Use of a plk1 inhibitor for the preparation of a medicament for the treatment of small cell cancer of the ovary of the hypercalcemic type

Abstract

The application provides application of a PLK1 inhibitor in preparation of a drug for treating ovarian hypercalcemia type small cell carcinoma. The drug containing the PLK1 inhibitor can effectively treat the ovarian hypercalcemia type small cell carcinoma, inhibit growth of a lesion of the ovarian hypercalcemia type small cell carcinoma, has a quick effect, and can produce obvious therapeutic effect 20 days after administration.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of biological medicine, and particularly relates to application of a drug containing a PLK1 inhibitor in preparation of a drug for treating small cell carcinoma of the ovary-hypercalcemic type. BACKGROUND

[0002] Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a kind of highly malignant and extremely poor-prognosis rare gynecological tumor originating from the ovary, and there are less than 500 cases of global case reports so far. Small cell carcinoma of the ovary-hypercalcemic type is commonly seen in young women (14 months-58 years old, with a median age of onset of 24 years old). The tumor is prone to recurrence, and has poor prognosis, with a 1-year survival rate of only 50% and a 5-year survival rate of less than 10%.

[0003] Due to the rarity of small cell carcinoma of the ovary-hypercalcemic type, it is difficult to carry out clinical randomized controlled trials, and there is no standard treatment regimen at present. Moreover, small cell carcinoma of the ovary-hypercalcemic type has extremely high malignancy and extremely poor prognosis, and the research and development of new therapeutic drugs have become a problem to be solved in the clinical treatment of small cell carcinoma of the ovary-hypercalcemic type. Scientific research has found that the potential therapeutic drugs for small cell carcinoma of the ovary-hypercalcemic type at present mainly include: ① epigenetic therapy, such as EZH2 inhibitor, histone deacetylase (HDAC) inhibitor, lysine-specific histone demethylase 1 (LSD1) inhibitor; ② kinase inhibitor, such as RTK inhibitor, CDK4 / 6 inhibitor; ③ immunotherapy, PD-1 monoclonal antibody. However, not all patients respond to these drugs.

[0004] Although small cell carcinoma of the ovary-hypercalcemic type is a rare malignant ovarian tumor, in the populous China, there are still many patients and families suffering from this disease. Therefore, the invention of a new treatment method has a far-reaching significance for the treatment of patients with small cell carcinoma of the ovary-hypercalcemic type, and may add a glimmer of hope for the treatment of this disease.

[0005] Therefore, it is urgent to provide a drug for treating small cell carcinoma of the ovary-hypercalcemic type in the clinic, which has universality, is convenient to use, and has good treatment effect. SUMMARY

[0006] In view of the above-mentioned shortcomings of the prior art, the purpose of the present application is to provide application of a drug containing a PLK1 inhibitor in preparation of a drug for treating small cell carcinoma of the ovary-hypercalcemic type and application of a drug containing a PLK1 inhibitor in preparation of a drug for inhibiting growth of a lesion of small cell carcinoma of the ovary-hypercalcemic type, so as to solve the problems in the prior art.

[0007] To achieve the above object and other related objects, the present application provides the use of a medicament containing a PLK1 inhibitor in the preparation of a medicament for treating small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) and the use of a medicament containing a PLK1 inhibitor in the preparation of a medicament for inhibiting the growth of a lesion of small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT). As a new possible effective treatment for patients with small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT), the present application can prolong the life of patients with small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT).

[0008] The first aspect of the present application provides the use of a medicament containing a PLK1 inhibitor in the preparation of a medicament for treating small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT).

[0009] PLK1 inhibitor: A PLK1 inhibitor is an inhibitor of PLK1 protein, PLK1 is a serine / threonine protein kinase, PLK1 is highly expressed in various cancers, is necessary for the rapid proliferation of tumors, and in some cancers, is often associated with poor prognosis, it is inferred that PLK1 acts as an oncogene to accelerate the occurrence and development of tumors, and a PLK1 inhibitor can inhibit the function and activity of PLK1 protein.

[0010] Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a rare and highly invasive malignant tumor of the ovary. The genome of small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is diploid, characterized by mutations in SMARCA4 and loss of expression of SMARCA2. The loss of expression of BRG1 and BRM proteins encoded by the two in immunohistochemical staining becomes an important means for identifying the tumor in pathological diagnosis. Since it is a rare ovarian cancer, current research is mostly retrospective, there is no randomized controlled study, and there is no internationally recognized best treatment plan.

[0011] As certain embodiments of the present application, the PLK1 inhibitor in the medicament containing a PLK1 inhibitor is selected from the group consisting of: BI 2536, CFI-400945, WAY-619275, TAK-960 dihydrochloride, Rigosertib (ON-01910), Onvansertib (PCM-075, NMS-1286937, NMS-P937), TC-S 7005, HMN-176, Mpsl-IN-2, ON1231320, also known as GBO-006, SBE13 hydrochloride, HMN-214, TAK-960, Ro3280, MLN0905, GW843682X, Rigosertib (ON-01910) sodium, GSK461364, Volasertib (BI 6727), SBP-7455, BL-918, MRT68921 dihydrochloride, LYN-1604 dihydrochloride, ULK-101, LYN-16042HCl.

[0012] As certain embodiments of the present application, the medicament containing a PLK1 inhibitor further comprises a pharmaceutically acceptable carrier, excipient, and / or stabilizer.

[0013] The carrier pharmaceutically acceptable carrier includes one or more components selected from the group consisting of a binder, a filler, a lubricant, a glidant, a disintegrant, and a humectant.

[0014] The excipient includes hydroxypropyl methylcellulose, microcrystalline cellulose, starch glycolate, lactose, and magnesium stearate.

[0015] The stabilizer includes adipic acid, DL-alanine, dl-camphor, D-sorbitol solution, d-borneol, D-sorbitol, D-mannitol, L-ascorbic acid stearate, L-ascorbic acid sodium, L-aspartic acid, L-aspartic acid sodium, L-arginine, 1-menthol, beta-cyclodextrin, ascorbic acid, aminoethanesulfonic acid, sodium alginate, propylene glycol alginate, albumin, sulfur, inositol, anise powder, ethanol, calcium disodium edetate, sodium edetate, erythorbic acid, sodium erythorbate, cocoa butter, carboxyvinyl polymer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, agar, xanthan gum, xylitol, citric acid, calcium citrate.

[0016] The binder includes acacia, alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, dextrose, dextrin, dextrose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, sorbitol, starch, sugar syrup.

[0017] The filler includes calcium carbonate, calcium phosphate, calcium sulfate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, concentrated sugar, sugar paste sugar, dextrose, dextrin, dextrose, dicalcium phosphate dihydrate, calcium hydrogen phosphate, fructose, glyceryl palmitostearate, glycerin, hydrogenated vegetable oil-1, kaolin, lactose, corn starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylate, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar ball, talc, calcium phosphate, and xylitol.

[0018] Examples of the lubricant include calcium stearate, glycerin monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, sodium stearyl fumarate, talc, and zinc stearate.

[0019] The glidant includes colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc.

[0020] The disintegrant includes alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinized starch, sodium alginate, sodium lauryl sulfate, and sodium starch glycolate.

[0021] As certain embodiments of the present application, the pharmaceutical containing the PLK1 inhibitor is formulated into a solid, semi-solid, or liquid preparation for oral administration.

[0022] Preferably, the formulation of the pharmaceutical containing the PLK1 inhibitor includes a tablet, granules, microparticles, powder, capsule, soft capsule, pill, suspension, emulsion, liquid preparation for internal administration, syrup, or dry syrup; or the pharmaceutical containing the PLK1 inhibitor is made into microparticles before the preparation of the formulation.

[0023] Preferably, the pharmaceutical containing the PLK1 inhibitor is made into a microcapsule, nanocapsule, microsphere, or nanosphere.

[0024] As certain embodiments of the present application, the pharmaceutical comprising the PLK1 inhibitor is administered orally, sublingually, atomization, subcutaneously, intravenously, transdermally, enterally.

[0025] As certain embodiments of the present application, the human dosage of the pharmaceutical comprising the PLK1 inhibitor is 2-10 mg / kg of the PLK1 inhibitor.

[0026] The human dosage of the pharmaceutical comprising the PLK1 inhibitor is selected from the group consisting of 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0 mg / kg of the PLK1 inhibitor.

[0027] The present application also provides the use of the pharmaceutical comprising the PLK1 inhibitor in the preparation of a medicament for inhibiting the growth of a small cell lung cancer lesion of the hypercalcemic type.

[0028] As certain embodiments of the present application, the PLK1 inhibitor in the medicament containing a PLK1 inhibitor is selected from the group consisting of: BI 2536, CFI-400945, WAY-619275, TAK-960 dihydrochloride, Rigosertib (ON-01910), Onvansertib (PCM-075, NMS-1286937, NMS-P937), TC-S 7005, HMN-176, Mpsl-IN-2, ON1231320, also known as GBO-006, SBE13 hydrochloride, HMN-214, TAK-960, Ro3280, MLN0905, GW843682X, Rigosertib (ON-01910) sodium, GSK461364, Volasertib (BI 6727), SBP-7455, BL-918, MRT68921 dihydrochloride, LYN-1604 dihydrochloride, ULK-101, LYN-16042HCl.

[0029] As certain embodiments of the present application, the medicament containing a PLK1 inhibitor further comprises a pharmaceutically acceptable carrier, excipient and / or stabilizer.

[0030] The pharmaceutically acceptable carrier includes one or more components selected from the group consisting of a binder, a filler, a lubricant, a glidant, a disintegrant and a humectant.

[0031] The excipient includes hydroxypropyl methylcellulose, microcrystalline cellulose, starch glycolate, lactose and magnesium stearate.

[0032] The stabilizer includes adipic acid, DL-alanine, dl-camphor, D-sorbitol solution, d-borneol, D-sorbitol, D-mannitol, L-ascorbic acid stearate, L-ascorbic acid sodium, L-aspartic acid, L-aspartic acid sodium, L-arginine, 1-menthol, beta-cyclodextrin, ascorbic acid, aminoethanesulfonic acid, sodium alginate, propylene glycol alginate, albumin, sulfur, inositol, anise powder, ethanol, calcium disodium edetate, sodium edetate, erythorbic acid, sodium erythorbate, cocoa butter, carboxyvinyl polymer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, agar, xanthan gum, xylitol, citric acid, calcium citrate.

[0033] The binder includes acacia, alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, dextrose, dextrin, dextrose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, sorbitol, starch, sugar syrup.

[0034] The filler includes calcium carbonate, calcium phosphate, calcium sulfate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, concentrated sugar, sugar paste sugar, dextrose, dextrin, dextrose, dicalcium phosphate dihydrate, calcium hydrogen phosphate, fructose, glyceryl palmitostearate, glycerin, hydrogenated vegetable oil-1, kaolin, lactose, corn starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylate, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar ball, talc, calcium phosphate, and xylitol.

[0035] Examples of the lubricant include calcium stearate, glycerin monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, sodium stearyl fumarate, talc, and zinc stearate.

[0036] The glidant includes colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc.

[0037] The disintegrant includes alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinized starch, sodium alginate, sodium lauryl sulfate, and sodium starch glycolate.

[0038] As certain embodiments of the present application, the pharmaceutical containing the PLK1 inhibitor is prepared into a solid, semi-solid, or liquid formulation for oral administration.

[0039] Preferably, the formulation of the pharmaceutical containing the PLK1 inhibitor includes a tablet, granules, microparticles, powder, capsule, soft capsule, pill, suspension, emulsion, liquid formulation for internal administration, syrup, or dry syrup; or the pharmaceutical containing the PLK1 inhibitor is prepared into microparticles before the preparation of the formulation.

[0040] Preferably, the pharmaceutical containing the PLK1 inhibitor is prepared into a microcapsule, nanocapsule, microsphere, or nanosphere.

[0041] As certain embodiments of the present application, the PLK1 inhibitor-containing medicament is administered orally, sublingually, atomization, subcutaneously, intravenously, transdermally, or enterally.

[0042] As certain embodiments of the present application, the PLK1 inhibitor-containing medicament is administered orally, sublingually, atomization, subcutaneously, intravenously, transdermally, or enterally.

[0043] The PLK1 inhibitor-containing medicament is administered in an amount of 2-10 mg / kg of the PLK1 inhibitor.

[0044] As certain embodiments of the present application, the PLK1 inhibitor-containing medicament is administered orally, sublingually, atomization, subcutaneously, intravenously, transdermally, or enterally.

[0045] The PLK1 inhibitor-containing medicament is administered in an amount of 2-10 mg / kg of the PLK1 inhibitor. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 Figure 1 shows the comparison of tumor size of the CDX (cell derived xenograft) animal model of the ovarian hypercalcemia type small cell carcinoma patient of the present application injected with BI2536 and control solvent twice a week, after 30 days;

[0047] Figure 2 Figure 2 shows the change of tumor volume of the CDX (cell derived xenograft) animal model of the ovarian hypercalcemia type small cell carcinoma patient of the present application injected with BI2536 and control solvent twice a week, over time. DETAILED DESCRIPTION

[0048] The present application is further described in connection with the following embodiments, which are not intended to limit the scope of the application. Those skilled in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially the same results. The applications set forth in the following specification can be implemented as sets of instructions stored in a machine- accessible storage medium so as when executed by a machine to cause the machine to perform the operations described. The applications can also be implemented as machine-executable instructions capable of remote execution. While the applications have been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the applications and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains.

[0049] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The materials, methods, and examples provided herein are illustrative only and, accordingly, can not be intended to limit the scope of the application. Unless otherwise indicated, the materials, methods, and examples that can be used in the present application are described in more detail below.

[0051] Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed in the present application all use conventional techniques in the art and conventional techniques in related fields.

[0052] Materials and Methods

[0053] 1. Experimental materials and methods

[0054] 1.1 Materials

[0055] Cell derived xenograft (CDX), which is to inoculate tumor cells cultured in vitro into immunodeficient mice, and to make tumors in nude mice.

[0056] Nude mice tumor formation experiment, which is to inject tumor cells subcutaneously into nude mice, and to observe tumor formation, development, and the effect of anti-tumor drugs.

[0057] 2. Experimental methods

[0058] Eight 5-week-old nude mice were taken, and 1x10 6SCCOHT-CH-1 (ovarian hypercalcemia type small cell carcinoma primary tumor cells) were subcutaneously inoculated into nude mice. After 5 days of inoculation, when 8 nude mice were subcutaneously tumorous and the average tumor volume reached 100 mm 3 When the average tumor volume reached 100 mm

[0059] The tumor size was measured twice a week, and the body weight was measured every day. The calculation formula of the tumor size was: tumor volume = tumor long diameter x tumor short diameter 2 × 0.5

[0060] After 30 days of administration of the PLK1 inhibitor and the control reagent, the sizes of the subcutaneous tumors of the mice in the control group and the experimental group were observed. It was observed that the tumor of the mouse in the control group reached about 3000 mm 3 , and all the mice were sacrificed, and the tumor mass was stripped out. The sizes of the tumor masses of the experimental group and the control group were compared to determine the inhibition effect of the PLK1.

[0061] The calculation formula of the tumor inhibition rate was:

[0062] Tumor inhibition rate (T / C) = (1-T / C) x 100, wherein T represents the average size of the tumor in the test group, and C represents the average size of the tumor in the control group.

[0063] Example 1

[0064] After the end of the experiment, the sizes of the tumors of the control group and the group administered with the PLK1 inhibitor were measured, as shown in Table 1:

[0065] Table 1

[0066] Group 1 2 3 4 Control group 3151 mm 3 ]]> 2971 mm 3 ]]> 2898 mm 3 ]] 3174 mm 3 ]] PLK1 inhibitor administration group 940 mm 3 ]] 2349 mm 3 ]] 303 mm 3 ]] 2157 mm 3 ]]

[0067] The comparison of the tumor masses of the two groups is shown in Figure 1 . It can be seen that the injection of the PLK1 inhibitor drug BI2536 can effectively reduce the tumor mass size. According to the progress of the experiment, 13 days after the first injection of the PLK1 inhibitor drug, the tumor mass sizes of the two groups changed significantly. After 30 days of the experiment, the tumor volume of the group using the PLK1 inhibitor drug was significantly reduced.

[0068] Figure 2 The average sizes of the tumor masses of the two groups over time are shown. According to the average sizes of the tumor masses of the two groups on the 30th day, the inhibition efficiency of the PLK1 inhibitor drug on the tumor was calculated to be 53%, indicating that the PLK1 inhibitor drug can effectively inhibit the growth of the tumor.

[0069] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application in any form or in essence. It should be noted that those skilled in the art can make some improvements and supplements without departing from the method of the present application, and these improvements and supplements should also be considered as the protection scope of the present application. For those skilled in the art, some slight changes, modifications and equivalent changes made by using the disclosed technical content without departing from the spirit and scope of the present application are equivalent embodiments of the present application; meanwhile, any equivalent changes, modifications and evolution made according to the essential technology of the present application to the above embodiments are still within the scope of the technical solutions of the present application.

Claims

1. Use of a medicament comprising a PLK1 inhibitor for the manufacture of a medicament for the treatment of small cell cancer of the hypercalcemic type of ovary, said medicament comprising a PLK1 inhibitor in an amount of 2-10 mg / kg of body weight of PLK1 inhibitor; said PLK1 inhibitor being selected from the group consisting of BI 2536.

2. Use of a medicament comprising a PLK1 inhibitor for the manufacture of a medicament for the inhibition of the growth of a lesion of small cell cancer of the hypercalcemic type of ovary, said medicament comprising a PLK1 inhibitor in an amount of 2-10 mg / kg of body weight of PLK1 inhibitor; said PLK1 inhibitor being selected from the group consisting of BI 2536.

3. Use according to claim 1 or 2, characterized in that, said medicament comprising a PLK1 inhibitor further comprises a pharmaceutically acceptable carrier.

4. Use according to claim 1 or 2, characterized in that, said medicament comprising a PLK1 inhibitor is prepared as a solid, semi-solid or liquid preparation for oral administration.

5. Use according to claim 1 or 2, characterized in that, said medicament comprising a PLK1 inhibitor is prepared as a tablet, granule, powder, capsule, pill, suspension, emulsion or syrup.

6. Use according to claim 1 or 2, characterized in that, said medicament comprising a PLK1 inhibitor is prepared as a microparticle before being prepared as a formulation.

7. Use according to claim 1 or 2, characterized in that, said medicament comprising a PLK1 inhibitor is administered orally, sublingually, subcutaneously or intravenously.

Images