Use of combination of BMI1 inhibitor and Myc inhibitor for treatment of cancer

Abstract

The invention belongs to the technical field of biological medicines, and relates to application of a combination of a BMI1 inhibitor and a Myc inhibitor to treatment of cancers. After the BMI1 inhibitor and the Myc inhibitor are combined to be used for treating cancers, especially head and neck squamous cell carcinoma (HNSCC), tumor stem cells can be effectively and continuously eliminated, so that tumor growth is inhibited to treat cancers, and tumor recurrence can be prevented.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine and relates to the use of a combination of a BMI1 inhibitor and a Myc inhibitor for treating cancer. Background Art

[0002] Head and neck squamous cell carcinoma (HNSCC) originates from the oral cavity, oropharynx, larynx and hypopharynx, and is a highly invasive tumor type. The disease usually occurs in various parts of the oral cavity, including the tongue, floor of the mouth, buccal mucosa, gums and lips. The occurrence of HNSCC is related to many factors, including environmental factors, lifestyle habits and genetic factors. Since the early symptoms of HNSCC are not obvious, patients are often in the late stage when diagnosed, which seriously affects the quality of life and prognosis of patients.

[0003] Currently, the main treatment modalities for HNSCC include surgery, radiotherapy, and chemotherapy. However, due to the lack of obvious early symptoms, many patients are already in the advanced stage when diagnosed. For locally advanced HNSCC, concurrent chemoradiotherapy (CRT) is the main treatment. However, even after CRT treatment, about 50% of patients still relapse within 3 years, which shows that the current treatment model has limitations in controlling HNSCC disease.

[0004] In recent years, targeted therapy and immunotherapy have made significant progress in the treatment of HNSCC. For example, cetuximab targeting EGFR has been used in the treatment of HNSCC; immune checkpoint inhibitors (ICIs), such as PD-1 / PD-L1 antibodies, have shown potential in the treatment of HNSCC. However, the response rate of immunotherapy is not 100%, and approximately 70% to 90% of RM-HNSCC patients may not respond to ICIs; and the efficacy of targeted therapy is limited by tumor heterogeneity and drug resistance. This suggests that further research is needed on the treatment of HNSCC to improve the treatment effect.

[0005] Tumor recurrence, metastasis, and drug resistance are the main causes of death in cancer patients, which may originate from a subpopulation of cancer cells called cancer stem cells (CSCs). Therefore, researchers have worked hard to find potential targets to eliminate CSCs. Despite recent advances in treatment, the 5-year survival rate of HNSCC patients remains relatively low due to tumor recurrence, metastasis, and drug resistance. Based on the CSCs theory, in order to obtain the best therapeutic effect, CSCs must be eradicated in the continuous treatment of HNSCC.

[0006] Using an in vivo lineage tracing mouse model, the latest studies have shown that BMI1+ cells are slow-cycle CSCs in HNSCC and are closely related to tumor recurrence, metastasis and drug resistance. BMI1 (Blymphoma Mo-MLV insertion region1) is one of the core members of the polycomb gene family and is involved in regulating a variety of basic cell biological processes, including cell proliferation, apoptosis and senescence. Studies have shown that BMI1 is abnormally highly expressed in a variety of human malignant tumors, closely related to tumor development, stem cell homeostasis and poor prognosis of patients, and is considered to be a new tumor diagnostic marker and potential therapeutic target. PTC-209, a small molecule inhibitor of BMI1, can significantly downregulate the expression of BMI1 protein levels in HNSCC cells, and has concentration- and time-dependent effects, which may be through post-transcriptional inhibition and ubiquitin-proteasome degradation pathways (see: Wang, Q., et al., Pharmacological inhibition of Bmi1 by PTC-209 impaired tumor growth inhead neck squamous cell carcinoma. Cancer Cell Int, 2017.17: p.107.). After PTC-209 treatment, ubiquitinated histone uH2A in HNSCC cells increased significantly, inhibiting BMI1 transcription and leading to derepression of its downstream target gene p16 (see: Storti, B., et al., Fluorescence imaging of biochemical relationship between ubiquitinated histone 2A and Polycomb complex protein BMI1. Biophys Chem, 2019. 253: p. 106225.). PTC-209 intervention in vitro can significantly inhibit cell proliferation, and has a synergistic anticancer effect when combined with cisplatin and 5-FU. In addition, PTC-209 can cause cell cycle arrest, promote cell apoptosis, inhibit cell migration and invasion, and reduce cell clone formation rate and tumor sphere formation as well as the proportion of ALDH-positive subpopulation cells. The heterotopic transplant tumor model was constructed by subcutaneously injecting HNSCC cells into nude mice and observing the effect of intraperitoneal injection of PTC-209 on the growth of transplanted tumors. The results showed that PTC-209 may significantly inhibit the growth of head and neck squamous cell carcinoma transplant tumors by downregulating the expression of BMI1 and inhibiting cell proliferation. The applicant's research shows that the combined treatment of anti-PD1 and cisplatin acts on BMI1 in HNSCC. +In contrast, pharmacological and genetic inhibition of BMI1 eliminated BMI1+ CSCs and enabled PD1 blockade therapy, thereby suppressing metastatic HNSCC and preventing HNSCC recurrence. + In addition to CSCs, BMI1 inhibition also promotes the recruitment and activation of CD8 + T cells strongly induce tumor cell-intrinsic immune responses. + CSCs can limit the growth and metastasis of HNSCC, but this does not lead to tumor regression or eradication.

[0007] The v-myc myelocytomatosis viral oncogene homolog, or MYC, is a proto-oncogene that affects cell cycle progression, apoptosis, and transformation by encoding a nuclear phosphoprotein, and also functions as a transcription factor that controls gene expression. Increasing evidence suggests that MYC regulates tumor formation through multiple mechanisms and plays a functional role in up to 70% of human cancers. Multiple studies have demonstrated that MYC plays an important role in tumor formation and is considered an attractive target for cancer therapy (see: Han, H., et al., Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell, 2019. 36(5): p. 483-497e15; Holmes, AG, et al., A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression. Sci Adv, 2022. 8(17): p. eabh3635; Zhang, Y., et al., The m(6)A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresseschemosensitivity by activating the mTOR pathway. Mol Cancer, 2022.21(1):p.174.). Recently, the applicant's study showed that MYC is associated with lymph node metastasis and poor prognosis of HNSCC. MYCi975 is a small molecule inhibitor of MYC that can destroy MYC-MAX dimers, promote MYC degradation and kill tumor cells. It increases proteasome-mediated MYC degradation by enhancing MYC phosphorylation on threonine. However, it is not clear whether MYCi975 is beneficial for the treatment of HNSCC.

[0008] In summary, the treatment of HNSCC faces multiple challenges, including tumor recurrence, metastasis, and drug resistance. In addition, treatment-related toxicity and side effects are also issues that need to be addressed. For example, although synchronous chemoradiotherapy is effective, short-term and long-term toxicity is still significant, and new treatment strategies need to be found to reduce these side effects. The therapeutic effects of immunotherapy and targeted therapy need to be improved. The above results suggest that further research is needed to overcome these challenges. Summary of the invention

[0009] The purpose of the present invention is to provide a use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, so that after the BMI1 inhibitor and the Myc inhibitor are used in combination for the treatment of cancer, especially head and neck squamous cell carcinoma (HNSCC), tumor stem cells can be effectively and continuously eliminated, thereby inhibiting tumor growth to treat cancer and preventing tumor recurrence.

[0010] To achieve this object, in a basic embodiment, the present invention provides the use of a combination of a BMI1 inhibitor and a Myc inhibitor for the preparation of a medicament for treating cancer.

[0011] In a preferred embodiment, the present invention provides use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, wherein the BMI1 inhibitor is PTC-209.

[0012] In a preferred embodiment, the present invention provides use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, wherein the Myc inhibitor is MYCi975.

[0013] In a preferred embodiment, the present invention provides use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, wherein the mass ratio of the BMI1 inhibitor to the Myc inhibitor in the combination is 3:5.

[0014] In a preferred embodiment, the present invention provides use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, wherein the combination is in the form of a composition, and the dosage form of the composition is preferably a solution.

[0015] In a preferred embodiment, the present invention provides use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, wherein the combination is used to prepare a medicament for treating cancer by eliminating tumor stem cells.

[0016] In a preferred embodiment, the present invention provides use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, wherein the cancer is head and neck squamous cell carcinoma.

[0017] In a preferred embodiment, the present invention provides use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer, wherein the cancer is oral squamous cell carcinoma.

[0018] The beneficial effect of the present invention is that after the BMI1 inhibitor and the Myc inhibitor are used in combination for the treatment of cancer, especially head and neck squamous cell carcinoma (HNSCC), the present invention can effectively and continuously eliminate tumor stem cells, thereby inhibiting tumor growth and treating cancer, and can prevent tumor recurrence. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The experimental results of Example 2, wherein A is a schematic diagram of the time points of PTC209 treatment of PDX#3; B is the tumor volume in different treatment groups (n=12), ns, no statistical difference, p>0.05; *p<0.05, and **p<0.01, t-test; C is the tumor weight in different treatment groups (n=12), ns, no statistical difference, p>0.05, t-test; D is the ALDEFLUOR experimental flow cytometry analysis of PDX#3 tumors at different treatment times, wherein the +DEAB group is the control group to control the interference of background fluorescence in the experiment.

[0020] Figure 2 The test results of Example 3 are shown in Figure 3, where A is the tumor volume in different treatment groups; B is the overall survival rate in different treatment groups; C is the median survival time of experimental mice after treatment, where the first column is the category of inter-group comparison, the second column is the statistical analysis result of inter-group comparison using the log-rank test, * indicates that the p value is less than 0.05, ** indicates that the p value is less than 0.01, and the values ​​outside the brackets in the third column are the medians of the overall survival time of the two groups before and after "vs.", separated by "-", and the percentages in the brackets indicate the proportion of the overall survival time of the latter group compared with the former group.

[0021] Figure 3 The experimental results of Example 5, wherein A is a schematic diagram of the experimental design; B is the expression of Bmi1 in frozen sections of tongue tumors of transgenic mice + Tumor stem cells (tomato red fluorescence) images, the white dotted line indicates the boundary between tumor and stromal tissue, scale bar, 50 μm; C is a tongue tumor of transgenic mice Bmi1 + Statistical graph of the percentage of tumor stem cells, ns, no statistical difference, p>0.05; **p<0.01. DETAILED DESCRIPTION

[0022] The specific implementation modes of the present invention are further described below through examples.

[0023] Example 1: Construction of HNSCC human tumor xenograft mouse model (PDX model)

[0024] The PDX model (Patient-Derived tumor Xenograft model) refers to a xenogeneic tumor transplantation model in which fresh tumor tissue from a patient is transplanted into immunodeficient mice and grows in the environment provided by the mice (see: Liu, Y., et al., Patient-derived xenograft models in cancer therapy: technologies and applications. Signal Transduct Target Ther, 2023.8(1): p.160.).

[0025] 1.1 Operations before tumor tissue transplantation

[0026] The tumor specimens in this experimental study were derived from patients with head and neck squamous cell carcinoma who underwent surgery at Peking University School of Stomatology from 2020 to 2022, and were approved by the Biomedical Ethics Committee of Peking University School of Stomatology. Patient inclusion criteria were: (1) pathological results confirmed squamous cell carcinoma;

[0027] (2) The tumor was located in the tongue of the patient; (3) The primary cancer was removed and the neck was dissected without preoperative radiotherapy or chemotherapy; (4) The patient voluntarily signed the informed consent.

[0028] After the tumor tissue was removed during the operation, the most representative tumor tissue in the tumor lesion was collected, avoiding the liquefied and necrotic part in the center of the tumor, and cut into several small pieces, placed in PBS solution, stored in an ice bath and sent to the animal laboratory. In the biosafety cabinet, the collected tumor tissue was placed in a cell culture dish, and the inactive tumor tissue such as liquefied and necrotic visible to the naked eye was further processed. After repeated washing with PBS, it was cut into tissue blocks of approximately 2mm×2mm×2mm in size for subsequent experiments.

[0029] (II) Construction of primary (P0) PDX model

[0030] In a biological safety cabinet, female NOD / SCID mice (nude mice, Viton Liva) aged 6-8 weeks were anesthetized with pentobarbital and fixed. Use 75% alcohol to disinfect the skin on the back of the mouse, shave the inoculation area with a razor and disinfect it again. Use autoclaved tissue scissors to cut a small opening of about 0.5 cm in the inoculation area, and separate it sharply with tissue scissors. The processed tumor tissue blocks (3-4 pieces) were implanted subcutaneously in the inoculation area, and the wound was sutured with wound clips. The mice with tumor transplantation were placed in a breeding cage in an animal laboratory free of specific pathogens (SPF grade) and the length, width and weight of the mouse tumor were measured every 3 days with a micro-vernier caliper. Remove the wound clip with a needle holder after one week.

[0031] 3. PDX model generation

[0032] In a biosafety cabinet, mice were anesthetized and the tumor was completely removed surgically. The tumor was processed according to the construction method of the primary model and inoculated into the next generation of mice to form a P1 generation PDX model. The original measurement and construction methods were still used for subculture.

[0033] Example 2: Animal Experiment on Treatment of HNSCC (I)

[0034] Twenty-four PDX model mice constructed in Example 1 (PDX#3, the tumor volume of each mouse was about 100 cm 3 The mice in the control group were injected with 100 μl of PBS on days 1, 4, 8, 11, and 15, respectively; the mice in the PTC-209 group were injected with 60 mg / kg of PTC-209 on days 1, 4, 8, 11, and 15, respectively. The mice were administered and observed for 36 days. The tumor length (L, the longest diameter of the tumor) and width (W, the shortest diameter of the tumor) of each mouse were measured and recorded every three days with a micro-vernier caliper. The tumor volume was calculated as (L×W 2 / 2). All mice were killed on day 36 and the tumors were removed and weighed. Figure 1 A to Figure 1 As shown in C, for the PTC-209 group, as long as the drug is continuously administered, the tumor growth of mice will be inhibited, but after drug withdrawal, the tumor will quickly recur and gradually increase in size.

[0035] Cancer stem cells are a rare but critical cell subpopulation within tumors that can self-renew and produce different types of tumor cells, thereby maintaining tumor growth and heterogeneity (see: Batlle, E. and H. Clevers, Cancer stem cells revisited. Nat Med, 2017. 23(10): p. 1124-1134.).

[0036] The rapid regeneration of tumors after the cessation of PTC-209 administration prompted the applicant to further explore the dynamic changes of tumor stem cells. To this end, the applicant took mouse tumor tissues at 0, 1, 18, and 36 days of PTC-209 treatment, minced them, and digested them with enzymes at 37°C to form a single cell suspension, and adjusted the concentration of the single cell suspension to 1×10 6 Pieces / ml. Subsequently, the ALDEFLUOR analysis kit was used for flow cytometry staining and analysis of changes in tumor stem cells (see: Chen, D., et al., Targeting BMI1(+) Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma. Cell Stem Cell, 2017. 20(5): p. 621-634e6; Dong, J., et al., Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma. Nat Commun, 2021. 12(1): p. 3974; Zhang, W., et al., Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress. Mol Cell, 2021. 81(10): p. 2148-2165e9; Qin, Z., et al., PVT1 inhibition Stimulates anti-tumorimmunity, prevents metastasis, and depletes cancer stem cells in squamous cellcarcinoma. Cell Death Dis, 2023.14(3):p.187.). The result is like Figure 1 D, where the +DEAB group is the control group to control the interference of background fluorescence in the experiment. The experimental results show that after one day of single administration of PTC-209, ALDH + CSCs decreased from 1.99% to 1.09%, and the number of these tumor stem cells decreased to 0.14% within an 18-day treatment cycle. However, the number of tumor stem cells detected in tumors collected 18 days after stopping PTC-209 treatment was 2.33%, indicating that it had returned to the level before drug administration. These results indicate that targeting tumor stem cells with PTC-209 alone is not sufficient to eradicate cancer.

[0037] Example 3: Animal experiment on the treatment of HNSCC (II)

[0038] 48 PDX model mice constructed in Example 1 (PDX#1, the tumor volume of each mouse was about 100 cm 3 They were randomly divided into 4 groups, with 12 mice in each group, namely solvent control group (hereinafter referred to as the “control group”), PTC-209 treatment group (hereinafter referred to as the “PTC-209 group”), MYCi975 treatment group (hereinafter referred to as the “MYCi975 group”), and PTC-209 and MYCi975 combined treatment group (hereinafter referred to as the “combined treatment group”). Each mouse in the control group was intraperitoneally injected with 100 μl of PBS on days 1, 4, 8, 11, and 15; each mouse in the PTC-209 group was intraperitoneally injected with 60 mg / kg of PTC-209 on days 1, 4, 8, 11, and 15; each mouse in the MYCi975 group was intraperitoneally injected with 100 mg / kg of MYCi975 on days 1, 4, 8, 11, and 15; each mouse in the combined treatment group was intraperitoneally injected with 60 mg / kg of PTC-209 and 100 mg / kg of MYCi975 on days 1, 4, 8, 11, and 15. The mice were observed until they died. During the process, the length (L), width (W) of the tumor of each mouse and the weight of each mouse were measured and recorded every three days with a micro-vernier caliper. The tumor volume was calculated as (L×W 2 / 2). The criteria for mouse death were: (1) natural death; (2) the longest diameter of the mouse tumor reached 15 mm; (3) the mouse weight loss was >20%. The tumors of the dead mice were removed and weighed. The tumor volume statistics of the continuous observation for 36 days are as follows Figure 2 As shown in A, it shows that:

[0039] (1) For the control group, the tumor volume of mice continued to grow rapidly because no drug treatment intervention was performed.

[0040] (2) For the PTC-209 group, as long as the drug was continuously administered, the tumor growth of the mice was inhibited and the tumor volume growth slowed down, but after drug withdrawal, the tumor quickly recurred and the volume increased rapidly. This indicates that only continuous PTC-209 treatment can prevent tumor progression.

[0041] (3) For the MYCi975 group, the observations were similar to those in the PTC-209 group, indicating that tumor progression can only be prevented by continuous MYCi975 treatment.

[0042] (4) For the combined treatment group, the tumor growth of mice was inhibited during the continuous administration phase, and there was no significant change in tumor volume after drug withdrawal. This indicates that for HNSCC, the combined treatment of PTC-209 and MYCi975 can not only effectively treat HNSCC during the administration phase, but also effectively prevent the recurrence of HNSCC after drug withdrawal.

[0043] like Figure 2 As shown in B, the overall survival rate of mice in the combination treatment group was improved compared with mice treated with PTC209 or MYCi975 alone. Figure 2 As shown in C, the median overall survival of the control group, PTC-209 group, MYCi975 group, and combined treatment group were 14 days, 26 days, 27 days, and 48 days, respectively. The results showed that the combined treatment of PTC-209 and MYCi975 can effectively improve the overall survival of mice.

[0044] Example 4: Construction of 4NQO tumor mouse model

[0045] Select 6-8 weeks old Bmi1 CreER ;Rosa tdTomato Transgenic mice (Jackson Laboratory, USA) were fed with drinking water containing 50 μg / ml 4-nitroquinoline-1-oxide (4NQO) for 16 weeks and then given normal drinking water for 6 weeks for tumor formation and lymph node metastasis, thereby inducing a 4NQO tumor mouse model of spontaneous HNSCC. For specific methods, see: Jia, L., W. Zhang, and CY Wang, BMI1 Inhibition Eliminates Residual Cancer Stem Cells after PD1 Blockade and Activates Antitumor Immunity to Prevent Metastasis and Relapse. Cell Stem Cell, 2020. 27(2): p. 238-253e6.

[0046] Example 5: Animal experiment on the treatment of HNSCC (III)

[0047] 1. Animal experiments

[0048] Forty-eight 4NQO tumor mouse model mice constructed in Example 4 (male, 6 weeks old, 4NQO water concentration of 50 μg / mL, water feeding for 16 weeks) were randomly divided into 4 groups, 12 mice in each group, namely, a solvent control group (hereinafter referred to as the "control group"), a PTC-209 treatment group (hereinafter referred to as the "PTC-209 group"), a MYCi975 treatment group (hereinafter referred to as the "MYCi975 group"), and a PTC-209 and MYCi975 combined treatment group (hereinafter referred to as the "combined treatment group"). Each mouse in the control group was intraperitoneally injected with 100 μl of PBS on the 1st and 4th day of each week for four consecutive weeks; each mouse in the PTC-209 group was intraperitoneally injected with 60 mg / kg of PTC-209 on the 1st and 4th day of each week for four consecutive weeks; each mouse in the MYCi975 group was intraperitoneally injected with 100 mg / kg of MYCi975 on the 1st and 4th day of each week for four consecutive weeks; each mouse in the combined treatment group was intraperitoneally injected with 60 mg / kg of PTC-209 and 100 mg / kg of MYCi975 on the 1st and 4th day of each week for four consecutive weeks. After the end of each group of medication, each mouse was given tamoxifen (225 mg / kg, intraperitoneal injection) to induce Bmi1 + The tumor stem cells fluoresced red, allowing for visualization in frozen sections, and the mice were sacrificed four weeks after tamoxifen administration.

[0049] (II) Preparation of frozen sections

[0050] After killing the mice, the tongue was collected, photographed and the size of the tumor lesion area was measured. The tongue was fixed in 4wt% paraformaldehyde overnight. The tongue was then cut in half longitudinally, and half was randomly selected and placed in a PBS solution containing 30wt% sucrose to reduce the water content of the tissue. After 1-3 days, it was embedded in OCT embedding agent. To avoid bubbles during the process, it was stored in a -20°C refrigerator. When in use, take out the treated tongue and select a suitable base. Slice it in a freezing microtome, with each slice being 5μm thick. When slicing, make sure that the blade and the cross-section of the tongue are parallel to each other so that the cut plane can be relatively flat. Mark each group of slices and let them dry at room temperature for 20-30 minutes before use. They can also be stored in a -20°C refrigerator for later use.

[0051] 3. Staining and observation of frozen sections

[0052] The staining and observation methods of frozen sections are as follows:

[0053] (1) Take the slices out of the refrigerator and place them at room temperature for 30 minutes to rewarm;

[0054] (2) Immerse the slices in PBS solution and wash quickly on a shaker for 5 min, three times;

[0055] (3) Gently shake off the water and circle the tissue with an immunohistochemistry pen to prevent subsequent antibody overflow;

[0056] (4) Block nonspecific binding sites with donkey serum for 30 min at room temperature;

[0057] (5) Gently shake off the blocking solution, immerse in PBS solution and quickly wash on a shaker for 5 min, three times;

[0058] (6) Add DAPI and stain for 5 min before rapid washing with PBS solution for 5 min, three times;

[0059] (7) Sealing: Wipe off the liquid around the tissue, drop fluorescent mounting medium on the tissue, and store at 4°C away from light;

[0060] (8) The stained sections were photographed under an optical microscope, and the area ratio of the positive expression area (red) was calculated.

[0061] The test results are as follows Figure 3 As shown, the red fluorescence is Bmi1 + Tumor stem cells. The picture shows that there was no statistical difference in the number of tumor stem cells between the PTC-209 group and the MYCi975 group after treatment compared with the control group, indicating a recurrence of HNSCC. In contrast, the combined treatment group showed a persistent inhibitory effect on HNSCC growth and significantly reduced the number of tumor stem cells.

[0062] 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 changes and variations. The above embodiments or implementations are merely illustrative of the present invention, and the present invention may also be implemented in other specific ways or other specific forms without departing from the gist or essential features of the present invention. Therefore, the described implementations should be considered illustrative rather than restrictive in any respect. The scope of the present invention should be described by the appended claims, and any changes equivalent to the intent and scope of the claims should also be included within the scope of the present invention.

Claims

1. Use of a combination of a BMI1 inhibitor and a Myc inhibitor for preparing a medicament for treating cancer.

2. The use according to claim 1, characterized in that: The BMI1 inhibitor is PTC-209.

3. The use according to claim 1, characterized in that: The Myc inhibitor is MYCi975.

4. The use according to any one of claims 1 to 3, characterized in that: The mass ratio of the BMI1 inhibitor to the Myc inhibitor in the combination is 3:

5.

5. The use according to any one of claims 1 to 3, characterized in that: The combination is a solution.

6. The use according to any one of claims 1 to 3, characterized in that: The combination is used to prepare a medicament for treating cancer by eliminating tumor stem cells.

7. The use according to any one of claims 1 to 3, characterized in that: The cancer is head and neck squamous cell carcinoma.

8. The use according to any one of claims 1 to 3, characterized in that: The cancer is oral squamous cell carcinoma.

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