Use of homovanillyl alcohol for the preparation of a medicament for the treatment of ovarian tumors

Abstract

The application discloses use of homovanillyl alcohol in preparation of a drug for treating ovarian tumors and belongs to the technical field of medicines. The homovanillyl alcohol is a component of a queen mandible gland pheromone. Experimental results show that the homovanillyl alcohol can selectively inhibit ovarian tumor cell proliferation and has no obvious inhibiting effect on normal ovarian epithelial cells; the mechanism of action is to induce DNA replication fork stasis and cell cycle S phase arrest, thereby inhibiting tumor cell proliferation. Animal experiments further show that the homovanillyl alcohol can significantly inhibit ovarian tumor growth, no obvious toxic side effects are observed in a therapeutically effective amount range, and the homovanillyl alcohol has good safety. The application provides a basis for application of the homovanillyl alcohol in preparation of a drug for treating ovarian tumors, and is especially suitable for preparation of a drug for treating high-grade serous ovarian cancer.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of homovanillyl alcohol, a component of the queen bee's maxillary gland pheromone, in the preparation of drugs for treating ovarian tumors. Background Technology

[0002] High-grade serous ovarian cancer (HGSOC) is the most common histological type of ovarian cancer, characterized by high genetic heterogeneity and aggressiveness. Current treatments primarily involve surgery and chemotherapy, but these come with a range of side effects, necessitating the development of new treatment strategies and drugs.

[0003] Evolutionary developmental biology research shows that humans and distantly related animals such as bees share a highly conserved set of developmental regulatory genes, or a genetic toolkit. For example, bees have evolved a queen mandibular pheromone (QMP), which can inhibit worker bee reproduction by suppressing ovarian development and inducing ovarian cell apoptosis (Duncan, EJ, et al Notch signaling mediates reproductive constraint in the adult worker honeybee. Nature Communications , 2016, 7(1): 12427; Ronai, I., et al Queen pheromone regulates programmed cell death in the honey bee worker ovary. Insect Molecular Biology , 2016, 25(5): 646-652.). Further research found that the queen bee's mandibular gland pheromone can also inhibit ovarian development in distant arthropods such as termites, ants, crustaceans, and fruit flies (Carlisle, DB and CG Butler. The 'Queen-Substance' of Honeybees and the Ovary-inhibiting Hormone of Crustaceans). Nature, 1956, 177(4502): 276-277.; Camiletti, AL, et al Honey bee queen mandibular pheromone inhibits ovary development and fertility in a fruit fly. Entomologia Experimentalis et Applica (2013, 147(3): 262-268.). The above study suggests that queen bee mandibular gland pheromones can regulate highly conserved developmental regulatory pathways related to cell proliferation across species. Based on this, it is necessary to further investigate whether queen bee mandibular gland pheromones can also produce cross-species biological effects on mammals.

[0004] To date, no studies have reported that queen bee maxillary gland pheromones or their components have the effect of inhibiting the proliferation of human cancer cells. Summary of the Invention

[0005] The purpose of this invention is to identify that homovanillyl alcohol (HVA), an active component of queen mandibular pheromone (QMP), has a therapeutic effect on ovarian tumors, thereby providing a new approach for the safe and effective clinical treatment of ovarian tumors, especially high-grade serous ovarian cancer (HGSOC).

[0006] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides the use of homovanillyl alcohol (HVA) in the preparation of a medicament for treating ovarian tumors. Homovanillyl alcohol is a component of queen bee maxillary gland pheromone (QMP), sometimes also called vanillylmethanol, with the chemical name 2-(3-methoxy-4-hydroxyphenyl)ethanol (also known as 4-hydroxy-3-methoxyphenylethanol), its molecular formula being HOC6H3(OCH3)CH2CH2OH, and its structural formula being shown in formula (I). (I).

[0007] This invention has found that homovanillin can significantly reduce the in vitro survival rate of ovarian tumor cells, while having no significant inhibitory effect on normal ovarian cells. Simultaneously, homovanillin can significantly inhibit the growth of ovarian tumors in mice. Animal experiments showed that no significant toxic side effects were observed with homovanillin at doses not exceeding 480 mg / kg. Therefore, homovanillin can be developed as a candidate drug for the treatment of ovarian tumors.

[0008] Furthermore, the ovarian tumor verified in this invention is high-grade serous ovarian cancer (HSC). High-grade serous ovarian cancer is one of the most common and most aggressive histological subtypes of ovarian cancer. This invention provides a new treatment option for high-grade serous ovarian cancer.

[0009] Further studies on the mechanism of action have shown that homovanillin inhibits the proliferation of ovarian tumor cells by inducing DNA replication fork arrest and inhibiting DNA replication in S-phase cells.

[0010] Further mechanistic studies suggest that heterophilic and polyphilic retroviral receptor 1 (XPR1) may be an important molecular target mediating the antitumor effects of homovanillin.

[0011] Another object of the present invention is to provide a pharmaceutical composition for treating ovarian cancer, said pharmaceutical composition comprising a therapeutically effective amount of pervanillin and a pharmaceutically acceptable carrier.

[0012] The "therapeutic effective dose" as described in this invention refers to the dosage of a compound that can produce a therapeutic effect during the treatment of a subject's disease. The therapeutic effective dose can be adjusted according to the severity of the disease and factors such as the subject's physical condition, age, weight, and gender.

[0013] The pharmaceutically acceptable carrier refers to a carrier or excipient capable of delivering a therapeutically effective amount of the active ingredient without affecting its biological activity and without toxic side effects on the host or subject. The pharmaceutically acceptable carrier includes one or more components selected from fillers, wetting agents, binders, disintegrants, and lubricants.

[0014] The pharmaceutical composition can be prepared into the corresponding dosage form according to the method described in the pharmacopoeia, and the dosage form can be a liquid preparation or a solid preparation.

[0015] Furthermore, the dosage form of the pharmaceutical composition may be an injectable formulation, but is not limited thereto.

[0016] The present invention also provides the use of the pharmaceutical composition in the preparation of a medicament for treating ovarian cancer.

[0017] Furthermore, the ovarian cancer includes, but is not limited to, high-grade serous ovarian cancer.

[0018] Compared with the prior art, the present invention has the following beneficial effects: This invention discovers a novel use for homovanillin in the preparation of drugs for treating ovarian tumors. Homovanillin is a component of queen bee maxillary gland pheromones (QMPs). The results of this invention show that homovanillin can specifically inhibit the survival of ovarian tumor cells. Its mechanism of action involves inducing replication stress and arresting the cell cycle in the S phase, thereby inhibiting tumor cell proliferation. Furthermore, within the therapeutically effective range, homovanillin did not exhibit significant toxic side effects and demonstrated good biocompatibility. Therefore, this invention provides new insights into the development of novel clinical applications for homovanillin and offers a new pathway for developing new drugs to treat ovarian tumors, especially high-grade serous ovarian cancer. Attached Figure Description

[0019] Figure 1 This figure shows the screening results of the inhibitory effect of homovanillin (HVA) on the proliferation of high-grade serous ovarian cancer (HGSOC) cell lines and control cell lines. Among them, SPCA, OVCAR4, Kuramochi, and IGROV1 are HGSOC cell lines; IOSE is a normal ovarian epithelial cell line; and SCCOHT1 is a non-HGSOC ovarian cancer cell line.

[0020] Figure 2 This image shows the cell cycle analysis results of Kuramoch ovarian cancer cells after HVA treatment. Cells were treated with either the solvent control or HVA for 72 hours, then stained with propidium iodide (PI) and analyzed by flow cytometry. In the figure, A represents cell cycle analysis after solvent control treatment; B represents cell cycle analysis after HVA treatment.

[0021] Figure 3 This is a statistical graph for cell cycle analysis. * indicates a significant difference between groups. P <0.05, ** indicates P <0.01.

[0022] Figure 4 Flow cytometry analysis of the effect of HVA treatment on apoptosis, using Annexin V staining. Cells were treated with solvent control, HVA for 3 days, and cisplatin for 3 days, respectively, before Annexin V staining and flow cytometry analysis. The cisplatin group served as a positive control. The percentage of Annexin V-positive cells in each group is indicated in the figure.

[0023] Figure 5The image shows the results of DNA replication fork analysis. A represents the DNA fiber image, where two nucleotide analogs infiltrated into the nascent DNA strand were labeled with red and green fluorescent dyes using specific antibodies. Compared to the solvent control group, the length of the nascent DNA strand treated with HVA was significantly shortened, indicating that DNA replication fork propagation was inhibited and halted. Hydroxyurea was used as a positive control to induce replication fork stagnation. B shows the quantitative statistical results of DNA replication fork velocity in each treatment group. * indicates significant differences between groups, and **** indicates... P <0.0001.

[0024] Figure 6 This figure shows the results of a mouse experiment using HVA to treat orthotopic xenografts of OVCAR4 high-grade serous ovarian cancer. OVCAR4 cells were orthotopically inoculated into the ovarian bursa of mice. One week after transplantation, treatment with 480 mg / kg HVA was initiated, administered 5 days a week for 3 consecutive weeks. The scale bar in the figure is 1 cm.

[0025] Figure 7 Tumor growth statistics in tumor-bearing mice after 3 weeks of continuous treatment with 480 mg / kg HVA. In the figure, A represents the tumor weight of each group; B represents the tumor volume of each group. * indicates significant differences between groups, and ** indicates significant differences between groups. P <0.01, *** indicates P <0.001.

[0026] Figure 8 The figure shows the changes in body weight of tumor-bearing mice after 3 weeks of continuous treatment with 240 mg / kg and 480 mg / kg HVA, respectively.

[0027] Figure 9 This figure presents the results of mass spectrometry analysis to identify the binding of homovanillin to XPR1. Potential binding proteins were enriched using biotin-labeled HVA, and candidate target genes were identified by mass spectrometry. In the figure, the horizontal axis represents the enrichment fold of candidate proteins compared to the control group, and the vertical axis represents the -log10 (BDFR) value based on the significance level after multiple test correction.

[0028] Figure 10 To verify the binding of homovanillin to XPR1 using Western blot, affinity enrichment of biotin-labeled homovanillin was performed, followed by detection of XPR1 using Western blot to validate the binding of homovanillin to XPR1. Detailed Implementation

[0029] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions or improvements made to the present invention by those skilled in the art without departing from the spirit and substance of the present invention shall fall within the scope of protection of the present invention.

[0030] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods in the art; the materials, reagents and instruments used are all available from commercial sources.

[0031] Experimental Example 1: Screening of cell lines with high vanillin levels inhibiting cell proliferation activity 1. Cell Culture Methods Kuramochi, IGROWV1, SCCOHT1, OVCAR4, and IOSE121 cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS).

[0032] SPCA cells are one of five mouse cell lines constructed in Robert A. Weinberg's laboratory to mimic the molecular subtype of high-grade serous ovarian cancer (HGSOC) (Iyer, S., et al Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of Combination Immunotherapy: Genetically Defined High-Grade Serous Ovarian Cancer Models. Cancer Discovery , 2021, 11(2): 384-407.). According to the provided culture conditions, DMEM medium containing 10% fetal bovine serum was used for culture, and the culture was passaged every 3 days.

[0033] 2. Reagents Homovanillyl alcohol (HVA, catalog number: TRC-V097630, Toronto Research Chemicals; catalog number: 148830, Sigma); Hydroxyurea (catalog number: H8627-10G, Sigma).

[0034] 3. Screening of cell lines with high vanillin levels that inhibit cell proliferation Experimental Methods: A 5-day crystal violet cell proliferation assay was used to detect the effect of high vanillin (HVA) on the proliferation of different ovarian cancer cell lines. Cells were seeded at a density of approximately 20,000 cells / well in 6-well plates, depending on the cell line. Cells were then treated daily with DMSO or a corresponding compound at a specified concentration for 5 consecutive days. Cells were then fixed with 1×PBS containing 4% formaldehyde and stained with 0.1% crystal violet dissolved in 10% ethanol. After drying the culture plates overnight, the crystal violet dye was dissolved in 500 μL of 10% acetic acid. Absorbance was measured using a multi-mode microplate reader (EnSpire, PerkinElmer). Proliferation curves were plotted using GraphPadPrism software, and the half-maximal inhibitory concentration (IC50) was calculated by fitting the curve to a nonlinear regression sigmoid model. 50 ( ), which is the drug concentration at which the cell survival rate decreases to 50% relative to the solvent control group.

[0035] Experimental results: such as Figure 1 As shown, high vanillin significantly inhibited the proliferation of high-grade serous ovarian cancer (HGSOC) cell lines, but had no significant inhibitory effect on normal ovarian epithelial cell line IOSE and non-HGSOC ovarian cancer cell line SCCOHT1.

[0036] The above results indicate that high vanillin can selectively inhibit the survival of HGSOC cells, providing a basis for further research on its mechanism of action in inhibiting the proliferation of ovarian tumor cells.

[0037] Experimental Example 2: High vanillin-induced S-phase arrest in high-grade serous ovarian cancer cells 1. Experimental Objective The inhibitory effect of homovanillin on tumor cell proliferation may be achieved through inducing cell cycle arrest (cytostatic effect) or inducing cell death (cytotoxic effect). To clarify the mechanism of action of homovanillin on tumor cells, this embodiment uses propidium iodide (PI) combined with flow cytometry to analyze the cell cycle and distinguish between the two mechanisms of action.

[0038] PI is a fluorescent nuclear dye that binds to DNA. It can be used to determine the distribution of cells in different stages of the cell cycle based on cellular DNA content, thereby identifying cell cycle arrest. A strong S-phase signal usually indicates that cell proliferation has stopped, but it cannot identify apoptosis.

[0039] To determine whether high vanillin promotes apoptosis, we used Annexin V, an early apoptosis indicator, for staining.

[0040] 2. Experimental Methods Kuramochchi cells were seeded in 10 cm culture dishes and treated with either dimethyl sulfoxide (DMSO) or 0.7 mM homovanillin (HVA) once daily for 3 consecutive days. In cell cycle assays, treatment with 2 mmol / L hydroxyurea for 2 h served as a positive control. In apoptosis assays, cisplatin treatment served as a positive control.

[0041] Cells were collected, washed with phosphate-buffered saline (PBS), and fixed with 70% ethanol, followed by two more washes with PBS. Cells were resuspended in 400 μL of FxCycle PI / RNase staining solution (catalog number: F10779, Invitrogen) and incubated at room temperature in the dark for 30 min. Cell cycle distribution was analyzed using a FACSCanto II flow cytometer (BD Biosciences) and ModFit LT 4.1.7 software (Verity Software House, Maine, USA).

[0042] After another batch of cells were collected, they were first fixed, then detected and quantified using FITC-labeled annexin V antibody, and subsequently analyzed by flow cytometry.

[0043] 3. Experimental Results like Figure 2 and Figure 3 As shown, high-grade serous ovarian cancer (HGSOC) cells were significantly arrested in S phase after being treated with 0.7 mM vanillin for 3 days.

[0044] like Figure 4 As shown, in the apoptosis assay, the proportion of Annexin V-positive cells was 3.28%, only slightly higher than the 2.75% in the negative control group; in contrast, the proportion of Annexin V-positive cells in the cisplatin-positive control group was significantly higher at 61.9%. These results indicate that under the experimental conditions, HVA treatment did not significantly induce apoptosis.

[0045] Experimental Example 3: Study on DNA Replication Fork Arrest Induced by High Vanillin 1. Experimental Objective Since high vanillin can induce S-phase arrest in high-grade serous ovarian cancer cells, this embodiment further investigates whether cell accumulation in the S-phase is related to DNA replication defects.

[0046] 2. Experimental Methods Kuramochi cells in asynchronous growth were seeded in 6-well plates and treated for 24 hours with DMSO, 2 mM homovanillin (HVA), and hydroxyurea (Hydroxyurea, HU, positive control), respectively. Subsequently, nascent DNA was labeled with the thymidine analog 5-chloro-2′-deoxyuridine (CldU, 30 μmol / L, catalog number: C6891, Sigma-Aldrich) for 30 min. After washing three times with 1×PBS, cells were labeled again with 5-iodo-2′-deoxyuridine (IdU, 250 μmol / L, catalog number: I7125, Sigma-Aldrich) for 30 min. After labeling, cells were collected and resuspended in 1×PBS to a final cell concentration of 1000 cells / μL. Add 2.2 μL of cell suspension to a glass slide and allow it to air dry at room temperature until the droplet volume slightly decreases. Then add 7.5 μL of lysis buffer (0.5% SDS, 200 mmol / L Tris-HCl (pH 7.4), and 50 mmol / L EDTA), mix well, and incubate at room temperature for 3 min. Subsequently, tilt the glass slide at approximately 15° to allow the DNA fibers to spread fully under gravity.

[0047] DNA fibers were fixed at room temperature for 10 min using pre-cooled, freshly prepared methanol / glacial acetic acid (3:1 v / v) fixative. Immunofluorescence staining was then performed for 2 h using primary antibodies. Anti-BrdU antibody ab6326 (rat-derived, recognizes CldU, 1:100) and anti-BrdU antibody 347580 (mouse-derived, BD Biosciences, recognizes IdU, 1:25) were both prepared in PBS containing 5% BSA. Images were acquired using a Zeiss LSM 800 Airyscan confocal microscope (Oberkochen, Germany), and the lengths of CldU and IdU-labeled fragments in individual DNA fibers were measured using ImageJ software. The replication fork extension rate was calculated using the following formula: Copy fork extension rate = (CldU fragment length + IdU fragment length) ÷ total marking time (60 min).

[0048] 3. Experimental Results like Figure 5 As shown, after treating high-grade serous ovarian cancer (HGSOC) cells with homovanillin (HVA) for 24 h, the newly formed DNA fibers labeled with CldU and IdU were immunofluorescently stained, and the length of the DNA fibers was measured. The results showed that, compared with the control group, the length of the newly formed DNA fibers was significantly shortened after homovanillin treatment, suggesting that DNA replication fork arrest occurred.

[0049] The above results indicate that high vanillinol inhibits the proliferation of ovarian tumor cells by inducing DNA replication fork arrest and inhibiting DNA replication in S-phase cells.

[0050] Experimental Example 4: Inhibitory effect of high vanillin on the in vivo growth of ovarian tumors 1. Experimental Objective To verify whether the tumor cell growth inhibition effect observed in in vitro experiments by high vanillin is also applicable to in vivo tumor models, this embodiment uses an orthotopic ovarian cancer transplantation mouse model to evaluate the inhibitory effect of high vanillin on tumor growth.

[0051] 2. Experimental Methods First, a dose-escalation experiment was used to evaluate the toxicity of high vanillinol (HVA) in mice and determine its maximum tolerated dose, while monitoring toxicity indicators such as changes in mouse body weight. No significant toxic reactions were observed in C57BL / 6 mice and NOD SCID mice when the administered dose did not exceed 480 mg / kg.

[0052] Subsequently, the in vivo antitumor effect of homovanillin was evaluated using an orthotopic ovarian cancer transplantation mouse model. An orthotopic tumor model was established by injecting OVCAR4 cell suspension (resuspended in PBS) into the ovarian bursa of one side of immunodeficient NOD SCID mice (Charles River Laboratories). One week after tumor growth, administration began with intraperitoneal injection of homovanillin at 480 mg / kg, once daily for 5 days a week for 3 consecutive weeks. Six mice were included in each of the treatment and solvent control groups.

[0053] After the experiment, the mice were euthanized, the tumor tissue was isolated, fixed in formaldehyde, and the tumor weight was measured. The major and minor diameters of the tumor were measured using a digital caliper, and the tumor volume was calculated using the following formula: Tumor volume (mm) 3 = 1 / 2 × major diameter (mm) × [minor diameter (mm)] 2 .

[0054] All animal experiments were conducted in accordance with the standard operating procedures and ethical guidelines for animal experiments approved by Lady Davis Institute for Medical Research and McGill University (Animal Experiment Approval No.: JGH-7805).

[0055] 3. Experimental Results like Figure 6 and Figure 7As shown, compared with the solvent control group, the tumor weight and tumor volume of mice treated with high vanillin (HVA) were significantly reduced.

[0056] like Figure 8 As shown, tumor-bearing mice treated with 240 mg / kg or 480 mg / kg of high vanillin did not show a significant decrease in body weight, indicating that high vanillin did not cause significant systemic toxicity at the above dosages.

[0057] The above results indicate that in a mouse model of orthotopic ovarian cancer transplantation, high vanillin can significantly inhibit ovarian tumor growth without showing obvious toxic side effects.

[0058] Experimental Example 5: Verification of the binding of hypervanillin to XPR1 1. Experimental Objective To identify the target of homovanillin (HVA) in high-grade serous ovarian cancer (HGSOC) cells, this embodiment screened and validated proteins that can bind to homovanillin.

[0059] 2. Experimental Methods Lysate from high-grade serous ovarian cancer cells (Kuramochi) was incubated with either biotin-labeled homovanillinol (Biotin-HVA) or biotin-labeled p-hydroxybenzoate (Biotin-HOB), a component of the queen bee maxillary gland pheromone. Proteins bound to the biotin-labeled compounds were enriched using streptavidin beads, and identified and validated by mass spectrometry and Western blot after elution.

[0060] 3. Experimental Results Mass spectrometry analysis results as follows Figure 9 As shown, heterophilic and polyphilic retroviral receptor 1 (XPR1) is one of the main candidate proteins for binding to homovanillin (HVA). XPR1 is a cell surface protein involved in the efflux of intracellular phosphate. Previous studies have shown that XPR1 is highly expressed in ovarian cancer and can promote the proliferation of ovarian cancer cells (Bondeson). et al Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer. Nature cancer, 2022, 3(6): 681-695.).

[0061] Further validation was performed using Western blot, employing the XPR1 antibody (Thermo Fisher; catalog number MA5-56923). Results are as follows: Figure 10 As shown, the results indicate that: (1) high vanillin can bind to XPR1; (2) unlabeled high vanillin can competitively inhibit the binding of biotin-labeled high vanillin (Biotin-HVA) to XPR1; and (3) another component of queen bee maxillary gland pheromone (QMP), p-hydroxybenzoic acid (HOB), cannot bind to XPR1.

[0062] The above results indicate that XPR1 is a binding target protein of high vanillin, and this binding characteristic is not shared by all components of the queen bee's mandibular gland pheromone.

[0063] Summary of results: In summary, homovanillyl alcohol (HVA), a component of queen mandibular pheromone (QMP), significantly inhibited the proliferation of high-grade serous ovarian cancer (HGSOC) cells in vitro, while having no significant effect on normal ovarian epithelial cells. Further studies showed that homovanillyl alcohol exerts its antitumor effect by inducing DNA replication fork arrest and cell cycle S-phase arrest. In a mouse model of orthotopic ovarian cancer transplantation, homovanillyl alcohol significantly inhibited tumor growth without exhibiting significant toxic side effects. Furthermore, homovanillyl alcohol specifically binds to XPR1, suggesting that XPR1 may be an important molecular target mediating its antitumor effect.

[0064] The present invention has been described in detail above with reference to specific embodiments, but the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions or variations made to the present invention by those skilled in the art without departing from the spirit and substance of the present invention shall fall within the scope of protection of the present invention.

Claims

1. Use of homovanillyl alcohol for the preparation of a medicament for the treatment of ovarian tumors, characterized in that, The structural formula of the high vanillinol is shown in formula (I). （I）。 2. Use according to claim 1, characterized in that, The ovarian tumor was high-grade serous ovarian cancer.

3. Use according to claim 1, characterized in that, The high vanillinol inhibits the proliferation of ovarian tumor cells by inducing DNA replication fork arrest and inhibiting DNA replication in S-phase cells.

4. A pharmaceutical composition for treating ovarian cancer, characterized by, The pharmaceutical composition comprises a therapeutically effective amount of vanillin and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein, The pharmaceutically acceptable carrier includes one or more components selected from fillers, wetting agents, disintegrants, binders, and lubricants.

6. The pharmaceutical composition of claim 4, wherein, The pharmaceutical composition is a liquid or solid dosage form.

7. The pharmaceutical composition of claim 4, wherein, The pharmaceutical composition is an injectable formulation.

8. Use of the pharmaceutical composition according to any one of claims 4-7 in the preparation of a medicament for treating ovarian cancer.

9. Use according to claim 8, characterized in that, The ovarian cancer in question is high-grade serous ovarian cancer.

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