofluorescence staining results of antibodies against H3K27me3 are as follows: Figure 2 As shown in Figure C, the statistical results are as follows: Figure 2 As shown in Figure D. Figure 2 As shown in Figures C and D, the expression level of H3K27me3 in the affected skin tissue of patients with lymphedema was significantly increased by about 63 times compared with the skin tissue of healthy controls.

[0068] Example 2: EZH2 inhibitors can effectively alleviate skin fibrosis in a mouse model of lymphedema.

[0069] In this embodiment, male C57BL6 mice (purchased from Zhuhai Beston Biotechnology Co., Ltd.) around 8 weeks old and weighing 20-25g were used as experimental animals to investigate the therapeutic effects of EZH2 inhibitors EPZ6438 or GSK126 on lymphedema mice.

[0070] The C57BL6 mice used in this embodiment were purchased from Zhuhai Beston Biotechnology Co., Ltd., and the inhibitor drugs EPZ6438 and GSK126 were purchased from Selleck Chemicals. The catalog number of EPZ6438 is S7128 and the catalog number of GSK126 is S7061.

[0071] (1) Preparation of EPZ6438 injection, GSK126 injection and control injection

[0072] When preparing the injection solution, first dissolve the EPZ6438 or GSK126 drug powder in DMSO to prepare a stock solution with a concentration of 50 mg / mL; before use, add corn oil to the EPZ6438 or GSK126 stock solution to dilute it 10 times to prepare a solution with a concentration of 5 mg / mL, which is the EPZ6438 or GSK126 injection solution.

[0073] In addition, take DMSO, add corn oil and dilute it 10 times to prepare a control injection solution.

[0074] During injection, the injection volume was calculated based on the mouse's body weight. The dosage of EPZ6438 or GSK126 was 50 mg / kg body weight, while the dosage of the control injection was 10 mL / kg body weight (i.e., the injection volume per kilogram of mouse body weight was equivalent to that of EPZ6438 or GSK126 injection).

[0075] (2) Construction of a mouse model of lower limb lymphedema

[0076] Following the method for constructing and identifying a mouse lower limb lymphedema model described in the applicant's published article Chen, Z., et al., PPARγagonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα+mesenchymal cells. JCI insight, 2023.8(24), a mouse lower limb lymphedema model was constructed by surgically destroying the mouse lower limb lymphatic system (including removing the popliteal lymph nodes, superficial inguinal lymph nodes, deep inguinal lymph nodes, and femoral lymphatic vessels).

[0077] (3) Effects of EZH2 inhibitors EPZ6438 or GSK126 on lymphedema mice

[0078] The experimental groups and the treatment methods for each group are as follows:

[0079] 1) EPZ6438 treatment group: The mouse lower limb lymphedema model was constructed according to the method described in (2) above. On the 1st day and the 4th day after the operation, the EPZ6438 injection solution prepared in (1) above was injected into the peritoneum of the mice at a dose of 50 mg / kg body weight as subsequent treatment.

[0080] 2) GSK126 treatment group: The mouse lower limb lymphedema model was constructed according to the method described in (2) above. On the 1st day after surgery and the 4th day after surgery, the mice were injected intraperitoneally with the GSK126 injection solution prepared in (1) above at a dose of 50 mg / kg body weight as subsequent treatment.

[0081] 3) Lymphedema model group: The mouse lower limb lymphedema model was constructed according to the method described in (2) above. On the 1st day and the 4th day after surgery, the control injection prepared in (1) above was injected into the peritoneum of the mice at a dose of 10 mL / kg body weight as a subsequent treatment.

[0082] 4) Sham surgery group: The mouse skin was cut along the surgical path used to construct the mouse lower limb lymphedema model, the regional lymph nodes were fully exposed but the lymph node tissue was not removed, and then the mouse skin was sutured as in the lymphedema model. Then, on the 1st and 4th day after the operation, the control injection prepared in (1) above was injected into the mouse peritoneum at a dose of 10 mL / kg body weight as a follow-up treatment.

[0083] Each experimental group contained 6 mice. Skin tissue samples from the hind limbs of the mice in each group were collected on day 7 post-surgery for subsequent testing. A detailed flowchart of the above procedure can be found below. Figure 3 .

[0084] Next, following the method described in Example 1, the hind limb skin tissue of mice in each experimental group was prepared into tissue sections. Then, using the hematoxylin-eosin staining kit, the modified Sirius red staining kit, and the Masson trichrome staining kit, and according to the instructions of each kit, the hind limb skin tissue sections of mice in each experimental group were stained with hematoxylin-eosin, Sirius red, and Masson, respectively. The staining results are as follows: Figure 4 The figures A, B, and C are shown in the diagram.

[0085] Furthermore, based on the above staining results of the hind limb skin tissue samples from each experimental group of mice, the thickness of the skin tissue, epidermal tissue, and fibroadipose tissue was measured, and fibrosis was quantified (the fibrosis quantification method is as described in Chen, Z., et al., specifically using the ratio of the fibrotic area to the total tissue area calculated by the image analysis software ImageJ for quantitative evaluation). The results are as follows: Figure 5 The figures A, B, C, and D are shown in the diagram.

[0086] Depend on Figure 4 Figures A, B, and C in the diagram and Figure 5 From diagrams A, B, C, and D, we can conclude that:

[0087] Compared with the sham-operated group, the lymphedema model group showed significantly thicker skin tissue, more fibrous tissue proliferation, and a significantly higher degree of fibrosis, indicating the successful establishment of the lymphedema model. After treating the lymphedema mice with the EZH2 inhibitor EPZ6438 or GSK126, the thickness of the skin tissue, epidermal tissue, fibroadipose tissue, and degree of fibrosis were all significantly reduced compared with the lymphedema model group, even reaching a level close to that of the sham-operated mice.

[0088] The above results indicate that treatment with EZH2 inhibitors EPZ6438 or GSK126 in mice with lower limb lymphedema significantly alleviated their skin fibrosis symptoms and markedly inhibited the progression of lymphedema. This suggests that EZH2 inhibitors can significantly reduce the degree of fibrosis in lymphedema, thereby significantly inhibiting the progression of lymphedema.

[0089] Example 3: Safety assessment of EZH2 inhibitors in a mouse model of lymphedema

[0090] In this embodiment, the safety of EZH2 inhibitors EPZ6438 or GSK126 in a mouse model of lymphedema was evaluated based on the mice in each experimental group in Example 2.

[0091] Specifically, on the 7th day after the modeling surgery, heart, liver, spleen, lung, kidney and small intestine tissues of mice in each experimental group were collected. The collected tissue samples were fixed in 4% paraformaldehyde for 48 hours, and then dehydrated using graded alcohols. After dehydration, the tissues were embedded in paraffin and sectioned. Hematoxylin-eosin staining was performed on each tissue section according to the instructions of the hematoxylin-eosin staining kit, and the tissue structure was evaluated by microscopic observation.

[0092] The results are as follows Figure 6 As shown in the AF diagram; by Figure 6 It was found that the hind limb lymphedema modeling surgery in mice did not affect the tissue structure of other internal organs; furthermore, after treatment with the EZH2 inhibitors EPZ6438 or GSK126, the tissue structure of various internal organs in mice showed no significant difference compared with the sham-operated group. These results fully demonstrate that EZH2 inhibitors exhibit good safety in the lymphedema mouse model.

[0093] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The use of EZH2 inhibitors in the preparation of drugs for the prevention and / or treatment of lymphedema; wherein, The EZH2 inhibitor is selected from any one or more of the following: EPZ6438, GSK126 and their pharmaceutically acceptable salts, and the prevention and / or treatment of lymphedema includes preventing, reducing, alleviating and / or improving the skin fibrosis symptoms of lymphedema.

2. The use according to claim 1, characterized in that, The lymphedema is primary lymphedema and / or secondary lymphedema.

3. The use according to claim 2, characterized in that, The lymphedema mentioned is secondary lymphedema following cancer surgery.

4. The use according to any one of claims 1-3, characterized in that, The subjects were mammals; And / or, in the medicament for preventing and / or treating lymphedema, the EZH2 inhibitor is the sole active ingredient or one of the active ingredients; And / or, the drug may also include a pharmaceutically acceptable carrier and / or excipient.

5. The use according to claim 4, characterized in that, The subjects were humans.

6. The use according to claim 5, characterized in that, For human subjects, the effective dose for prevention of the EZH2 inhibitor is 1-3 mg / kg body weight, and the effective dose for treatment is 3-5 mg / kg body weight.

7. The use according to claim 6, characterized in that, For human subjects, the effective dose for prevention of the EZH2 inhibitor is 2 mg / kg body weight, and the effective dose for treatment is 4 mg / kg body weight.

8. The use according to claim 1, characterized in that, The drug is selected from the following dosage forms: oral dosage form, injectable dosage form, implantable dosage form and / or transdermal dosage form.

9. The use according to claim 8, characterized in that, The oral dosage forms are selected from: tablets, capsules, granules, oral liquids, pills, powders, tinctures, and syrups; And / or, the injectable dosage form is an injection solution or a powder for injection; And / or, the implantable drug delivery dosage form is selected from: implantable tablets, implantable rods, implantable microspheres and / or implantable nanoparticles; And / or, the transdermal dosage form is selected from: ointments, creams, gels, patches and / or aerosols.

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