Application of ATR kinase inhibitors in the treatment of spinal cord glioma

Abstract

The present invention provides the use of an ATR kinase inhibitor in the treatment of spinal cord gliomas. Experiments in this application confirm that the ATR kinase inhibitor AZD6738 has a therapeutic effect on spinal cord gliomas and can also increase the sensitivity of spinal cord gliomas to radiotherapy, providing a new direction for the clinical treatment of spinal cord gliomas and having broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to the application of an ATR kinase inhibitor in the treatment of spinal cord glioma. Background Art

[0002] Spinal cord gliomas mainly include ependymal tumors, oligodendrogliomas, astrocytomas, and glioblastoma multiforme. Their incidence is relatively low among central nervous system tumors, accounting for 8%-10% of all primary intraspinal tumors, with an annual incidence of approximately 0.22 / 100,000. Due to the particularity and rarity of spinal cord gliomas, research progress has been slow, and there is still a lack of large-scale clinical trials and standardized treatment guidelines. In addition, compared with intracranial space-occupying lesions, the narrower operating space within the spinal canal and the important physiological functions of the spinal cord increase the difficulty of treating spinal cord gliomas, making it more likely to cause various complications after surgery, reduce the patient's quality of life, and place a heavy burden on the patient. Therefore, it is of great significance to actively explore the best treatment method for spinal cord gliomas. Summary of the Invention

[0003] To overcome the deficiencies of the prior art, the present invention provides the use of an ATR kinase inhibitor in the treatment of spinal cord glioma.

[0004] To achieve the above objectives, the present invention adopts the following technical solutions.

[0005] A first aspect of the present invention provides a drug for treating spinal cord glioma / enhancing the radiotherapy sensitivity of spinal cord glioma, wherein the drug comprises an ATR kinase inhibitor.

[0006] Furthermore, the ATR kinase inhibitor is selected from AZD6738.

[0007] Furthermore, the spinal cord glioma is selected from mutant spinal cord glioma.

[0008] Furthermore, the mutant spinal cord glioma is selected from H3 K27M mutant spinal cord glioma.

[0009] Furthermore, the drug also includes a pharmaceutically acceptable carrier.

[0010] Furthermore, the dosage form of the pharmaceutical composition includes solid preparations, semisolid preparations or liquid preparations.

[0011] Furthermore, the solid preparation includes tablets, lozenges, capsules, pills or granules.

[0012] Furthermore, the semi-solid preparation includes a cream, a gel, an ointment or an emulsion.

[0013] Furthermore, the liquid preparation includes a solution or a suspension.

[0014] The second aspect of the present invention provides the use of an ATR kinase inhibitor in the preparation of a medicament for treating spinal cord glioma.

[0015] Furthermore, the ATR kinase inhibitor is selected from AZD6738.

[0016] Furthermore, the spinal cord glioma is selected from mutant spinal cord glioma.

[0017] Furthermore, the mutant spinal cord glioma is selected from H3 K27M mutant spinal cord glioma.

[0018] Furthermore, the medicine also includes other active drugs.

[0019] Furthermore, the other active drugs include methotrexate, cytarabine, palbociclib, temozolomide, and doxorubicin.

[0020] The third aspect of the present invention provides the use of an ATR kinase inhibitor in the preparation of a drug for enhancing the radiotherapy sensitivity of spinal cord glioma.

[0021] Furthermore, the ATR kinase inhibitor is selected from AZD6738.

[0022] Furthermore, the spinal cord glioma is selected from mutant spinal cord glioma.

[0023] Furthermore, the mutant spinal cord glioma is selected from H3 K27M mutant spinal cord glioma.

[0024] Furthermore, the drug also includes other drugs that enhance the sensitivity of spinal cord glioma to radiotherapy.

[0025] Furthermore, the other drugs that enhance the radiotherapy sensitivity of spinal glioma include metronidazole, misonidazole, nitroimidazole, benzamide, nicotinamide, cisplatin, mitomycin, tenizamine, nitrosourea, and mercaptopurine.

[0026] The fourth aspect of the present invention provides the use of an ATR kinase inhibitor in inhibiting the growth of spinal cord glioma cells or in the preparation of a medicament for inhibiting the growth of spinal cord glioma cells.

[0027] Furthermore, the ATR kinase inhibitor is selected from AZD6738.

[0028] Furthermore, the spinal cord glioma is selected from mutant spinal cord glioma.

[0029] Furthermore, the mutant spinal cord glioma is selected from H3 K27M mutant spinal cord glioma.

[0030] A fifth aspect of the present invention provides a method for regulating the growth of spinal cord glioma cells in vitro, the method comprising administering an ATR kinase inhibitor.

[0031] Furthermore, the ATR kinase inhibitor is selected from AZD6738.

[0032] Furthermore, the spinal cord glioma is selected from mutant spinal cord glioma.

[0033] Furthermore, the mutant spinal cord glioma is selected from H3 K27M mutant spinal cord glioma.

[0034] Advantages and beneficial effects of the present invention:

[0035] The present application experimentally confirms that the ATR kinase inhibitor AZD6738 has a therapeutic effect on spinal cord gliomas and can increase the sensitivity of spinal cord gliomas to radiotherapy, providing a new direction for the clinical treatment of spinal cord gliomas and having broad application prospects.

[0036] Biomaterial deposit information

[0037] SCA-S02:

[0038] Scientific description: human cells; depository: General Microbiology Center of China Culture Collection Administration of Microorganisms (CGMCC); deposit address: No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; deposit date: January 22, 2024; deposit number: CGMCC NO.45809.

[0039] SCA-S09:

[0040] Scientific description: human cells; depository: General Microbiology Center of China Culture Collection Administration of Microorganisms (CGMCC); deposit address: No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; deposit date: January 22, 2024; deposit number: CGMCC NO.45810.

[0041] SCA-S10:

[0042] Scientific description: human cells; depository: General Microbiology Center of China Culture Collection Administration of Microorganisms (CGMCC); deposit address: No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; deposit date: January 22, 2024; deposit number: CGMCC NO.45811.

[0043] SCA-S12:

[0044] Scientific description: human cells; depository: General Microbiology Center of China Culture Collection Administration of Microorganisms (CGMCC); deposit address: No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; deposit date: January 22, 2024; deposit number: CGMCC NO.45812.

[0045] SCA-S41:

[0046] Scientific description: human cells; depository: General Microbiology Center of China Culture Collection Administration of Microorganisms (CGMCC); deposit address: No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; deposit date: January 22, 2024; deposit number: CGMCC NO.45813. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is a diagram of the gene mutations in spinal cord glioma cells;

[0048] Figure 2 This is a graph showing the sensitivity of spinal cord glioma cells to AZD6738;

[0049] Figure 3 This is a graph measuring the sensitivity of spinal cord glioma cells to the combination of AZD6738 and radiotherapy;

[0050] Figure 4 This is a live fluorescence imaging of spinal cord glioma cells in mice;

[0051] Figure 5 This is a graph showing the growth curve of spinal cord glioma cells in mice;

[0052] Figure 6 This is a survival curve of mice after spinal cord glioma cells were implanted into mice;

[0053] Figure 7 This is a diagram showing the inhibitory effect of anti-tumor drugs on spinal cord glioma cells SCA_S02;

[0054] Figure 8 This is a diagram showing the inhibitory effect of anti-tumor drugs on spinal cord glioma cells SCA_S09. DETAILED DESCRIPTION

[0055] The following provides definitions of some terms used in this specification. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0056] The present invention provides a drug for treating spinal cord glioma / enhancing the radiotherapy sensitivity of spinal cord glioma. The drug comprises an ATR kinase inhibitor.

[0057] In some embodiments, ATR kinase inhibitors include but are not limited to AZD6738 (also known as Cerasertib or Ceralasertib), ATG-018, Abd110.

[0058] In a specific embodiment, the ATR kinase inhibitor is selected from AZD6738, including pharmaceutically acceptable salts of AZD6738. Representative pharmaceutically acceptable salts include alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble salts and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, propionate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, bis(o)aminophen, Pharmaceutically acceptable salts may have more than one charged atom in their structure. In this case, the pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. These pharmaceutically acceptable salts are prepared by methods known in the art, for example, by dissolving a free amine base with an excess of acid in an aqueous alcohol solution, or by neutralizing a free carboxylic acid with an alkali metal base (e.g., hydroxide) or with an amine.

[0059] The drug further includes a pharmaceutically acceptable carrier.

[0060] In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance, which is involved in carrying or transporting the test chemical from one organ or part of the body to another organ or part of the body. Various carriers are "acceptable" in the sense that they are compatible with the other components of the formulation and will not cause harm to the patient. Some examples of substances that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, etc. Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0061] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coatings, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the pharmaceutical.

[0062] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0063] In some embodiments, the medicine of the present application includes compositions suitable for oral administration, nasal administration, topical administration (including oral and sublingual administration), rectal administration, vaginal administration, aerosol administration and / or parenteral administration. The composition can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. Depending on the subject to be treated, the specific mode of administration, the amount of active ingredient that can be combined with a carrier material to produce a single dosage form can be different. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces a therapeutic effect. Typically, in addition to 100%, the range of this amount is from about 1% to about 99% active ingredient, from about 5% to about 70%, or from about 10% to about 30%.

[0064] The dosage form of the drug includes solid preparation, semisolid preparation or liquid preparation.

[0065] In a solid dosage form (tablet, lozenge, capsule, pill or granule) of the drug of the present application for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or expanders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) preservatives. Wetting agents such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents such as paraffin wax; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clays; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the drug may also contain a buffering agent. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose (or milk sugars) and high molecular weight polyethylene glycols.

[0066] Tablets can be optionally prepared by compression or molding with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant, or a dispersant. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine.

[0067] Tablets and other solid dosage forms of drugs, such as lozenges, capsules, pills or granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the art of pharmacy. Hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres in different proportions, for example, that provide the desired release curve (profile), can also be used to formulate so as to provide a sustained or controlled release of the active ingredient therein. They can be sterilized, for example, by filtering through a bacteria-retaining filter, or by introducing a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water, or by introducing some other sterile injectable medium immediately before use. These compositions can also optionally contain an opacifier and, optionally, in a delayed manner, can be a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract. Examples of implantable compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microcapsule form, if appropriate, in microcapsule form with one or more of the above-mentioned excipients.

[0068] Liquid dosage forms (solutions or suspensions) for oral administration of the drug include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0069] Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0070] In some embodiments, the dosage regimen of the drug of the present application will vary according to known factors, such as the pharmacodynamic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health, medical condition, and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, and the desired effect. In certain embodiments, the drug of the present application can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times, or four times daily.

[0071] In some embodiments, treatment refers to reducing or alleviating, or improving or eradicating a disease or one or more symptoms associated with a disease. In certain embodiments, the term refers to minimizing the spread or worsening of a disease due to administration of one or more preventive or therapeutic agents to a patient suffering from the disease. For the purposes of the various aspects and embodiments provided herein, treatment includes, but is not limited to, alleviating, relieving or improving one or more clinical manifestations or side effects of the disease or condition being treated, improving one or more clinical outcomes, reducing the extent of the disease, delaying or slowing the progression of the disease, improving, alleviating or stabilizing the disease state, and other beneficial outcomes described herein.

[0072] The present invention will be further described below with reference to specific examples. It should be understood that the specific embodiments described herein are presented by way of example and are not intended to limit the present invention. The main features of the present invention may be applied to various embodiments without departing from the scope of the present invention.

[0073] Example

[0074] Example 1

[0075] The process of suspension culture of spinal cord glioma cells: Place the brain glioma tissue block (brain glioma tissue surgically removed at Tiantan Hospital in accordance with medical ethics) in a beaker, rinse it three times with Hanks solution to remove blood stains; then place it in a mixture containing penicillin and streptomycin for 60 minutes; use ophthalmic scissors to cut the tissue into 2-3 mm pieces for easy digestion; add trypsin solution equivalent to 50 times the volume of the total amount of tissue block, and then pour it into a conical flask, tie the bottle mouth or plug it with a rubber stopper; place it in a 37°C incubator for digestion, and shake it every 20 minutes during the digestion process; the digestion time is 60 minutes; then filter out the tissue blocks that have not been fully digested through a suitable stainless steel sieve; centrifuge the digestion solution at 800 rpm to obtain sample cells, aspirate the supernatant, and add primary culture medium to the precipitate to a cell density of 10 5 / mL, and then cultured in a constant temperature incubator at 37°C. The base medium of the primary culture medium is a suspension medium, which includes: 20ng / mL EGF cytokine, 20ng / mL bFGF cytokine, 20ng / mL streptomycin and 20ng / mL penicillin, B27 (50×) and 20ng / mL transferrin.

[0076] The single cell suspension obtained by the above suspension culture was inoculated into an ultra-low adsorption culture dish for culture, and then digested into single cells with digestive enzymes. When the operation was repeated and subcultured to the fourth generation, some primary cells died, stopped growing, or grew slowly, while other primary cells were able to show a good proliferation state in a serum-free suspension culture medium. These cell lines showing a good proliferation state were selected as further screening objects, and MTT experiments and Transwell experiments were performed to detect the proliferation and migration abilities of the cell lines. The cell lines finally obtained included SCA-S10, SCA-S12, SCA-S41, SCA-S09, and SCA-S02. The gene mutations and copy number variations of the spinal cord glioma cells were detected by whole exome sequencing. The results are as follows Figure 1 As shown, it can be seen that different spinal cord glioma cells all have H3 K27M mutation (H3F3AK27M).

[0077] In this example, the spinal cord H3 K27M mutant cells derived from the above patients were divided into two groups: "high proliferation and replication stress type" and "high immune infiltration type". Among them, SCA-S10 and SCA-S12 are "high immune infiltration type" tumor patient-derived cell models, and SCA-S41, SCA-S09, and SCA-S02 are "high proliferation and replication stress type" cell models.

[0078] The sensitivity of AZD6738 (Cerasertib) to the compound was evaluated using the aforementioned cell model. The specific procedure was as follows: Glioblastoma cells in the logarithmic growth phase were trypsinized and centrifuged to obtain a cell pellet. The pellets were resuspended in complete culture medium and counted. Based on the counts, 5,000 cells were seeded per well in a 96-well cell culture plate and incubated at 37°C in a 5% CO2 atmosphere. After 24 hours, the cells were treated with the drug. AZD6738 (Cerasertib) was dissolved in DMSO to prepare a stock solution, which was then diluted in complete culture medium to various drug concentrations. Nedisertib (M3814) was added at a gradient of 0, 0.04, 0.2, and 1.5 μM. The medium was removed from the wells, and 100 μL of the corresponding drug solution was added to each well. The plates were returned to the incubator, and cell proliferation was measured after 6 days. For testing, prepare the CCK8 working solution in advance, adding 100 μL of serum-free medium and 10 μL of CCK8 to each well. Store in the dark. Remove the plate from the incubator, remove the cell culture medium from the test wells, and add 110 μL of CCK8 working solution to each well. Incubate for another 2 hours, then measure the absorbance at 450 nm on a microplate reader. Calculate the inhibition rate corresponding to each concentration, and calculate the IC50 value at the corresponding time point using GraphPad 7.0 software.

[0079] Subsequently, their sensitivity to ATR kinase inhibitor (AZD6738) was evaluated in cell models. The results showed that the "high immune infiltration" SCA-S10 and SCA-S12 cells were relatively resistant to the treatment of ATR kinase inhibitor (AZD6738), while the "high proliferation and replication stress" cells "SCA-S41, SCA-S09, SCA-S02" were relatively sensitive to the treatment of ATR kinase inhibitor (AZD6738). Figure 2 ).

[0080] Radiotherapy is currently the standard treatment for H3 K27 variant spinal cord gliomas. Next, we evaluated whether AZD6738 combined with radiotherapy could effectively enhance the effect of radiotherapy. The results showed that for highly proliferative and replication-stressed H3 K27 variant spinal cord glioma cells, increasing the concentration of AZD6738 significantly enhanced the effect of radiotherapy ( Figure 3 ).

[0081] Example 2

[0082] To investigate the effects of AZD6738 alone or combined with radiotherapy in the treatment of "highly proliferative and replication-stressed" spinal cord H3K27-mutant gliomas in vivo, an orthotopic xenograft model was established by injecting luciferase-expressing spinal cord H3K27-mutant tumor cells SCA09 into the spinal cord of nude mice.

[0083] Subsequently, day 0 was set after 14 days of tumor growth after cells were injected into the tumor.

[0084] Control group: The rats were given normal saline by gavage on days 0, 1, 2, 7, 8, 9, 14, 15 and 16, and sham radiotherapy was given 4 hours after the administration.

[0085] AZD6738 group: AZD6738 was administered orally on days 0, 1, 2, 7, 8, 9, 14, 15, and 16, and simulated radiotherapy was given 4 hours after administration.

[0086] Radiation group: The rats were given normal saline by gavage on days 0, 1, 2, 7, 8, 9, 14, 15, and 16, and 1 Gy of radiation therapy was given 4 hours after the administration.

[0087] AZD6738+radiation group: AZD6738 was administered orally on days 0, 1, 2, 7, 8, 9, 14, 15, and 16, and 1 Gy simulated radiotherapy was given 4 hours after administration.

[0088] The results showed that compared with the control group, both the AZD6738 group and the radiotherapy group could effectively reduce the tumor volume on day 28, while the AZD6738+radiotherapy group could significantly reduce the tumor volume on day 28 ( Figure 4 ).

[0089] At the same time, it can be seen from the tumor growth curve (change in average bioluminescence intensity) that the use of AZD6738 or radiotherapy alone can inhibit the growth rate of tumors to a certain extent, while the combination of AZD6738 and radiotherapy can more significantly inhibit the growth rate of mouse tumors ( Figure 5 ).

[0090] In addition, compared with the control group, AZD6738 or radiotherapy can prolong the survival of tumor-bearing mice to a certain extent, but the combination of AZD6738 and radiotherapy can further prolong the survival of mice ( Figure 6 ).

[0091] These findings highlight the therapeutic value of AZD6738 in spinal cord tumors, particularly its value in sensitizing to radiotherapy.

[0092] Comparative Example

[0093] This comparative example further measured the inhibitory effects of AZD6738 (Cerasertib) and other commonly used compounds on the H3 K27M subtype of spinal cord glioma according to the determination method of Example 1. The drug concentrations and effects are shown in Table 1. Figure 7-8 , IC50 values ​​(μM) are shown in Table 1.

[0094] Table 1 Inhibitory effects of drugs on spinal cord glioma

[0095]

[0096] It can be seen that compared with other anti-tumor drugs, the AZD6738 (Cerasertib) compound provided in this application can effectively inhibit the growth of H3 K27M mutant spinal cord gliomas and can further sensitize radiotherapy, providing a new solution for the treatment of H3 K27M subtype spinal cord gliomas.

[0097] The above embodiments are only provided for understanding the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by a person skilled in the art, and such improvements and modifications shall fall within the scope of protection of the claims of the present invention.

Claims

1. Application of ATR kinase inhibitors in the preparation of drugs for treating spinal cord gliomas; The ATR kinase inhibitor is selected from AZD6738; The spinal cord glioma is selected from H3 K27M mutant spinal cord glioma, and the H3 K27M mutant spinal cord glioma is a high proliferation and replication pressure type.

2. The use according to claim 1, characterized in that The medicament may also include other active drugs.

3. The use according to claim 2, characterized in that The other active drugs include methotrexate, cytarabine, palbociclib, temozolomide, and doxorubicin.

4. The use according to claim 1, characterized in that The drug further includes a pharmaceutically acceptable carrier.

5. The use according to claim 4, characterized in that The dosage form of the drug includes solid preparation, semisolid preparation or liquid preparation.

6. The use according to claim 5, characterized in that The solid preparations include tablets, dragees, capsules, pills or granules.

7. The use according to claim 5, characterized in that The semi-solid preparations include creams, gels, ointments or emulsions.

8. The use according to claim 5, characterized in that The liquid preparation includes a solution or a suspension.

9. Application of ATR kinase inhibitors in the preparation of drugs for enhancing the radiotherapy sensitivity of spinal cord gliomas; The ATR kinase inhibitor is selected from AZD6738; The spinal cord glioma is selected from H3 K27M mutant spinal cord glioma, and the H3 K27M mutant spinal cord glioma is a high proliferation and replication pressure type.

10. The use according to claim 9, characterized in that The drugs also include other drugs that enhance the sensitivity of spinal cord glioma to radiotherapy.

11. The use according to claim 10, characterized in that The other drugs that enhance the radiotherapy sensitivity of spinal glioma include metronidazole, misonidazole, nitroimidazole, benzamide, nicotinamide, cisplatin, mitomycin, tenizamine, nitrosourea, and mercaptopurine.

12. The use according to claim 9, characterized in that The drug further includes a pharmaceutically acceptable carrier.

13. The use according to claim 12, characterized in that The dosage form of the drug includes solid preparation, semisolid preparation or liquid preparation.

14. The use according to claim 13, characterized in that The solid preparations include tablets, dragees, capsules, pills or granules.

15. The use according to claim 13, characterized in that The semi-solid preparations include creams, gels, ointments or emulsions.

16. The use according to claim 13, characterized in that The liquid preparation includes a solution or a suspension.

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