Pancreatic cancer treatment

Abstract

To provide medicaments for effectively treating pancreatic cancer.SOLUTION: The pancreatic cancer treating agents of the invention comprise sirolimus and gemcitabine or TS-1 as effective ingredients.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an agent for effectively treating pancreatic cancer. [Background technology]

[0002] The number of deaths from pancreatic cancer in Japan is steadily increasing. According to the National Cancer Center's cancer registry and statistics, in 2018, 40,000 people were infected and 35,000 people died, making it the fourth most common organ-specific cause of death. The 5-year survival rate for stage IV is 1.4%, 6.4% for stage III, and 9% for all stages, making the prognosis of pancreatic cancer very poor. One of the reasons for this is that many cases have direct invasion into the retroperitoneum around the pancreas or metastasis to the liver, lungs, and lymph nodes, so only about 30% of cases are suitable for surgery. Another reason for the poor prognosis of pancreatic cancer is the delayed development of new, highly effective therapeutic drugs such as molecular targeted drugs.

[0003] Chemotherapy for pancreatic cancer can be divided into two categories: treatment for unresectable cases and postoperative adjuvant therapy. For unresectable cases, the first-choice treatment is FOLFIRINOX therapy using oxaliplatin + irinotecan + fluorouracil + levofolinate calcium, and gemcitabine (GEM) + nab-paclitaxel combination therapy. For adjuvant therapy, the first-choice treatment is monotherapy with TS-1 (a combination drug of tegafur, gimeracil, and oteracil potassium).

[0004] According to the Pancreatic Cancer Guidelines, gemcitabine monotherapy, TS1 monotherapy, FOLFIRINOX therapy, and gemcitabine + nab-paclitaxel combination therapy are proposed as first-line chemotherapy for locally advanced pancreatic cancer that is unresectable but does not have distant metastasis, with a weak recommendation level of C, while FOLFIRINOX therapy and gemcitabine + nab-paclitaxel combination therapy are recommended as first-line chemotherapy for advanced pancreatic cancer with distant metastasis, with a strong recommendation level of A. However, based on the median survival time of 5.7 months for gemcitabine monotherapy, TS1 monotherapy had a relatively long survival time of 9.7 months (hazard ratio 0.96), FOLFIRINOX therapy had a relatively long survival time of 11.1 months (hazard ratio 0.57), and gemcitabine + nab-paclitaxel combination therapy had a relatively long survival time of 8.7 months (hazard ratio 0.72). From the viewpoint of extending survival time, FOLFIRINOX therapy is the best, but considering that strong blood toxicity including febrile neutropenia is often observed in Japanese patients, the beneficial outcomes and harmful outcomes are close. In conclusion, at present, it is not possible to determine superiority or inferiority between gemcitabine + nab-paclitaxel combination therapy and FOLFIRINOX therapy.

[0005] Among gastrointestinal cancers, clinical trials of new drugs for gastric cancer, colon cancer, and liver cancer are being conducted mainly in Europe and the United States, but there are few clinical trials for pancreatic cancer. In order to solve the problem of being unable to determine whether gemcitabine + nab-paclitaxel combination therapy is superior to FOLFIRINOX therapy, it is important to quickly put into practical use in clinical practice a new therapy that is highly effective without increasing the frequency of side effects.

[0006] As mentioned above, one of the reasons for the poor prognosis of pancreatic cancer is the high invasive and metastatic potential of pancreatic cancer cells. The present inventors have found that in pancreatic cancer cells, human insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) forms a complex with mRNA, and is transported by KIF20A, a kinesin motor protein, to lamellipodia, which are essential for the motility and invasiveness of pancreatic cancer cells, and is involved in local translation of mRNA, and have developed a partial peptide of IGF2BP3 as a vaccine to suppress the invasion and metastasis of pancreatic cancer cells (Patent Document 1). The present inventors have also developed siRNA against IGF2BP3 as an inhibitor of the invasion and metastasis of pancreatic cancer cells (Patent Document 1). Patent Document 2). Furthermore, the present inventors have developed an agent for suppressing the invasion and metastasis of pancreatic cancer cells, which contains an ERK1 / 2 inhibitor and / or an mTOR inhibitor as an active ingredient (Patent Document 3). The present inventors have also demonstrated that the retroperitoneal invasion, peritoneal dissemination, and metastasis to the lungs of pancreatic cancer cells are suppressed by suppressing the expression of mTOR using small double-stranded RNA (siRNA) (Non-Patent Document 1). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] JP 2015-227292 A [Patent Document 2] International Publication No. 2016 / 002844 Brochure [Patent Document 3] JP 2019-206516 A [Non-patent literature]

[0008] [Non-Patent Document 1] TANIUCHI Keisuke et al., Oncotarget, 2019, 10, 2869-2886 Summary of the Invention [Problem to be solved by the invention]

[0009] As described above, there is a strong demand for a means capable of effectively treating pancreatic cancer, which has a poor prognosis. Therefore, an object of the present invention is to provide a drug for effectively treating pancreatic cancer. [Means for solving the problem]

[0010] The present inventors have conducted extensive research to solve the above problems, and as a result have found that pancreatic cancer can be effectively treated by combining specific active ingredients, thereby completing the present invention. The present invention will now be described.

[0011] [1] A pancreatic cancer treatment agent comprising sirolimus and gemcitabine or TS-1 as active ingredients. [2] The pancreatic cancer therapeutic agent according to the above [1], which contains the above gemcitabine and further contains paclitaxel as an active ingredient. [3] The method for treating pancreatic cancer according to the above [2], wherein the paclitaxel is nab-paclitaxel. [4] The pancreatic cancer therapeutic agent according to any one of the above [1] to [3], which comprises an oral formulation containing sirolimus, and an injectable formulation containing gemcitabine or an oral formulation containing TS-1. [5] The pancreatic cancer therapeutic agent according to the above [4], which contains an injectable formulation containing gemcitabine and further contains an injectable formulation containing paclitaxel. Effect of the Invention

[0012] The pancreatic cancer therapeutic agent according to the present invention can effectively suppress the motility and invasiveness of pancreatic cancer cells, and as a result, can effectively suppress the invasion and metastasis of pancreatic cancer cells. Therefore, for example, it is considered that it is possible to confine pancreatic cancer cells that have not been completely removed after surgical removal of pancreatic cancer in the abdominal cavity. It can also suppress the proliferation of pancreatic cancer cells. In fact, it has been demonstrated in animal experiments that the pancreatic cancer therapeutic agent according to the present invention can not only significantly suppress the proliferation of pancreatic cancer cells compared to existing therapeutic agents, but can also necrotize pancreatic cancer cells. Therefore, the present invention is very useful as a practical and new therapeutic method for pancreatic cancer. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a photograph showing the results of Western blotting indicating the effect of sirolimus on phosphorylation of p70S6K, a kinase of ribosomal protein S6, which is an indicator of mTOR activity in human pancreatic cancer cells. [Diagram 2] FIG. 2 is a graph showing the results of a cell proliferation test in the case where sirolimus was added or not added to a culture medium of human pancreatic cancer cells. [Diagram 3] FIG. 3 is a graph showing the results of a Matrigel invasion assay in the case where sirolimus was added or not added to a culture medium of human pancreatic cancer cells. [Figure 4] FIG. 4 is a graph showing the change over time in tumor volume after subcutaneous implantation of human pancreatic cancer cells in a mouse group administered with gemcitabine+paclitaxel and a mouse group administered with gemcitabine+paclitaxel+sirolimus. [Diagram 5] FIG. 5 shows enlarged stained photographs of pancreatic cancer tissues 9 weeks after human pancreatic cancer cells were subcutaneously implanted in mice treated with gemcitabine+paclitaxel and mice treated with gemcitabine+paclitaxel+sirolimus. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The pancreatic cancer therapeutic agent according to the present invention contains sirolimus and gemcitabine or TS-1 as active ingredients. In this disclosure, "containing as active ingredients" means that the ingredients are contained in an amount sufficient to exhibit their effects.

[0015] Sirolimus is a compound having the following structure and its chemical name is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12{-(1R)-2[-(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. Sirolimus inhibits the action of the mammalian target of rapamycin (mTOR), which regulates cell division, proliferation, and survival, and also has immunosuppressant effects. In Japan, it has been approved as an active ingredient in the treatment of lymphangioleiomyomatosis.

[0016] [ka]

[0017] The dosage of sirolimus may be adjusted appropriately depending on the severity, weight, symptoms, sex, age, etc. of the patient, and may be, for example, 1 mg or more and 10 mg or less per day. The dosage is preferably 2 mg or more per day, and preferably 8 mg or less per day, more preferably 6 mg or less per day or 4 mg or less per day. From this viewpoint, the dosage of one preparation, for example, one tablet, The content of sirolimus in the drug is preferably 0.5 mg or more and 2 mg or less, more preferably 1 ± 0.01 mg. The frequency of administration may also be appropriately adjusted, for example, from once every three days to twice a day, with once a day being preferred. A drug holiday or drug holiday period may also be provided.

[0018] Gemcitabine is a compound with the following structure, and its chemical name is (+)-2'-deoxy-2',2'-difluorocytidine monohydrochloride, or 2'-deoxy-2',2'-difluoro-cytidine monohydrochloride. Gemcitabine exerts its antitumor effect by being phosphorylated after being taken up into cells and inhibiting DNA synthesis.

[0019] [ka]

[0020] The dose of gemcitabine may be adjusted appropriately depending on the severity, symptoms, weight, sex, age, etc. of the patient. For example, the dose per body surface area of ​​the patient is 500 mg / m per day. 2 More than 2000mg / m 2 can be less than 1000±10mg / m 2 , 1250 ± 12.5 mg / m2 if inoperable 2 From this viewpoint, it is preferable to use The content of gemcitabine in the agent, for example, one injectable preparation, is preferably 100 mg or more and 2 g or less, more preferably 200 ± 2 mg or 1000 ± 10 mg. The frequency of administration may be adjusted appropriately, for example, 0.5 times / week or more and 2 times / week or less, preferably 1 time / week. In addition, after administration for 2 weeks or more and 4 weeks or less, a one-week break may be allowed, or such a cycle may be repeated.

[0021] TS-1 is a formulation containing tegafur, gimeracil, and oteracil potassium. Tegafur is a compound having the following structure, and its chemical name is 5-fluoro-1-[(2RS)-tetrahydrofuran-2-yl]uracil. Gimeracil is a compound having the following structure, and its chemical name is 5-chloro-2,4-dihydroxypyridine. Oteracil potassium is a compound having the following structure, and its chemical name is 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylic acid monopotassium salt.

[0022] [ka]

[0023] The antitumor effect of TS-1 is based on 5-fluorouracil derived from tegafur. Gimeracil selectively inhibits the 5-FU catabolic metabolic enzyme DPD, which is distributed mainly in the liver, thereby suppressing the decrease in the concentration of 5-fluorouracil produced by tegafur. As a result, 5-fluoronucleotides, which are phosphorylated metabolites of 5-fluorouracil, are maintained at high concentrations in the tumor, enhancing the antitumor effect. Oteracil potassium selectively competitively inhibits orotate phosphoribosyltransferase in gastrointestinal tissues, selectively suppressing the production of 5-fluorouracil to 5-fluoronucleotides, which is thought to reduce gastrointestinal toxicity.

[0024] The ratios of tegafur, gimeracil and oteracil potassium in the TS-1 formulation may be adjusted as appropriate; for example, the ratio of gimeracil to tegafur can be 0.2 to 0.4 by mass, preferably 0.3±0.003 by mass, and the ratio of oteracil potassium to tegafur can be 0.5 to 1.5 by mass, preferably 1±0.01 by mass.

[0025] The dosage of TS-1 may be adjusted appropriately depending on the severity, symptoms, body weight, sex, age, etc. of the patient. For example, the amount of tegafur contained in TS-1 may be 20 mg or more and 80 mg or less per administration, and preferably 40 mg or more and 75 mg or less. From this viewpoint, the content of tegafur per one formulation, for example, per TS-1 formulation, is preferably 10 mg or more and 50 mg or less, and more preferably 20 ± 0.2 mg or 25 ± 0.25 mg. The frequency of administration may also be adjusted appropriately, for example, 1 time / day or more and 4 times / day or less per week, and preferably 2 times / day. In addition, after administration for 20 days or more and 40 days or less, preferably 28 ± 1 days, the drug may be suspended for 10 days or more and 20 days, preferably 14 ± 1 days, and such a cycle may be repeated.

[0026] When gemcitabine is used in the present invention, it is preferable to use paclitaxel in combination. Paclitaxel is a compound having the following structure, and its chemical name is (-)-(1S,2S,3R,4S,5R,7S,8S,10R,13S)-4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1,7-dihydroxy-9-oxotax-11-en-13-yl(2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionic acid. Paclitaxel promotes the polymerization of microtubule proteins, causing stabilization and excessive formation of microtubules, and inhibits cell division by impairing the function of the spindle, thereby exerting antitumor activity.

[0027] [ka]

[0028] The dosage of paclitaxel may be adjusted appropriately depending on the severity, symptoms, weight, sex, age, etc. of the patient. For example, the dosage per patient's body surface area is 50 mg per day. / m 2 More than 200mg / m 2 and 125±1.25 mg / m 2 I like From this viewpoint, the content of paclitaxel per one preparation, for example, per one injectable preparation, is preferably 50 mg or more and 200 mg or less, more preferably 100±1 mg. The frequency of administration may be adjusted appropriately as well, for example, 0.5 times / week or more and 2 times / week or less, preferably 1 time / week. In addition, after administration for 2 weeks or more and 5 weeks or less, a one-week break may be allowed, or such a cycle may be repeated.

[0029] As the paclitaxel, nab-paclitaxel may be used. Nab-paclitaxel is a nanoparticle of paclitaxel bound to serum albumin, and while the water solubility of paclitaxel itself is relatively low, water can be used as a solvent. The content of serum albumin may be appropriately adjusted, and for example, the ratio of serum albumin to paclitaxel may be 5 times or more by mass and 10 times or less by mass, and is preferably 8±0.1 times by mass. The average particle size of nab-paclitaxel may be 130±10 nm.

[0030] The pancreatic cancer therapeutic agent according to the present invention may contain all active ingredients in one preparation, but in order to adjust the administration mode for each active ingredient, it is preferable that the agent is composed of two or more preparations, each of which contains one or more active ingredients. Each preparation may contain additional ingredients according to its dosage form. Examples of the additional ingredients include base materials, excipients, colorants, lubricants, flavoring agents, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, antioxidants, adjuvants, buffers, pH adjusters, sweeteners, and flavors.

[0031] For example, sirolimus is preferably used as an active ingredient in tablets, capsules, granules, powders, etc., and is preferably used as an active ingredient in tablets. Examples of tablet additives other than sirolimus include carnauba wax, crystalline cellulose, titanium oxide, magnesium stearate, sucrose, shellac, talc, tocopherol, lactose hydrate, povidone, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, glycerin monooleate, calcium sulfate, etc. Also, the tablets may be coated with sugar.

[0032] Gemcitabine is preferably used as an active ingredient in an injectable preparation, particularly an intravenous injection preparation. The injectable preparation may be, for example, a lyophilized preparation containing, in addition to the active ingredient gemcitabine, additives such as D-mannitol, sodium acetate hydrate, and a pH adjuster, which is dissolved in physiological saline when used.

[0033] TS-1 is preferably formulated as an oral preparation such as capsules, powders, granules, tablets, etc., containing tegafur, gimeracil, and oteracil potassium as active ingredients. For example, it can be formulated as an oral preparation containing additives such as lactose hydrate, magnesium stearate, gelatin, sodium lauryl sulfate, titanium oxide, D-mannitol, and hydroxypropyl cellulose in addition to the active ingredients tegafur, gimeracil, and oteracil potassium.

[0034] Paclitaxel is preferably used as an active ingredient in an injectable preparation, particularly an intravenous injection preparation. The injectable preparation may be, for example, a lyophilized preparation containing an additive such as serum albumin in addition to the active ingredient paclitaxel, and may be dissolved or suspended in physiological saline when used.

[0035] When the pancreatic cancer therapeutic agent of the present invention consists of two or more preparations, the preparations may be administered simultaneously, but it is preferable to administer them separately with an interval depending on the dosage and administration frequency of the active ingredient in each preparation.

[0036] The therapeutic agent for pancreatic cancer according to the present invention is administered to patients with pancreatic cancer, but may also be administered to patients whose pancreatic cancer cells have metastasized to lymph nodes or other organs in order to inhibit further invasion and metastasis of pancreatic cancer. EXAMPLES

[0037] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples, and it is possible to carry out the present invention by making appropriate modifications within the scope of the above and below-mentioned aims, and all of these modifications are included in the technical scope of the present invention.

[0038] Example 1: Effect of sirolimus on pancreatic cancer cells (1) Inhibition of mTOR Add 2 mL of Dulbecco's modified Eagle medium (DMEM, Gibco-BRL) to each well of a 6-well plate, and incubate with 3.0 × 10 human pancreatic cancer cell line S2-013. 5 cell s / well and precultured for 48 hours at 37° C. Then, sirolimus was added at a concentration of 20 nM or 200 nM, or was not added, and the cells were cultured at 37° C. for 18 hours. After incubation, the cell pellet was resuspended in 20 mM Hepes (pH 7.4), 100 mM potassium chloride, 2 mM magnesium chloride, 0.5% Triton (R) X-100, "Prote The cells were resuspended in a lysis buffer containing "Phosphatase Inhibitor Cocktail" (Roche) and "Phosphatase Inhibitor Cocktail" (Nacalai Tesque) to obtain cell lysates. The protein concentration in each cell lysate was then determined using the bicinchoninic acid (BCA) assay. Specifically, each cell lysate was suspended in a sample buffer (containing 50 mM Tris, 2% sodium dodecyl sulfate (SDS), 0.1% bromophenol blue, and 10% glycerol) so that the final concentration of total protein was 1 to 2 μg / μL, and analyzed by SDS-PAGE and Western blotting using anti-phosphorylated p70S6K antibody (Cell Signaling), anti-p70S6K antibody (Cell Signaling), and a 4-20% gradient gel (Bio-Rad). The results are shown in Figure 1. As shown in the results in FIG. 1, the addition of sirolimus at concentrations of 20 nM and 200 nM to the culture medium reduced p70S6K activity in pancreatic cancer cells in a concentration-dependent manner, demonstrating the inhibitory effect of sirolimus on mTOR activity in pancreatic cancer cells.

[0039] (2) Measurement of viable pancreatic cancer cells Add 2 mL of Dulbecco's modified Eagle medium (DMEM, Gibco-BRL) to each well of a 6-well plate, and incubate with 3.0 × 10 human pancreatic cancer cell line S2-013. 5 cell s / well and precultured for 48 hours at 37° C. Then, sirolimus was added at a concentration of 20 nM or 200 nM, or was not added, and the cells were cultured at 37° C. for 18 hours. Next, the number of viable cells was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. MTT is taken up into viable cells and reduced by dehydrogenase in mitochondria to produce a formazan dye. Since the amount of dye correlates with the number of metabolically active viable cells, the number of viable cells and the viability rate can be evaluated by measuring absorbance. Specifically, Cell Counting Kit-8 solution (200 μL) included in the MTT assay kit ("Cell Counting Kit-8" manufactured by Dojindo Laboratories) was added to each well and incubated at 37° C. for 3 hours. Next, the absorbance at 450 nm was measured using a Microplate Reader 550 (manufactured by Bio-Rad). The results are shown in FIG. 2. As shown in the results in FIG. 2, sirolimus did not inhibit the proliferation of human pancreatic cancer cells. The present inventors have experimentally demonstrated that everolimus, an mTOR inhibitor, significantly suppresses the proliferation of human pancreatic cancer cells (JP Patent Publication No. 2019-206516). Furthermore, sirolimus, another mTOR inhibitor, was shown not to inhibit the proliferation of human pancreatic cancer cells.

[0040] (3) Matrigel invasion assay Add 2 mL of Dulbecco's modified Eagle medium (DMEM, Gibco-BRL) to each well of a 6-well plate, and incubate with 3.0 × 10 human pancreatic cancer cell line S2-013. 5 cell s / well and pre-cultured at 37°C for 48 hours. Then, sirolimus was added at a concentration of 20 nM or 200 nM, or was not added, and cultured at 37°C for 18 hours. 4 The cells were cultured in the Matrigel Invas The cells were seeded into the wells of the upper chamber of a Becton Dickinson "Ion Chamber" (pore size: 8 μm), and 5% FCS containing a chemical attractant was added to the lower chamber. After 20 hours of incubation, four independent fields were examined under a microscope, and the number of cells that had migrated into the lower chamber was counted. The results are shown in Figure 3. In addition, "*" in Figure 3 indicates that there is a significant difference from the control at p<0.05 in the t-test. As shown in FIG. 3, the invasion of human pancreatic cancer cells was significantly inhibited by the addition of sirolimus in a concentration-dependent manner. The present inventors have experimentally demonstrated that everolimus, an mTOR inhibitor, suppresses the invasion of human pancreatic cancer cells (JP Patent Publication No. 2019-206516), but the inhibitory effect of sirolimus, another mTOR inhibitor, on the invasion of human pancreatic cancer cells was clearly stronger than that of everolimus.

[0041] Example 2: Animal studies Human pancreatic cancer cell line S2-013, human umbilical vein endothelial cells, and human mesenchymal stem cells were co-cultured to form human pancreatic cancer organoids with a size of approximately 500 μm. When human pancreatic cancer organoids were transplanted subcutaneously into the back of nude mice, tumors of several millimeters in size were confirmed one week later. Tumor tissues excised from mice transplanted with human pancreatic cancer organoids contained abundant cancer stroma, and areas exhibiting glandular and micropapillary structures were mixed. These findings were similar to the histological structure of clinical pancreatic cancers surgically excised from pancreatic cancer cases, and larger tumors showed an invasive adenocarcinoma image, making human pancreatic cancer organoids a suitable model for drug efficacy evaluation. Gemcitabine + paclitaxel or gemcitabine + paclitaxel + sirolimus were administered to human pancreatic cancer organoid transplant model mice to evaluate the efficacy of each. Specifically, 24 nude mice were randomly divided into a control group of 8 mice each, a group administered gemcitabine + paclitaxel, and a group administered gemcitabine + paclitaxel + sirolimus, and transplantation of human pancreatic cancer organoids was performed on the first day. The gemcitabine + paclitaxel group received 50mg / kg gemcitabine and 0.5mg / kg nab-paclitaxel by intraperitoneal injection once a week for three consecutive weeks from the third to the ninth week after transplantation, followed by a one-week break and then another three consecutive weeks of administration.The gemcitabine + paclitaxel + sirolimus group received 8mg / kg sirolimus by intraperitoneal injection once a week for five weeks after transplantation, in addition to the gemcitabine and nab-paclitaxel intraperitoneal injections. After transplantation of human pancreatic cancer organoids, the long and short diameters of the tumor were measured regularly every week using a vernier caliper, and the tumor volume was calculated based on the measured values ​​using the formula: long diameter x long diameter x short diameter / 2. The results are shown in Figure 4. In Figure 4, "Control" shows the results of the control group that did not receive medication, "GnP" shows the results of the gemcitabine + paclitaxel group, and "GnP + Lapa" shows the results of the gemcitabine + paclitaxel group. The results of the gemcitabine + paclitaxel + sirolimus group are shown, and "*" indicates a significant difference at p<0.05 compared to the gemcitabine + paclitaxel group. In addition, 9 weeks after transplantation of human pancreatic cancer organoids, the tumors were excised, fixed using formalin, and stained with hematoxylin-eosin for observation. The results are shown in Figure 5. As shown in Figure 4, the gemcitabine + paclitaxel group showed a significantly higher glioma rate than the control group. In the gemcitabine + paclitaxel + sirolimus group, tumor volume was significantly reduced compared to the gemcitabine + paclitaxel group, demonstrating a strong tumor growth inhibitory effect. As shown in the results in Figure 5, in the gemcitabine + paclitaxel + sirolimus group, the tumor was necrotic, tumor cell clusters were fragmented, and tumor volume was clearly reduced. In the gemcitabine + paclitaxel group, compared to the group in which sirolimus was administered in combination, the tendency toward necrosis was not as pronounced and no fragmentation of tumor tissue was observed. In accordance with the above results, it has been demonstrated that the combined use of gemcitabine, paclitaxel, and sirolimus not only suppresses the proliferation of pancreatic cancer cells, but also enables the treatment of pancreatic cancer.

Claims

1. An oral preparation for treating pancreatic cancer, comprising sirolimus as an active ingredient, A preparation for intravenous injection for treating pancreatic cancer containing gemcitabine as an active ingredient and a preparation for intravenous injection for treating pancreatic cancer containing paclitaxel as an active ingredient are administered simultaneously or separately at an interval; A therapeutic agent for pancreatic cancer, which is administered to a patient.

2. A preparation for intravenous injection for treating pancreatic cancer, comprising gemcitabine as an active ingredient, The oral preparation for treating pancreatic cancer containing sirolimus as an active ingredient and the intravenous preparation for treating pancreatic cancer containing paclitaxel as an active ingredient are administered simultaneously or separately at an interval. A therapeutic agent for pancreatic cancer, which is administered to a patient.

3. A preparation for intravenous injection for treating pancreatic cancer, comprising paclitaxel as an active ingredient, The oral preparation for treating pancreatic cancer containing sirolimus as an active ingredient and the intravenous preparation for treating pancreatic cancer containing gemcitabine as an active ingredient are administered simultaneously or separately at an interval. A therapeutic agent for pancreatic cancer, which is administered to a patient.

4. The therapeutic agent for pancreatic cancer according to any one of claims 1 to 3, wherein said paclitaxel is nab-paclitaxel.

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