Use of quisinostat in preparation of drug, and method for treating or preventing neuroendocrine tumors

Abstract

The use of Quisinostat or an isomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt, prodrug, or derivative thereof in the preparation of a drug for treating or preventing neuroendocrine tumors, and a method for treating or preventing neuroendocrine tumors. Studies have found that Quisinostat can inhibit neuroendocrine tumor growth in a dose-dependent manner, has high drug sensitivity and a significant tumor inhibition effect, is a new candidate drug for the clinical treatment of neuroendocrine tumors, and has high clinical value.

Description

Use of Quisinostat in the preparation of a medicament, method of treating or preventing neuroendocrine tumors TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to the use of Quisinostat or its isomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, its prodrugs or derivatives thereof in the preparation of a medicament for treating or preventing neuroendocrine tumors, a method of treating or preventing neuroendocrine tumors. BACKGROUND

[0002] Neuroendocrine tumors are a group of heterogeneous tumors originating from neuroendocrine cells, which are distributed in multiple organs throughout the body, including lung, gastrointestinal tract and pancreas, etc. According to the latest release of SEER database, the global incidence of neuroendocrine tumors is 6.98 / 100,000 per year, of which gastrointestinal pancreatic neuroendocrine tumors are about 3.56 / 100,000, accounting for 51%, and the top three are lung, small intestine and rectum. Although neuroendocrine tumors grow slowly as a whole, some types of neuroendocrine tumors, such as neuroendocrine subtype in small cell lung cancer, show high invasiveness and poor prognosis.

[0003] The current treatment of neuroendocrine tumors mainly includes surgery, drug therapy (such as somatostatin analogues, targeted therapy, chemotherapy, biological therapy), radiotherapy, interventional therapy and supportive therapy, etc., forming a multidimensional comprehensive treatment strategy. Although these methods can relieve symptoms, control tumor growth and even prolong patient survival to some extent, the existing treatment still faces many challenges. For example, surgery is not suitable for all patients, especially for advanced metastatic patients; in drug therapy, chemotherapy has limited efficacy on neuroendocrine tumors and obvious side effects; targeted therapy and immunotherapy show certain prospects, but the response rate and durability vary significantly among different patients; and small molecule drugs can more effectively penetrate cell membranes and target specific molecular targets in tumor cells, such as abnormally activated signaling pathways, thereby improving treatment efficiency while reducing damage to normal tissues. This high specificity and lower systemic toxicity make small molecule drugs an important direction to improve the precision of neuroendocrine tumor treatment and the quality of life of patients. Therefore, the development of small molecule drugs for neuroendocrine tumors has positive clinical value.

[0004] Quisinostat 2HCl is a highly active histone deacetylase (HDAC) inhibitor, belonging to the second generation of HDAC inhibitors. It regulates gene expression by acting on multiple HDAC enzymes (especially HDAC1, 2, 3, 6 and 10), thereby affecting cell proliferation, differentiation and apoptosis, etc. In cell and animal models, Quisinostat 2HCl shows significant anti-tumor activity and can inhibit the growth of various cancers (including but not limited to hematological tumors and solid tumors). Preclinical studies have shown that Quisinostat 2HCl can enhance the sensitivity of DNA damage repair pathways, promote tumor cell apoptosis, and reverse drug resistance phenotype, making it a potential candidate drug for tumors resistant to traditional therapy. Currently, Quisinostat 2HCl is in various clinical trial stages, including but not limited to acute myeloid leukemia, myelodysplastic syndrome, lymphoma, breast cancer, etc., but its therapeutic effect in neuroendocrine tumors has not been reported.

[0005] SUMMARY

[0006] The present application is based on the discovery and understanding of the inventors on the following problems:

[0007] The present application discovers the new effect of Quisinostat 2HCl in treating neuroendocrine tumors. The inventors found through in vitro and in vivo experiments that Quisinostat 2HCl can inhibit the growth and proliferation of neuroendocrine cervical cancer organoids in vitro in a dose-dependent manner, and can completely kill neuroendocrine cervical cancer organoids at working concentrations of 10 μM, 1 μM and 0.1 μM, with an IC 50 less than 10 nM, showing extremely high drug sensitivity. Further in vivo verification experiments in mice showed that Quisinostat 2HCl can effectively inhibit the growth of neuroendocrine cervical cancer organoid transplanted tumors in mice, and its effect is more significant than that of conventional chemotherapy drugs. The above results show that Quisinostat or its isomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, prodrugs or derivatives thereof are new candidate drugs for the clinical treatment of neuroendocrine tumors, especially neuroendocrine cervical cancer, with high clinical value.

[0008] Therefore, in a first aspect of the present application, the present application provides a use of Quisinostat or its isomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, prodrug or derivative thereof in the preparation of a medicament for treating or preventing neuroendocrine tumor. According to an embodiment of the present application, Quisinostat can inhibit the growth of neuroendocrine tumor in a dose-dependent manner, has high drug sensitivity, has a significant tumor inhibition effect, is a new candidate drug for clinical treatment of neuroendocrine tumor, and has high clinical value.

[0009] According to an embodiment of the present application, the neuroendocrine tumor originates from at least one of lung neuroendocrine cells, gastrointestinal neuroendocrine cells, pancreatic neuroendocrine cells, adrenal neuroendocrine cells, cervical neuroendocrine cells, thyroid neuroendocrine cells, pituitary neuroendocrine cells, liver neuroendocrine cells, skin neuroendocrine cells, breast neuroendocrine cells, nasal cavity neuroendocrine cells, laryngeal neuroendocrine cells, and kidney neuroendocrine cells.

[0010] According to an embodiment of the present application, the neuroendocrine tumor is at least one of lung neuroendocrine tumor, gastrointestinal neuroendocrine tumor, pancreatic neuroendocrine tumor, adrenal neuroendocrine tumor, neuroendocrine cervical cancer, thyroid neuroendocrine tumor, pituitary neuroendocrine tumor, liver neuroendocrine tumor, skin neuroendocrine tumor, breast neuroendocrine tumor, nasal cavity neuroendocrine tumor, laryngeal neuroendocrine tumor, and kidney neuroendocrine tumor.

[0011] According to an embodiment of the present application, the neuroendocrine tumor is neuroendocrine cervical cancer. Neuroendocrine cervical cancer is a rare subtype of cervical cancer, originates from cervical neuroendocrine cells, accounts for less than 5% of all cervical cancers, and usually has high invasiveness and poor response to traditional cervical cancer treatment methods. According to an embodiment of the present application, Quisinostat has a more significant effect on neuroendocrine cervical cancer than conventional chemotherapy drugs, and can significantly inhibit tumor growth in animals.

[0012] According to an embodiment of the present application, the pharmaceutically acceptable salt of Quisinostat is at least one of Quisinostat hydrochloride, Quisinostat mesylate, Quisinostat lactate, and Quisinostat mesylate.

[0013] According to an embodiment of the present application, the pharmaceutically acceptable salt of Quisinostat is Quisinostat hydrochloride.

[0014] According to an embodiment of the present application, the pharmaceutically acceptable salt of Quisinostat is Quisinostat 2HCl.

[0015] In a second aspect of the present application, the present application provides a method for treating or preventing a neuroendocrine tumor. According to an embodiment of the present application, the method comprises: administering to a subject a pharmaceutically acceptable amount of Quisinostat or its isomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, prodrug thereof or derivative thereof.

[0016] According to an embodiment of the present application, the neuroendocrine tumor originates from at least one of a lung neuroendocrine cell, a gastrointestinal neuroendocrine cell, a pancreatic neuroendocrine cell, an adrenal neuroendocrine cell, a cervical neuroendocrine cell, an adrenal neuroendocrine cell, a thyroid neuroendocrine cell, a pituitary neuroendocrine cell, a liver neuroendocrine cell, a skin neuroendocrine cell, a breast neuroendocrine cell, a nasal cavity neuroendocrine cell, a laryngeal neuroendocrine cell, a kidney neuroendocrine cell.

[0017] According to some optional embodiments of the present application, the neuroendocrine tumor is at least one of a lung neuroendocrine tumor, a gastrointestinal neuroendocrine tumor, a pancreatic neuroendocrine tumor, an adrenal neuroendocrine tumor, a neuroendocrine cervical cancer, a thyroid neuroendocrine tumor, a pituitary neuroendocrine tumor, a liver neuroendocrine tumor, a skin neuroendocrine tumor, a breast neuroendocrine tumor, a nasal cavity neuroendocrine tumor, a laryngeal neuroendocrine tumor, a kidney neuroendocrine tumor.

[0018] According to an embodiment of the present application, the neuroendocrine tumor is a neuroendocrine cervical cancer.

[0019] According to an embodiment of the present application, the pharmaceutically acceptable salt of Quisinostat is at least one of Quisinostat hydrochloride, Quisinostat mesylate, Quisinostat lactate, Quisinostat mesylate.

[0020] According to an embodiment of the present application, the pharmaceutically acceptable salt of Quisinostat is Quisinostat hydrochloride.

[0021] According to an embodiment of the present application, the pharmaceutically acceptable salt of Quisinostat is Quisinostat 2HCl.

[0022] Additional aspects and advantages of the present application will be given in part in the following description, will become apparent from the following description, or will be learned by practice of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0023] The above and / or additional aspects and advantages of the present application will become apparent and rational understood in connection with the following description of embodiments, taken together with the accompanying drawings, in which:

[0024] Figure 1 is a bright field image of neuroendocrine cervical cancer organoids treated with different working concentrations of Quisinostat 2HCl in Example 1 of the present application, wherein, from top to bottom, the organoids treated with control group (Control), 10 μM, 1 μM, and 0.1 μM working concentrations are shown, and from left to right, three wells are shown, and the scale bar is 200 μm;

[0025] Figure 2 is a graph showing the results of cell viability analysis of neuroendocrine cervical cancer organoids treated with different working concentrations of Quisinostat 2HCl in Example 1 of the present application;

[0026] Figure 3 is an IC 50 curve graph showing the inhibitory effect of Quisinostat 2HCl on neuroendocrine cervical cancer organoids in Example 2 of the present application;

[0027] Figure 4 is a bright field image of tumor tissue of neuroendocrine cervical cancer organoids after subcutaneous tumor formation in mice and treatment with Quisinostat 2HCl in Example 3 of the present application;

[0028] Figure 5 is a graph showing the results of tumor volume analysis of neuroendocrine cervical cancer organoids after subcutaneous tumor formation in mice and treatment with Quisinostat 2HCl in Example 3 of the present application;

[0029] Figure 6 is a graph showing the results of tumor weight analysis of neuroendocrine cervical cancer organoids after subcutaneous tumor formation in mice and treatment with Quisinostat 2HCl in Example 3 of the present application. DETAILED DESCRIPTION

[0030] Embodiments of the present application are described in detail below. The embodiments described below are exemplary only and are not intended to be limiting of the present application.

[0031] It should be noted that the terms "first", "second" are used only for the purpose of description, and should not be understood as indicating or implying relative importance or implying the number of the technical features indicated. Therefore, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. Further, in the description of the present application, unless otherwise specified, the meaning of "a plurality of" is two or more.

[0032] In the present text, the term "Quisinostat" is equivalent to "quinovac" and is a HDAC inhibitor with the chemical structure shown below:

[0033] The salts of Quisinostat generally have improved pharmaceutical solubility and stability, which facilitate the formulation and administration of the drug. In practical applications, the salt form of the drug does not change its basic pharmacological effect. Common salt forms of Quisinostat include, but are not limited to: Quisinostat Hydrochloride, Quisinostat besylate, Quisinostat Lactate.

[0034] The term "Quisinostat 2HCl" is a hydrochloride salt form of Quisinostat with the chemical structure shown below:

[0035] The term "Quisinostat HCl" is a hydrochloride salt form of Quisinostat with the chemical structure shown below:

[0036] In this context, the term "neuroendocrine tumor" is equivalent to "Neuroendocrine Neoplasms", "NENs", is a group of relatively rare tumors, which originate from neuroendocrine cells in various parts of the body. These cells have the ability to secrete hormones, can produce peptide hormones and biogenic amines, etc. Neuroendocrine tumors can be benign or malignant, and malignant neuroendocrine tumors can invade surrounding tissues or metastasize to distant organs. These neuroendocrine tumors all originate from neuroendocrine cells, which have both neural and endocrine properties, and can produce and secrete hormones and other bioactive substances. Neuroendocrine tumors are divided according to their origin, including but not limited to neuroendocrine tumors originating from lung neuroendocrine cells, gastrointestinal neuroendocrine cells, pancreatic neuroendocrine cells, adrenal neuroendocrine cells, cervical neuroendocrine cells, adrenal neuroendocrine cells, thyroid neuroendocrine cells, pituitary neuroendocrine cells, liver neuroendocrine cells, skin neuroendocrine cells, breast neuroendocrine cells, nasal neuroendocrine cells, laryngeal neuroendocrine cells, kidney neuroendocrine cells. Common neuroendocrine tumors include lung neuroendocrine tumors, gastrointestinal neuroendocrine tumors, pancreatic neuroendocrine tumors, adrenal neuroendocrine tumors, neuroendocrine cervical cancer, thyroid neuroendocrine tumors, pituitary neuroendocrine tumors, liver neuroendocrine tumors, skin neuroendocrine tumors, breast neuroendocrine tumors, nasal neuroendocrine tumors, laryngeal neuroendocrine tumors, and kidney neuroendocrine tumors. Although these tumors occur in different organs and tissues, they are similar in biological behavior and treatment strategies.

[0037] Neuroendocrine cervical cancer originates from neuroendocrine cells in the cervix, which can produce hormones and other bioactive substances. In the embodiments of the present application, neuroendocrine cervical cancer is selected as a representative disease of neuroendocrine tumors, and the therapeutic effect of Quisinostat on neuroendocrine tumors is investigated to provide patients with more clinical drug selection.

[0038] As used herein, the term "treatment" refers to obtaining a desired pharmacologic and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or can be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. "Treatment" as used herein covers the treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or condition from occurring in an individual which can be predisposed to the disease but has not yet developed the disease; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing the partial or complete regression of the disease. As used herein, "treatment" covers any administration of a drug or product to a subject for therapeutic, curative, alleviative, ameliorative, palliative, or inhibitory purposes, including, but not limited to, administration of a drug containing the drug described herein to a subject in need thereof.

[0039] As used herein, the term "prevention" is used to refer to an attempt to stop the appearance of a disease or condition before it occurs.

[0040] It is to be appreciated that the terms "subject," "individual," and "patient" are used interchangeably herein and refer to a mammal that is being assessed for treatment and / or treated. In one embodiment, the mammal is a human. The terms "subject," "individual," and "patient" include, but are not limited to, a patient having a neuroendocrine tumor, such as an individual having a neuroendocrine type of cervical cancer. The subject can be a human, but also includes other mammals, particularly mammals useful as laboratory models for human disease, e.g., mice, rats, etc.

[0041] As used herein, the term "pharmaceutically acceptable amount" is an amount that is suitable for use in humans and / or mammals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio, i.e., an amount that is sufficient to exhibit the desired biological activity yet low enough to avoid serious side effects.

[0042] As used herein, the term "administration" and the like, contemplate a route of administration by which a predetermined amount of a substance is introduced into a patient's body. The aforementioned drug can be administered by any common route of administration, as long as it can reach the intended tissue. Various modes of administration are contemplated, including intraperitoneal, intravenous, intramuscular, subcutaneous, and the like, but the present application is not limited to these exemplified modes of administration. The effective amount of the aforementioned drug can vary depending on the mode of administration and the severity of the disease to be treated, etc. Preferably, the effective amount can be determined by one of ordinary skill in the art (e.g., through clinical trials) according to various factors. The factors include, but are not limited to, pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated, the body weight of the patient, the immune status of the patient, the route of administration, etc. For example, several divided doses can be administered daily, or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation.

[0043] As used herein, the term "effective amount" or "effective dose" refers to an amount that is functional or active and acceptable to a human and / or animal.

[0044] The scheme of the present application will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only for illustration of the present application and should not be regarded as limiting the scope of the present application. The experimental methods in the following examples are routine methods unless otherwise specified. The reagents or instruments involved in the present application are not specified by the manufacturer, and can be purchased on the market.

[0045] Example 1: Quisinostat 2HCl significantly inhibits the proliferation of neuroendocrine cervical cancer organoids in vitro

[0046] In this example, neuroendocrine cervical cancer organoids are constructed from tumor cells isolated from patient neuroendocrine cervical cancer tissue. Based on this, if the above human neuroendocrine tumor cells are isolated from patient tumor tissue, research involving human tissue sampling must comply with government laws and regulations of all relevant agencies, and the informed consent of the patient must be obtained before sampling and testing. In this example, the method for investigating the significant inhibitory effect of Quisinostat 2HCl on the proliferation of neuroendocrine cervical cancer organoids in vitro is as follows:

[0047] Collect the organoids that have been successfully constructed and amplified in the culture well plates, digest them into single cells, measure the number of cells in the suspension, and resuspend them in the extracellular matrix at a density of 3000 cells / μL;

[0048] Add 3 μL of the mixture of cell clusters and extracellular matrix to each well of the 96-well plate, and add 100 μL of culture medium to each well;

[0049] After 5 days of culture, add different concentrations (10, 1, 0.1 μM) of Quisinostat 2HCl to the control group, add the same proportion of DMSO, and continue to culture in a 37°C incubator;

[0050] After 5 days of drug treatment, replace the culture medium with an organoid cell activity detection reagent, incubate at 37°C for 30 min, and then measure the fluorescence intensity (FI) at an excitation wavelength of 560 nm and an emission wavelength of 590 nm. At the same time, use the Cytation5 multifunctional cell imaging microplate detector to image each well, and according to the above results, determine the inhibitory effect of Quisinostat 2HCl on neuroendocrine cervical cancer organoids.

[0051] The inhibitory effect of different concentrations of Quisinostat 2HCl on neuroendocrine cervical cancer organoids is shown in Figures 1 and 2.

[0052] Results show:

[0053] In this example, the neuroendocrine cervical cancer organoids were constructed from tumor cells isolated from patient neuroendocrine cervical cancer tissue. Based on this, if the above-mentioned human neuroendocrine tumor cells are obtained by isolating patient tumor tissue, research involving the use of human tissue must comply with government laws and regulations of all relevant agencies, and the informed consent of the patient must be obtained before the tissue is taken and tested. In this example, Quisinostat 2HCl significantly inhibited the proliferation of neuroendocrine cervical cancer organoids in vitro. The method for investigating the effect is as follows:

[0054] Collect the organoids that have been successfully constructed and amplified in the culture well plate, digest them into single cells, measure the number of cells in the suspension, and resuspend them in the extracellular matrix at a density of 3000 cells / μL;

[0055] Add 3 μL of the mixture of cell clusters and extracellular matrix to each well of the 96-well plate, and add 100 μL of culture medium to each well;

[0056] After 5 days of culture, different concentrations (10, 1, 0.1 μM) of Quisinostat 2HCl were added to the control group, and the same proportion of DMSO was added, and the culture was continued in a 37°C incubator;

[0057] After 5 days of drug treatment, the culture medium was replaced with a cell activity detection reagent, and the fluorescence intensity (FI) at an excitation wavelength of 560 nm and an emission wavelength of 590 nm was measured after 37°C incubation for 30 min. At the same time, the Cytation5 multifunctional cell imaging microplate detector was used to image each well, and the above results were used to judge the inhibitory effect of Quisinostat 2HCl on neuroendocrine cervical cancer organoids.

[0058] The inhibitory effect of different concentrations of Quisinostat 2HCl on neuroendocrine cervical cancer organoids is shown in Figures 1 and 2.

[0059] The results show that compared with the control group (Control), the viability of neuroendocrine cervical cancer organoids treated with Quisinostat 2HCl at 10 μM, 1 μM, and 0.1 μM working concentrations was less than 1%. This indicates that Quisinostat 2HCl shows strong inhibitory effects on neuroendocrine cervical cancer organoids at these three concentrations.

[0060] Example 2: Quisinostat 2HCl inhibits neuroendocrine cervical cancer organoids in a dose-dependent manner

[0061] The organoids that have been successfully constructed and amplified in large quantities in the culture well plate are digested into single cells, the number of cells in the suspension is measured, and the cells are resuspended in the extracellular matrix at a density of 3000 cells / μL;

[0062] 3 μL of the mixture of cell clusters and extracellular matrix is added to each well of the 96-well plate, and 100 μL of culture medium is added to each well for culture in a 37°C incubator;

[0063] After 5 days of culture, 7 concentration gradients of Quisinostat 2HCl are set according to a 10-fold gradient, with a concentration range of 0.001 nM-1000 nM, and the control group is added with an equal proportion of DMSO, and the culture is continued in a 37°C incubator;

[0064] After 5 days of drug treatment, the culture medium is replaced with an organoid cell activity detection reagent, and the fluorescence intensity (FI) at an excitation wavelength of 560 nm and an emission wavelength of 590 nm is measured after 37°C incubation for 30 min, and the IC 50 curve of Quisinostat 2HCl on neuroendocrine cervical cancer organoids is plotted according to the above results.

[0065] The IC 50 curve of Quisinostat 2HCl on neuroendocrine cervical cancer organoids is shown in FIG. 3.

[0066] The results show that Quisinostat 2HCl inhibits neuroendocrine cervical cancer organoids in a dose-dependent manner; the IC 50 is less than 10 nM, indicating that neuroendocrine cervical cancer organoids are highly sensitive to Quisinostat 2HCl.

[0067] Example 3: Quisinostat 2HCl significantly inhibits the growth of neuroendocrine cervical cancer organoid xenografts in vivo

[0068] Three 6-week-old, 18-24 g immunodeficient mice of the BALB / c-Nude strain are selected for subcutaneous transplantation of neuroendocrine cervical cancer organoids, and each mouse is transplanted with 2x10 ^ 6 cells of organoids, and the mice are sacrificed when the tumor volume reaches 800-1000 mm 3 3, the tumor tissue is dissected, the capsule and necrotic parts are removed, and the tissue is cut into 2 mm 3 tissue fragments.

[0069] Eighteen 6-week-old, 18-24 g immunodeficient mice of the BALB / c-Nude strain are selected for subcutaneous transplantation of neuroendocrine cervical cancer tissue, and each mouse is transplanted with 2 pieces of 2 mm 3tumor tissue fragments, when the average tumor volume reaches 100-200mm 3 When the average tumor volume reaches 100-200mm 3 , the mice were randomly divided into three groups for treatment, including a blank control group (normal saline treatment group), a positive control group (combined treatment of paclitaxel and carboplatin group) and an experimental group (Quisinostat 2HCl treatment group), with 6 mice in each group. The treatment of the mice in the blank control group was intraperitoneal injection of normal saline once a week, with the injection volume being 100-200μL per mouse (the same volume as the experimental group); the treatment of the mice in the positive control group was intraperitoneal injection of a mixture of paclitaxel and carboplatin once a week, with the injection doses being 10mg / kg per mouse and 50mg / kg per mouse, respectively; the treatment of the mice in the experimental group was intraperitoneal injection of Quisinostat 2HCl every other day, with the injection dose being 10mg / kg per mouse. The experiment was terminated when the tumor volume of the mice in the blank control group exceeded 2000mm 3 . The measurement of the tumor volume used a vernier caliper, and the calculation of the tumor volume was V=a 2 ×b (where V is the volume, a is the length of the shortest side, and b is the length of the longest side).

[0070] The inhibitory effect of Quisinostat 2HCl on the growth of neuroendocrine cervical cancer in mice is shown in Figures 4, 5 and 6.

[0071] The results show that, compared with the blank control group, the tumor volume of the Quisinostat 2HCl treatment group was significantly reduced (Figures 4 and 5), the tumor weight was significantly reduced (Figure 6), and this inhibitory effect was more obvious than that of the positive control group, indicating that Quisinostat 2HCl can significantly inhibit the growth of neuroendocrine tumors, especially neuroendocrine cervical cancer, in vivo, and is more effective than the chemotherapeutic drugs used in clinical practice.

[0072] Although the embodiments of the present application have been shown and described above, it should be understood that the above-described embodiments are exemplary and should not be construed as limiting the present application, and those of ordinary skill in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

1. Use of Quisinostat or its isomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for the treatment or prevention of a neuroendocrine tumor.

2. Use according to claim 1, characterized in that, The neuroendocrine tumor originates from at least one of a pulmonary neuroendocrine cell, a gastrointestinal neuroendocrine cell, a pancreatic neuroendocrine cell, an adrenal neuroendocrine cell, a cervical neuroendocrine cell, a thyroid neuroendocrine cell, a pituitary neuroendocrine cell, a liver neuroendocrine cell, a skin neuroendocrine cell, a breast neuroendocrine cell, a nasal neuroendocrine cell, a laryngeal neuroendocrine cell, a renal neuroendocrine cell.

3. Use according to claim 1, characterized in that, The neuroendocrine tumor is at least one of a pulmonary neuroendocrine tumor, a gastrointestinal neuroendocrine tumor, a pancreatic neuroendocrine tumor, an adrenal neuroendocrine tumor, a neuroendocrine cervical cancer, a thyroid neuroendocrine tumor, a pituitary neuroendocrine tumor, a liver neuroendocrine tumor, a skin neuroendocrine tumor, a breast neuroendocrine tumor, a nasal neuroendocrine tumor, a laryngeal neuroendocrine tumor, a renal neuroendocrine tumor.

4. Use according to claim 3, characterized in that, The neuroendocrine tumor is a neuroendocrine cervical cancer.

5. Use according to any one of claims 1 to 4, characterized in that, The pharmaceutically acceptable salt of Quisinostat is at least one of Quisinostat hydrochloride, Quisinostat mesylate, Quisinostat lactate, Quisinostat mesylate.

6. Use according to claim 5, characterized in that, The pharmaceutically acceptable salt of Quisinostat is Quisinostat hydrochloride.

7. Use according to claim 5, characterized in that, The pharmaceutically acceptable salt of Quisinostat is Quisinostat 2HCI.

8. A method of treating or preventing a neuroendocrine tumor, characterized by, Comprising: administering to a subject a pharmaceutically acceptable amount of Quisinostat or its isomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, prodrug or derivative thereof.

9. The method of claim 8, wherein, The neuroendocrine tumor originates from at least one of a pulmonary neuroendocrine cell, a gastrointestinal neuroendocrine cell, a pancreatic neuroendocrine cell, an adrenal neuroendocrine cell, a cervical neuroendocrine cell, an adrenal neuroendocrine cell, a thyroid neuroendocrine cell, a pituitary neuroendocrine cell, a liver neuroendocrine cell, a skin neuroendocrine cell, a breast neuroendocrine cell, a nasal neuroendocrine cell, a laryngeal neuroendocrine cell, a renal neuroendocrine cell.

10. The method of claim 8, wherein, The neuroendocrine tumor is at least one of a pulmonary neuroendocrine tumor, a gastrointestinal neuroendocrine tumor, a pancreatic neuroendocrine tumor, an adrenal neuroendocrine tumor, a neuroendocrine cervical cancer, a thyroid neuroendocrine tumor, a pituitary neuroendocrine tumor, a liver neuroendocrine tumor, a skin neuroendocrine tumor, a breast neuroendocrine tumor, a nasal neuroendocrine tumor, a laryngeal neuroendocrine tumor, a renal neuroendocrine tumor.

11. The method of claim 10, wherein, The neuroendocrine tumor is a neuroendocrine cervical cancer.

12. The method according to any one of claims 8 to 11, characterized in that, The pharmaceutically acceptable salt of Quisinostat is selected from at least one of Quisinostat hydrochloride, Quisinostat mesylate, Quisinostat lactate, Quisinostat mesylate.

13. The method of claim 12, wherein, The pharmaceutically acceptable salt of Quisinostat is Quisinostat hydrochloride.

14. The method of claim 12, wherein, The pharmaceutically acceptable salt of Quisinostat is Quisinostat 2HCl.

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