Use of muparfostat in treatment of pancreatic cancer

Abstract

Use of muparfostat in preparing a medicament for treating non-functional pancreatic neuroendocrine tumors or exocrine pancreatic cancer. A pharmaceutical composition comprising muparfostat, which is for use in the treatment of non-functional pancreatic neuroendocrine tumors or exocrine pancreatic cancer. The pharmaceutical composition further comprises one or more additional antitumor drugs, such as chemotherapeutic drugs. The medicament or the pharmaceutical composition can reduce pancreatic tissue fibrosis in pancreatic cancer patients, thereby effectively treating pancreatic cancer.

Description

Use of Muparfostat in the treatment of pancreatic cancer Technical Field

[0001] The present application belongs to the field of medicine, and specifically relates to the use of Muparfostat for treating pancreatic cancer. Background Art

[0002] Pancreatic cancer can be divided into pancreatic neuroendocrine tumors (PETs) and exocrine pancreatic cancer. PETs are further divided into functional PNETs (e.g., islet cell tumors) and non-functional PNETs (e.g., pancreatic polypeptide-secreting tumors (PPoma)).

[0003] Currently, the main treatment for pancreatic cancer is chemotherapy. For example, gemcitabine is the first-line standard chemotherapy drug for advanced pancreatic cancer. However, chemotherapy drugs such as gemcitabine often cause severe side effects, such as low white blood cell counts, low platelets, elevated liver function tests, proteinuria, hematuria, and dyspnea, which seriously affect patients' quality of life and survival rates. Therefore, there is an urgent need for therapeutic agents that can effectively treat pancreatic cancer with minimal side effects, or that can reduce the side effects of these chemotherapy drugs.

[0004] Muparfostat is a heparanase inhibitor that is known to treat liver cancer. In addition, in a mouse model of autoimmune type 1 diabetes, muparfostat can protect pancreatic beta cells from apoptosis due to loss of heparan sulfate by maintaining the concentration of heparan sulfate in the islets, and inhibit the progression of type 1 diabetes. See Zhang J, Li K, Sun HR, Sun SK, Zhu YT, Ge YT, Wu YX, Zhou QY, Li GT, Chang XA, Sun P, Ding Y, Han X. The heparan sulfate mimetic muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase. Br J Pharmacol. 2023 Jul; 180(14): 1803-1818. doi: 10.1111 / bph.16047. Epub 2023 Feb 20. PMID: 36735592.

[0005] Other studies have shown that in a mouse model of pancreatic islet cell tumors, papastatin can inhibit the release of heparan sulfate binding proteins in the ECM, such as chemokines and angiogenic growth factors, by inhibiting heparanase. At the same time, heparan sulfate mimetic can also bind to this protein to inhibit its function and reduce the angiogenesis of precancerous lesions and tumors, thus having the potential to treat pancreatic islet cell tumors. See Joyce JA, Freeman C, Meyer-Morse N, Parish CR, Hanahan DA functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene. 2005 Jun 9; 24(25): 4037-51. doi: 10.1038 / sj.onc.1208602. Erratum in: Oncogene. 2005 Jun 9; 24(25): 4163. PMID: 15806157.

[0006] However, whether papastatin can effectively treat other types of pancreatic cancer (such as functional pancreatic neuroendocrine tumors that are not islet cell tumors) is currently unknown and remains to be studied.

[0007] Summary of the Invention

[0008] The present application provides the use of Mapasitine for treating pancreatic cancer. The inventors of the present application unexpectedly discovered in their research that Mapasitine has a good therapeutic effect on non-functional pancreatic neuroendocrine tumors or exocrine pancreatic cancer and can be used to prepare related drugs.

[0009] In a first aspect, the present application provides the use of mapastatin in the preparation of a drug for treating pancreatic cancer, wherein the pancreatic cancer is preferably a non-functional pancreatic neuroendocrine tumor or exocrine pancreatic cancer.

[0010] In a second aspect, the present application provides a method for treating pancreatic cancer in an individual, comprising administering a therapeutically effective amount of mapaxitin or a pharmaceutical composition comprising mapaxitin to the individual, wherein the pancreatic cancer is preferably a non-functional pancreatic neuroendocrine tumor or exocrine pancreatic cancer. In some embodiments, the individual is a subject or patient in need of treatment.

[0011] In a third aspect, the present application provides mapastatin or a pharmaceutical composition comprising mapastatin for treating pancreatic cancer, wherein the pancreatic cancer is preferably a non-functional pancreatic neuroendocrine tumor or exocrine pancreatic cancer.

[0012] In a fourth aspect, the present application provides a pharmaceutical composition for pancreatic cancer, which comprises mapastatin and one or more other anti-tumor drugs. The pancreatic cancer is preferably a non-functional pancreatic neuroendocrine tumor or exocrine pancreatic cancer.

[0013] In a fifth aspect, the present application provides the use of mapastatin in combination with one or more other anti-tumor drugs for the treatment of pancreatic cancer, wherein the pancreatic cancer is preferably a non-functional pancreatic neuroendocrine tumor or exocrine pancreatic cancer.

[0014] In some embodiments, the pancreatic cancer described in the first to fifth aspects above is selected from non-functional pancreatic neuroendocrine tumors or exocrine pancreatic cancer.

[0015] In some embodiments, the mupastin or pharmaceutical composition or drug comprising mupastin in the first to fifth aspects above can reduce fibrosis of pancreatic tissue in pancreatic cancer patients.

[0016] In some embodiments, the exocrine pancreatic cancer is selected from one or more of the following: ductal adenocarcinomas, acinar cell carcinomas, mucinous cystadenocarcinomas, giant cell carcinomas, pancreatoblastomas, adenosquamous carcinomas, intraductal papillary mucinous neoplasms (IPMNs), solid pseudopapillary neoplasms, pleomorphic carcinomas, sarcomatoid carcinomas, and undifferentiated carcinomas.

[0017] In some embodiments, the exocrine pancreatic cancer is pancreatic ductal adenocarcinoma.

[0018] In some embodiments, the dosage of the mapaxitin or mapaxitin in the medicament in the first to fifth aspects is 80 mg / day to 315 mg / day.

[0019] In some embodiments, the one or more other anti-tumor drugs described in the third and fourth aspects are chemotherapeutic drugs.

[0020] In some embodiments, the above-mentioned papastatin or drug is used for combination administration with one or more other chemotherapeutic drugs.

[0021] In some embodiments, the above-described mupastatin or drug is used for combination administration with low doses of one or more other chemotherapeutic drugs.

[0022] In some embodiments, the one or more additional chemotherapeutic drugs are selected from gemcitabine, Abraxane, or a combination thereof.

[0023] In some embodiments, the other chemotherapeutic drug comprises gemcitabine, and the dose of gemcitabine is 400 mg / m 2 -1250mg / m 2 .

[0024] In some embodiments, the other chemotherapeutic drug comprises benzodiazepine, and the dose of benzodiazepine is 80 mg / m 2 -125 mg / m 2 .

[0025] In some embodiments, the mupastin, pharmaceutical composition comprising mupastin, or drug described in the first to fifth aspects above is administered to a subject or patient in need of treatment in a clinically acceptable manner, such as orally, by injection, external use, topical administration, etc., preferably orally.

[0026] In some embodiments, mother pastin is formulated into clinically acceptable pharmaceutical dosage forms, such as oral preparations, injection preparations, external preparations etc., preferably oral preparations. In some embodiments, the medicine contains pharmaceutically acceptable adjuvants or excipients. In some embodiments, the amount that each dosage unit of the medicine contains mother pastin is 1mg-1000mg, preferably 5mg-500mg, 10mg-300mg, 20-200mg, 20-150mg or 25mg-100mg, for example, each dosage unit contains mother pastin 1mg, 5mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 75mg, 80mg, 100mg, 150mg, 200mg, 250mg, 300mg, 315mg, 350mg, 400mg or any value within the above-mentioned interval range. Medicine described in the application can be administered in single dose or divided dose.

[0027] In some embodiments, the mupastin described in the first to fifth aspects above is administered to a subject or patient in need of treatment in a therapeutically effective amount to treat pancreatic cancer, preferably non-functional pancreatic neuroendocrine tumors or exocrine pancreatic cancer. The therapeutically effective amount refers to a dose that can alleviate, inhibit tumor growth, or eliminate the tumor, benefiting the subject or patient, but does not cause intolerable toxic side effects.

[0028] In some embodiments, the therapeutically effective amount (in terms of pastacin) is 1mg / days-1000mg / days. In specific embodiments, the above-mentioned therapeutically effective amount can be 5mg / days-500mg / days, 10mg / days-300mg / days, 20mg / days-300mg / days, 25mg / days-250mg / days or 80mg / days-315mg / days. The above-mentioned therapeutically effective amount can be used once a day (QD), or can be divided into multiple administrations in one day as a daily total dose, for example, divided into twice a day (BID) or three times a day (TID) and administered. The above-mentioned therapeutically effective amount can also be administered at intervals, for example, administered once at intervals of 2-7 days, or administered once at intervals of 2-4 weeks.

[0029] In some embodiments, the other anti-tumor drugs described in the third to fourth aspects above, such as other chemotherapeutic drugs, can be included in the same preparation unit as pastatin, or can be included in different preparation units to form a combined package, such as a kit product. In some embodiments, the other drugs are selected from gemcitabine, Abraxane, or a combination thereof.

[0030] In some embodiments, mapasta, a pharmaceutical composition comprising mapasta or a drug can effectively treat non-functional pancreatic neuroendocrine tumors or exocrine pancreatic cancer, and can achieve one or more of the following effects: effectively inhibiting the tumor growth of pancreatic cancer, thereby reducing the size of the tumor, and improving patient survival rate, as well as reducing the degree of pancreatic fibrosis in patients with pancreatic cancer. Reducing the degree of pancreatic fibrosis represents reducing the malignancy of the tumor, and can delay the loss of normal physiological function of the pancreas, and also helps other therapeutic agents enter the pancreas, such as chemotherapeutic drugs. Therefore, in some embodiments, compared with using only chemotherapeutic drugs, when chemotherapy drugs are combined with mapasta, it can more effectively inhibit the tumor growth of pancreatic cancer, reduce the size of the tumor, and improve patient survival rate. In addition, in some embodiments, when chemotherapy drugs are combined with mapasta, the dosage of chemotherapy drugs can be reduced, thereby reducing the side effects caused by the chemotherapy drugs, greatly improving the quality of life and survival rate of patients. This suggests that administering mepastin in combination with existing pancreatic cancer chemotherapy drugs can achieve better efficacy than existing pancreatic cancer chemotherapy drugs in inhibiting tumor growth and / or improving survival rates, and has a synergistic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG1 shows the time course of administration of each therapeutic agent in Trial 1.

[0032] FIG2A shows the survival curves of Examples 1-4 and Comparative Examples 1-4.

[0033] FIG2B separately lists the survival curves of Example 1-2 and Comparative Example 1-2 in FIG2A .

[0034] FIG2C separately lists the survival curves of Examples 1 and 3 and Comparative Examples 1 and 3 in FIG2A .

[0035] FIG2D separately lists the survival curves of Examples 1 and 4 and Comparative Examples 1-4 in FIG2A .

[0036] FIG3A shows photographs of pancreatic tumors of Examples 1-4 and Comparative Examples 1-4.

[0037] FIG3B shows a statistical bar graph of the weights of pancreatic tumors in Examples 1-4 and Comparative Examples 1-4.

[0038] FIG4 shows images of IHC staining results of αSMA in pancreatic tumors of Examples 1-4 and Comparative Examples 1-4.

[0039] FIG5 shows the time course of administration of each therapeutic agent in Experiment 2.

[0040] FIG6A shows the survival curves of Examples 5-8 and Comparative Examples 5-8.

[0041] FIG6B shows the survival curves of Examples 5-6 and Comparative Examples 5-6 in FIG6A .

[0042] FIG6C separately lists the survival curves of Examples 5 and 7 and Comparative Examples 5 and 7 in FIG6A .

[0043] FIG6D separately lists the survival curves of Examples 5 and 8 and Comparative Examples 5-8 in FIG6A .

[0044] FIG7A shows photographs of pancreatic tumors of Examples 5-8 and Comparative Examples 5-8.

[0045] FIG7B shows a statistical bar graph of the pancreatic tumor weights of Examples 5-8 and Comparative Examples 5-8.

[0046] FIG8 shows images of IHC staining results of αSMA in pancreatic tumors of Example 5-8 and Comparative Example 5-8.

[0047] FIG9 shows the time course of administration of each therapeutic agent in Experiment 3.

[0048] FIG10A shows the survival curves of Examples 9-12 and Comparative Examples 9-12.

[0049] FIG10B separately lists the survival curves of Examples 9-10 and Comparative Examples 9-10 in FIG9A.

[0050] FIG10C separately lists the survival curves of Examples 9 and 11 and Comparative Examples 9 and 11 in FIG9A.

[0051] FIG10D separately lists the survival curves of Examples 9 and 12 and Comparative Examples 9-12 in FIG9A .

[0052] FIG11A shows photographs of pancreatic tumors of Examples 9-12 and Comparative Examples 9-12.

[0053] FIG11B shows a statistical bar graph of the pancreatic tumor weights of Examples 9-12 and Comparative Examples 9-12.

[0054] FIG12 shows images of the IHC staining results of αSMA in pancreatic tumors of Examples 9-12 and Comparative Examples 9-12. DETAILED DESCRIPTION

[0055] After in-depth research, the inventors of the present application found that the mapastin of the present application, the pharmaceutical composition or the drug containing mapastin can effectively inhibit the tumor growth of pancreatic cancer and thereby reduce the size of the tumor.

[0056] In addition, the present invention's mupastin, pharmaceutical compositions or drugs comprising mupastin can also reduce the degree of pancreatic fibrosis in pancreatic cancer patients. Specifically, in the pancreas of pancreatic cancer patients, stellate cells are activated and produce extracellular matrix proteins (ECM), pro-inflammatory hormones, chemokines and growth factors, etc., thereby causing fibrosis. The present invention's mupastin, pharmaceutical compositions or drugs comprising mupastin can reduce the degree of fibrosis caused by stellate cells in the pancreas of pancreatic cancer patients.

[0057] The dosage of mupastin in the drug or pharmaceutical composition of the present application is 80 mg / day-315 mg / day, for example, 80 mg / day, 106 mg / day, 140 mg / day, 160 mg / day, 190 mg / day, 250 mg / day and 315 mg / day.

[0058] When the drug or pharmaceutical composition of the present application comprises gemcitabine, the dose of gemcitabine may be 400 mg / m 2 -1250mg / m 2 , preferably 400 mg / m 2 -800mg / m 2 , more preferably 400 mg / m 2 .

[0059] When the drug or pharmaceutical composition of the present application contains iberisin, the dosage of iberisin can be 80 mg / m 2 -125 mg / m 2 , preferably 80 mg / m 2 -100mg / m 2 , more preferably 80 mg / m 2 .

[0060] Herein, the term "low dose" refers to a dose that is significantly lower than the common clinical dose of the relevant chemotherapy drug or the highest permissible dose when considering safety. In some embodiments, "low dose" refers to the lowest permissible dose when considering effectiveness. For example, according to the guidelines for the diagnosis and treatment of pancreatic cancer, the highest permissible dose of gemcitabine in clinical practice when considering safety is 1250 mg / m 2 “Low dose” gemcitabine can be 400 mg / m 2 -800mg / m 2 In some embodiments, a "low dose" of gemcitabine may be 400 mg / m 2 For example, according to the guidelines for the diagnosis and treatment of pancreatic cancer, the maximum allowable dose of benzodiazepine in clinical practice is 125 mg / m 2 A "low dose" of benzodiazepine can be 80 mg / m 2 -100mg / m 2 In some embodiments, a "low dose" of albuterol may be 80 mg / m 2 .

[0061] In order to provide a more concise description, some quantitative data in this article do not use the term "about". It should be understood that, regardless of whether the term "about" is explicitly used or not, each numerical value given here includes not only the actual given value (given value), but also means to include an approximate value of such given value reasonably inferred by a person of ordinary skill in the art, including equivalents and approximate values ​​of such given value resulting from experimental and / or measurement conditions. The approximate value is preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, ±1% based on the given value.

[0062] The term "individual" as used herein refers to mammals, including but not limited to primates, cows, horses, pigs, sheep, goats, dogs, cats, and rodents such as rats and mice.

[0063] Throughout the specification and claims of this application, the words “comprises,” “includes,” and “contains” mean “including but not limited to,” and are not intended to exclude other parts, additives, components, or steps.

[0064] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present application method. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0065] The drugs, test materials, cell lines, test animals, etc. involved in the following specific embodiments can all be purchased through commercial channels or prepared by conventional methods in the prior art.

[0066] Example

[0067] The following examples and comparative examples illustrate the efficacy of the drug containing papastatin in treating pancreatic cancer. The data of each example were analyzed by Student's t-test and one-way ANOVA.

[0068] Pancreatic cancer mouse model

[0069] [Corrected 29.02.2024 according to Rule 26] A pancreatic cancer mouse model was established by implanting the KPC cell line into the mouse pancreas by orthotopic injection. The KPC cell line refers to a cell line derived from spontaneous pancreatic ductal adenocarcinoma in KPC mice. The KPC cell line used in the following examples and comparative examples is derived from a mouse model with the genotype Pdx1-Cre; Kras G12D / + Trp53 - / - KPC mice (National Sun Yat-sen University, Taiwan, China) were cultured under the following conditions: RPMI 1640 medium (SH30027.01, Hyclone) was supplemented with 10% fetal bovine serum (Hyclone), 2 mM L-glutamine, 100 units / mL penicillin, and 100 units / mL penicillin-streptomycin, and cultured at 37°C in a humidified atmosphere with 5% CO2.

[0070] KPC cell lines were orthotopically injected into the pancreas of 6-8 week old C57BL / 6 male mice to establish the KPC mouse model of pancreatic cancer.

[0071] Test 1: Examples 1-4 and Comparative Examples 1-4

[0072] Three weeks after the KPC cell line was implanted, the mice were divided into groups such as Examples 1-4 and Comparative Examples 1-4, and the therapeutic agents were administered via intraperitoneal and subcutaneous injections for drug treatment. The therapeutic agents administered to each group were:

[0073] Example 1: Motherpastin;

[0074] Example 2: Motherpastacin and gemcitabine (Gem);

[0075] Example 3: Mupastin and Abx;

[0076] Example 4: pasitine, gemcitabine and albuterol;

[0077] Comparative Example 1: No therapeutic agent was administered (experimental control group, hereinafter referred to as the control group);

[0078] Comparative Example 2: Gemcitabine;

[0079] Comparative Example 3: Abel Fir;

[0080] Comparative Example 4: gemcitabine and albuterol;

[0081] In the above-mentioned groups, the dose of mapastatin was 5 mg / kg, the dose of gemcitabine was 20 mg / kg (low dose), and the dose of aborsine was 30 mg / kg (low dose). They were administered approximately once a week, and different therapeutic agents were separated by two to four days for a total of three weeks. The time course for administering each therapeutic agent is shown in Figure 1. During the treatment process, the survival curve of each group of mice was recorded, and the pancreatic tumors were removed after the death of the mice for observation and weight measurement. The removed pancreatic tumors were stained with immunohistochemistry (IHC). As mentioned above, the activation of stellate cells can lead to pancreatic fibrosis. Since activated stellate cells produce alpha smooth muscle actin (αSMA), the appearance of αSMA is the most common pancreatic fibrosis indicator. Accordingly, pancreatic tumors were stained with IHC to observe the appearance of αSMA in pancreatic tumors, thereby assessing the degree of pancreatic fibrosis. The IHC staining procedure is as follows: paraffin-embed pancreatic tumors and slice tissue sections. After dewaxing, the sections are sterilized in patching buffer (DAKO, pH 6.0) at 121°C under autoclave for 10 minutes and patched for antigen exposure. Next, the sections are incubated in blocking buffer (DAKO) for 30 minutes. Next, a primary antibody recognizing αSMA is diluted in antibody diluent (DAKO) and stained at 4°C. Next, the sections are incubated with a secondary antibody at room temperature for 30 minutes. Finally, staining is performed using the DAB chromogen system (DAKO), and images of the immunohistochemically stained sections are obtained using a FACS-like tissue cytometry system (Tissue Gnostics).

[0082] As shown in FIG. 2A to FIG. 2D , compared with Comparative Example 1 (control group), the mice in Example 1 using mupastin survived longer, which indicates that mupastin can effectively improve the survival rate.

[0083] As shown in Figure 2B, compared with Comparative Example 2 using only gemcitabine, Example 2 using both gemcitabine and basuline has a longer survival period. As shown in Figure 2D, compared with Comparative Examples 2-4 using only gemcitabine and / or basuline, Example 4 using both gemcitabine, basuline, and basuline has a longer survival period. The above results indicate that the combined administration of basuline with existing pancreatic cancer chemotherapy drugs can achieve better efficacy in improving survival rates than existing pancreatic cancer chemotherapy drugs.

[0084] As shown in FIG3B , compared with Comparative Example 1 (control group), the average weight of the pancreatic tumor in Example 1 using Mapastin was lower, indicating that Mapastin was able to effectively reduce the size of the tumor.

[0085] Moreover, compared with Comparative Example 2 using only gemcitabine, the mean weight of the pancreatic tumor in Example 2, which used gemcitabine and basuline simultaneously, was slightly lower. Similarly, compared with Comparative Example 4 using only gemcitabine and basuline, the mean weight of the pancreatic tumor in Example 4, which used gemcitabine, basuline, and basuline simultaneously, was lower. The above results indicate that the combined administration of basuline with existing pancreatic cancer chemotherapy drugs can achieve better efficacy in reducing tumor size than existing pancreatic cancer chemotherapy drugs.

[0086] In the tissue staining image of Figure 4, the smaller dots (purple) are cell nuclei. The banded lines (deep red) are αSMA, representing the part of the pancreas where fibrosis occurs (the same applies to Figures 8 and 11 below). As can be seen from Figure 4, in the pancreas of Comparative Examples 2-4 using existing pancreatic cancer chemotherapy drugs, there is still obvious fibrosis. In the pancreas of Examples 1-4 using Mapastin, the area of ​​fibrosis is significantly smaller than that of Comparative Examples 1-4 without Mapastin, which indicates that Mapastin can effectively reduce the degree of pancreatic fibrosis.

[0087] Test 2: Examples 5-8 and Comparative Examples 5-8

[0088] The types and dosages of therapeutic agents administered in Examples 5-8 and Comparative Examples 5-8 corresponded to those in Examples 1-4 and Comparative Examples 1-4, respectively. The only difference was that in these groups, the therapeutic agents were administered two weeks after implantation of the KPC cell line, with the intervals between administration of the different therapeutic agents being 0 to 1 day. The administration schedules for each therapeutic agent are shown in FIG5 .

[0089] As shown in FIG. 6A to FIG. 6D , compared with Comparative Example 5 (control group), the survival period of Example 5 using paxifen is longer, which indicates that paxifen can effectively improve the survival rate.

[0090] As can be seen from Figures 6B to 6D, compared with Comparative Examples 6-8 using only gemcitabine and / or iberafenidone, the survival period of Examples 6-8 using both mapastin and gemcitabine and / or iberafenidone was longer, indicating that the combined administration of mapastin and existing pancreatic cancer chemotherapy drugs can achieve better efficacy in improving survival rate than existing pancreatic cancer chemotherapy drugs.

[0091] As shown in FIG7B , the mean weight of the pancreatic tumor in Example 5 using paxistatin was lower than that in Comparative Example 5 (control group), indicating that paxistatin can effectively reduce the size of the tumor.

[0092] Moreover, compared with Comparative Examples 6-8 using only gemcitabine and / or ibersen, the weight average value of the pancreatic tumors of Example 6-8 using both mapastin and gemcitabine and / or ibersen is lower. As can also be seen from Figure 7A, the tumor size of Example 6-8 in which mapastin and chemotherapeutics are administered in combination is smaller than that of Comparative Examples 6-8 in which chemotherapeutics are used alone. The above results indicate that administering mapastin in combination with existing pancreatic cancer chemotherapeutics can achieve better efficacy than existing pancreatic cancer chemotherapeutics in reducing tumor size.

[0093] As shown in Figure 8, the pancreases of Comparative Examples 6-8, which used existing pancreatic cancer chemotherapy drugs, still showed significant fibrosis. However, the pancreases of Examples 5-8, which used Mapastin, showed significantly smaller areas of fibrosis than those of Comparative Examples 5-8, which did not use Mapastin. This indicates that Mapastin can effectively reduce the degree of pancreatic fibrosis.

[0094] Test 3: Examples 9-12 and Comparative Examples 9-12

[0095] The therapeutic agents administered in Examples 9-12 and Comparative Examples 9-12 correspond to those in Examples 1-4 and Comparative Examples 1-4, respectively. The only difference is that in these groups, the therapeutic agents were administered three weeks after KPC cell line implantation, with a one-day interval between administrations. The administration schedules for each therapeutic agent are shown in Figure 9 . The doses of gemcitabine were 100 mg / kg and ibefoxim were 60 mg / kg. These doses correspond to commonly used clinical doses.

[0096] As shown in FIG. 10A to FIG. 10D , compared with Comparative Example 9 (control group), the survival period of Example 9 using paxifen is longer, indicating that paxifen can effectively improve the survival rate.

[0097] As can be seen from Figures 10B and 10D, compared with Comparative Examples 10-12 using only gemcitabine and / or iberafenidone, Examples 10-12 using both mapastatin and gemcitabine and / or iberafenidone have longer survival periods, indicating that the combined administration of mapastatin and existing pancreatic cancer chemotherapy drugs can achieve better efficacy in improving survival rates than existing pancreatic cancer chemotherapy drugs.

[0098] As shown in FIG11B , compared with Comparative Example 9 (control group), the average pancreatic tumor weight of Example 9 using Mapastin was lower, indicating that Mapastin was able to effectively reduce the size of the tumor.

[0099] Moreover, compared to Comparative Examples 10-12 using only gemcitabine and / or ibersen, the pancreatic tumor weight average value of Example 10-12 using both mapasutin and gemcitabine and / or ibersen is lower. As can also be seen from Figure 11A, the tumor size of Example 10-12 using a combination of mapasutin and a chemotherapeutic drug is smaller than that of Comparative Examples 10-12 using only a chemotherapeutic drug. The above results also show that the combination of mapasutin and existing pancreatic cancer chemotherapeutic drugs can achieve better efficacy than existing pancreatic cancer chemotherapeutic drugs in reducing the size of the tumor.

[0100] As shown in Figure 12, the pancreases of Comparative Examples 10-12, which used existing pancreatic cancer chemotherapy drugs, still showed significant fibrosis. However, the pancreases of Examples 9-12, which used Mapaxitin, showed significantly smaller areas of fibrosis than those of Comparative Examples 5-8, which did not use Mapaxitin. This indicates that Mapaxitin can effectively reduce the degree of pancreatic fibrosis.

[0101] In addition, by comparing FIG6B with FIG10B, FIG6C with FIG10C, and FIG6D with FIG10D, it can be seen that, compared with comparative examples 10-12 using only general clinical doses of gemcitabine and / or Abel, the survival period of Example 6-8 using both motherpasitine and low-dose gemcitabine and / or Abel is longer. By comparing FIG7A, FIG7B with FIG11A, FIG11B respectively, it can be seen that, compared with comparative examples 10-12 using only general clinical doses of gemcitabine and / or Abel, the tumors of Example 6-8 using both motherpasitine and low-dose gemcitabine and / or Abel are significantly smaller and have lower weight. The above results indicate that the administration of motherpasitine in combination with existing pancreatic cancer chemotherapy drugs can reduce the dosage of the aforementioned chemotherapy drugs, thereby reducing the side effect of reduced survival rate brought about by the aforementioned chemotherapy drugs, thereby more effectively treating pancreatic cancer, and achieving better efficacy compared with the generally commonly used higher-dose chemotherapy drug treatment methods in clinical practice.

[0102] It is understood that although the inventions described herein are described in the aforementioned specific forms, these inventions are not limited to the specific contents described in these specific forms. It is obvious to those skilled in the art that various equivalent variations may be made to the technical features of the inventions described herein without departing from the spirit of the inventions described herein, and such variations should fall within the scope of the inventions.

Claims

1. Use of Muparfostat in the preparation of a medicament for treating pancreatic cancer, wherein the pancreatic cancer is a non-functional pancreatic neuroendocrine tumor or exocrine pancreatic cancer.

2. The method according to claim 1, wherein the drug is capable of reducing fibrosis of pancreatic tissue in patients with pancreatic cancer.

3. The method of claim 1, wherein the exocrine pancreatic cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, acinar cell carcinoma, mucinous cystic adenocarcinoma, giant cell carcinoma, pancreatoblastoma, adenoid squamous cell carcinoma, intraductal papillary mucinous neoplasm, solid pseudopapillary neoplasm, pleomorphic carcinoma, sarcomatoid carcinoma, and undifferentiated carcinoma. Preferably, the exocrine pancreatic cancer is pancreatic ductal adenocarcinoma.

4. The use according to claim 1, wherein the drug is administered in combination with one or more other anti-tumor drugs, preferably chemotherapeutic drugs, more preferably, the drug is administered in combination with a low dose of one or more other chemotherapeutic drugs.

5. The use according to claim 4, wherein the one or more other chemotherapeutic drugs are selected from gemcitabine, abraxane or a combination thereof.

6. The method of claim 1, wherein the dosage of mupastin is 80 mg / day to 315 mg / day.

7. The method of claim 5, wherein the other chemotherapeutic drug comprises gemcitabine, and the dose of gemcitabine is 400 mg / m 2 -1250mg / m 2 and / or the other chemotherapy drugs include ibersen, and the dose of ibersen is 80 mg / m 2 -125 mg / m 2 .

8. A method for treating pancreatic cancer in an individual, comprising administering to the individual a therapeutically effective amount of mapastatin, or a pharmaceutical composition comprising mapastatin, wherein the pancreatic cancer is a non-functional pancreatic neuroendocrine tumor or an exocrine pancreatic cancer.

9. The method of claim 8, wherein the pharmaceutical composition further comprises one or more other anti-tumor drugs, preferably, the other anti-tumor drugs are chemotherapeutic drugs; more preferably, the chemotherapeutic drugs are selected from gemcitabine, albuterol, or a combination thereof.

10. The method of claim 8, wherein the dosage of mupastatin administered is 80 mg / day to 315 mg / day.

11. The method of claim 9, wherein the chemotherapeutic drug comprises gemcitabine, and the dose of gemcitabine is 400 mg / m 2 -1250mg / m 2 and / or the other chemotherapy drugs include ibersen, and the dose of ibersen is 80 mg / m 2 -125 mg / m 2 .

12. Mapastin, or a pharmaceutical composition comprising Mapastin, for treating pancreatic cancer, wherein the pancreatic cancer is non-functional pancreatic neuroendocrine tumor or exocrine pancreatic cancer.

13. The mupastinine or the pharmaceutical composition comprising mupastinine according to claim 12, wherein the pharmaceutical composition further comprises one or more other anti-tumor drugs, preferably, the other anti-tumor drugs are chemotherapeutic drugs; more preferably, the chemotherapeutic drugs are selected from gemcitabine, albuterol or a combination thereof.

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