Drug for treating pancreatic cancer and use thereof

Abstract

A drug for treating pancreatic cancer and use thereof. Cell experiments demonstrate that the pharmaceutical composition has a synergistic effect of inhibiting the survival of human pancreatic cancer cells and inducing the periodic inhibition and apoptosis of human pancreatic cancer cells. Moreover, anti-tumor efficacy experiments on a CDX model and clinical trials demonstrate that, compared with the prior art, the pharmaceutical combination achieves an unexpected therapeutic effect and exhibits a synergistic effect of inhibiting tumor growth. The present invention provides a better option for the treatment of pancreatic cancer.

Description

TECHNICAL FIELD The present disclosure pertains to the technical field of biopharmaceuticals and particularly relates to a drug for treating pancreatic cancer and use thereof. BACKGROUND In recent years, there has been a significant upward trend worldwide in the incidence of pancreatic cancer, one of the most malignant tumors of the digestive system. Surgical resection is the only effective method offering a chance of cure and long-term survival for patients with pancreatic cancer; however, more than 80% of patients with pancreatic cancer lose the opportunity for surgery due to late stages of the disease. Drug therapy can be applied to patients with pancreatic cancer at various stages, including preoperative neoadjuvant / conversion therapy for resectable or borderline resectable cases, adjuvant therapy for patients after radical surgery, and treatments for patients with locally advanced or metastatic recurrent disease. Drug therapy can not only extend the survival of patients but also palliate pain and improve quality of life in terminal patients. According to the Guidelines for Diagnosis and Treatment of Pancreatic Cancer (2022 Edition), neoadjuvant / conversion therapy regimens for resectable or borderline resectable pancreatic cancer mainly include: gemcitabine + paclitaxel protein-bound, FOLFIRINOX, and mFOLFIRINOX. The FOLFIRINOX and mFOLFIRINOX regimens use different doses of oxaliplatin, irinotecan, calcium folinate, and 5-fluorouracil in combination. For postoperative adjuvant therapy, treatments based on gemcitabine or a fluorouracil drug (5-fluorouracil, capecitabine, or tegafur-gimeracil-oteracil) are recommended. For the treatment of unresectable locally advanced or metastatic pancreatic cancer, commonly used drugs include: gemcitabine, paclitaxel protein-bound, 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, tegafur-gimeracil-oteracil, capecitabine, erlotinib, etc. There remains a need for the development of new drugs for pancreatic cancer to meet patients’ clinical needs. 5-Fluorouracil inhibits DNA synthesis by inhibiting the thymine nucleotide synthase and shows good efficacy against digestive tract tumors and other solid tumors. It is the most widely used antimetabolite anti-tumor drug. Gemcitabine is a small-molecule DNA synthesis inhibitor, primarily used in the treatment of diseases including tumors, diseases of the digestive system, endocrine and metabolic diseases, and diseases of the respiratory system, and has been approved for indications including non-small cell lung cancer, peripheral T-cell lymphoma, biliary tract tumors, bladder cancer, urothelial carcinoma, etc. Chiauranib is a small-molecule anti-tumor targeted drug targeting multiple protein kinases, independently developed and synthesized by Shenzhen Chipscreen Biosciences Co., Ltd. It has highly selective inhibitory activity against the VEGFR / PDGFR / c-Kit, Aurora B, and CSF-1R targets and exhibits a comprehensive anti-tumor effect through a three-pathway anti-tumor synergistic mechanism: inhibiting tumor angiogenesis, inhibiting tumor cell mitosis, and regulating the inflammatory tumor microenvironment. In addition, its high target selectivity also reduces the risk of side effects caused by off-target effects. Currently, chiauranib is being investigated for indications including soft tissue sarcoma, liver cancer, ovarian cancer, hepatocellular carcinoma, triple-negative breast cancer, etc. Paclitaxel is a natural alkaloid with a strong anti-tumor effect. Its primary mechanism involves preventing the mitosis of tumor cells by binding to and stabilizing microtubules. This causes the cell cycle to be arrested at the mitotic phase, ultimately resulting in tumor cell apoptosis or the inability of tumor cells to continue to proliferate. Paclitaxel is a microtubule stabilizer discovered relatively early and is considered an important advancement in chemotherapy. Microtubules are long, filamentous, tubular protein polymers that form the main component of the cytoskeleton. Paclitaxel binds to the N-terminal 31 amino acids of the P—tubulin subunit in microtubules. This binding stabilizes the microtubules and increases their polymerization, leading to cell death. In the prior art, there are no studies or reports related to the use of chiauranib alone or in combination with other drugs to treat pancreatic cancer. SUMMARY Technical Problems to be Solved by the Present Disclosure In view of the significant need for clinical medications among patients with pancreatic cancer who face high incidence and mortality rates, the present disclosure aims to provide a new pharmaceutical composition for preventing and / or treating and / or ameliorating pancreatic cancer. The pharmaceutical composition achieves an unexpected therapeutic effect compared to the prior art and shows an unexpected synergy between the active pharmaceutical ingredients. Description of the Invention: A first aspect of the present disclosure provides a pharmaceutical composition for first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer, comprising a DNA synthesis blocker and an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor. DNA synthesis blockers, also known as DNA synthesis inhibitors, refer to a class of substances that can participate in DNA synthesis activities in the cell cycle to inhibit / block DNA synthesis. The pharmaceutical composition for first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer further comprises a tubulin inhibitor (or referred to as a tubulin stabilizer). A second aspect of the present disclosure provides use of an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor in the preparation of a medicament for use in combination with a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer. The present disclosure further provides use of an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor in the preparation of a medicament for use in combination with a tubulin inhibitor and a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer. A third aspect of the present disclosure provides use of an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor in combination with a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer. The present disclosure further provides use of an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor in combination with a tubulin inhibitor and a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer. In some specific embodiments, the DNA synthesis blocker described herein is selected from a pyrimidine drug, including a uracil drug, a cytosine drug, or a T thymine drug. In some specific embodiments, the DNA synthesis blocker described herein is selected from a uracil drug and a cytosine drug. In some specific embodiments, the DNA synthesis blocker described herein is selected from a uracil drug. In some specific embodiments, the DNA synthesis blocker described herein is selected from a fluorouracil drug. In some specific embodiments, the DNA synthesis blocker described herein is selected from 5-fluorouracil, tegafur, tegafur-gimeracil-oteracil, cytarabine, capecitabine, gemcitabine, maribavir, fexinidazole, miriplatin, miriplatin hydrate, metronidazole, benzoylmetronidazole, losoxantrone hydrochloride, clofarabine, oxaliplatin, levofolinate calcium, ciclopirox, metronidazole hydrochloride, secnidazole, cisplatin, bleomycin sulfate, bleomycin hydrochloride, azathioprine, thiotepa, glyfosfin, metronidazole disodium phosphate, and nimorazole, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs. In some specific embodiments, the DNA synthesis blocker described herein is selected from 5-fluorouracil, cytarabine, gemcitabine, tegafur, and tegafur-gimeracil-oteracil, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs. In some specific embodiments, the DNA blocker described herein is selected from 5-fluorouracil and gemcitabine, and crystalline forms thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, prodrugs thereof, and metabolites thereof. In some specific embodiments, the DNA blocker described herein is selected from 5-fluorouracil, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof. In some specific embodiments, the DNA synthesis blocker described herein is selected from 5-fluorouracil, tegafur, and tegafur-gimeracil-oteracil, and crystalline forms and pharmaceutically acceptable salts of the aforementioned drugs. In some specific embodiments, the DNA blocker described herein is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof. In some specific embodiments, the DNA synthesis blocker described herein is selected from 5-fluorouracil, tegafur, and tegafur-gimeracil-oteracil. In some specific embodiments, the DNA blocker described herein is selected from 5-fluorouracil. In some specific embodiments, the DNA blocker described herein is selected from gemcitabine, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof. In some specific embodiments, the DNA blocker described herein is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof. In some specific embodiments, the DNA synthesis blocker described herein is selected from gemcitabine. In some specific embodiments, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multitarget kinase inhibitor described herein is selected from: chiauranib, apatinib, bevacizumab, barasertib (AZD1152), ZM-447439, GSK-1070916, AT9283, PHA-739358, MK0457 (VX-680), MK0475, ENMD-2076, CY-116, hesperadin, SN-314, R763 / AS703569, BI811283, and AMG 900, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drug. In some specific embodiments, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi target kinase inhibitor described herein is selected from chiauranib, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof. In some specific embodiments, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multitarget kinase inhibitor described herein is selected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof. In some specific embodiments, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multitarget kinase inhibitor described herein is selected from chiauranib. In some specific embodiments, the tubulin inhibitor described herein is selected from a paclitaxel compound and a vincristine compound. In some specific embodiments, the tubulin inhibitor described herein is selected from utidelone, docetaxel, eribulin, cabazitaxel, vinflunine tartrate, ixabepilone, paclitaxel protein-bound, BNC-105P, OXI-4503, CPC634, ortataxel, SCB-01A, verubulin, NSC-631570, colchicine, paclitaxel, podofilox, vindesine sulfate, griseofulvin, vinblastine, sabizabulin, albumin-bound docetaxel, paclitaxel poliglumex, paclitaxel-hyaluronic acid, paclitide, ARC-100, crolibulin, combretastatin A4 phosphate disodium salt, isofludelone, fluorapacin, MAP-4343,  JJH-201601, larotaxel, ModraPac005 / r, patupilone, salutaxel, aqitasai, ARC-01, BT-1769, and CAP-6, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs. In some specific embodiments, the tubulin inhibitor described herein is selected from docetaxel, paclitaxel protein-bound, colchicine, paclitaxel, vinblastine, albumin-bound docetaxel, paclitaxel poliglumex, and paclitaxel-hyaluronic acid, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs. In some specific embodiments, the tubulin inhibitor is selected from paclitaxel proteinbound, paclitaxel, paclitaxel poliglumex, and paclitaxel-hyaluronic acid. In some specific embodiments, the tubulin inhibitor described herein is selected from paclitaxel protein-bound. In some specific embodiments, the pancreatic cancer described herein is locally advanced or metastatic pancreatic cancer. In some specific embodiments, the pancreatic cancer described herein is pancreatic ductal adenocarcinoma. In some specific embodiments, the pancreatic cancer described herein is locally advanced or metastatic pancreatic ductal adenocarcinoma. In some specific embodiments, a unit dose of the chiauranib described herein is about 1-100 mg, preferably about 5-80 mg, more preferably about 10-50 mg, and most preferably about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg. In some specific embodiments, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multitarget kinase inhibitor described herein is selected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the chiauranib is about 1-100 mg, preferably about 5-80 mg, more preferably about 1050 mg, and most preferably about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg, as calculated based on chiauranib. In some specific embodiments, the chiauranib is an oral formulation, preferably a tablet or a capsule, and is administered orally. In some specific embodiments, the DNA blocker described herein is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the 5-fluorouracil is 10-500 mg, preferably 25-300 mg, and most preferably 50 mg, 125 mg, or 250 mg, as calculated based on 5-fluorouracil. In some specific embodiments, the 5-fluorouracil is an injectable formulation and is administered by injection. In some specific embodiments, the 5-fluorouracil is an oral formulation, preferably a tablet, and is administered orally. In some specific embodiments, the DNA blocker described herein is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the gemcitabine is 100-2000 mg, preferably 200-1000 mg, and most preferably 200 mg or 1000 mg, as calculated based on gemcitabine. In some specific embodiments, the gemcitabine is an injectable formulation and is administered by injection. In some specific embodiments, the tubulin inhibitor described herein is selected from paclitaxel, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the paclitaxel is 20 mg, 50 mg, 100 mg, 500 mg, 1 g, or 2 g, as calculated based on paclitaxel. In some specific embodiments, the paclitaxel is an injectable formulation and is administered by injection. In some specific embodiments, the tubulin inhibitor is paclitaxel protein-bound and is administered by injection. In some specific embodiments, the pharmaceutical composition described above is used for preventing and / or treating and / or ameliorating pancreatic cancer. A fourth aspect of the present disclosure provides a kit comprising the pharmaceutical composition described above. In some specific embodiments, in the kit, the DNA synthesis blocker, the tubulin inhibitor, and the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor are unit formulations with identical or different strengths, and the DNA synthesis blocker, the tubulin inhibitor, and the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multitarget kinase inhibitor are placed in the same container or are placed in different containers, respectively. In some specific embodiments, in the kit, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is in a dosage form for gastrointestinal administration, preferably an oral formulation; the DNA synthesis blocker is in a dosage form for gastrointestinal administration or parenteral administration, preferably an oral formulation or an injectable formulation; the tubulin inhibitor is in a dosage form for gastrointestinal administration or parenteral administration, preferably an oral formulation or an injectable formulation, and more preferably an injectable formulation. In some specific embodiments, the kit further comprises instructions for use or other information. A fifth aspect of the present disclosure provides a method for preventing and / or treating and / or ameliorating pancreatic cancer, comprising administering to a patient in need thereof a prophylactically and / or therapeutically and / or amelioratively effective amount of the pharmaceutical composition described above. In some specific embodiments, in the method for preventing and / or treating and / or ameliorating pancreatic cancer, the DNA synthesis blocker, the tubulin inhibitor, and the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor are administered simultaneously, separately, or sequentially. In some specific embodiments, in the method for preventing and / or treating and / or ameliorating pancreatic cancer, the chiauranib is an oral formulation, preferably a capsule or a tablet, and is administered orally. In some specific embodiments, in the method for preventing and / or treating and / or ameliorating pancreatic cancer, the gemcitabine is an injectable formulation and is administered by injection. In some specific embodiments, in the method for preventing and / or treating and / or ameliorating pancreatic cancer, the paclitaxel is an injectable formulation and is administered by injection. Definitions of Terms: In the present disclosure, the crystalline forms include non-solvated crystalline forms, solvated crystalline forms, and an amorphous structure. The crystalline forms of chiauranib include non-solvated crystals A, B, and C thereof. The non-solvated crystals A, B, and C of chiauranib and preparation methods therefor are disclosed in CN201610856945.2, which is incorporated herein by reference in its entirety. In the present disclosure, the isomers include conformational isomers, enantiomers, and diastereomers. The term “pharmaceutically acceptable salt” in the present disclosure refers to an acid addition salt or a base addition salt prepared by reacting a drug, such as chiauranib, paclitaxel, gemcitabine, or 5-fluorouracil, with a pharmaceutically acceptable acid or base. The pharmaceutically acceptable acid is preferably selected from an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid) and an organic acid (e.g., oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, or benzoic acid). The pharmaceutically acceptable base is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, ammonia water, ammonium bicarbonate, etc. The prodrugs in the present disclosure, also known as precursor drugs, drug precursors, or the like, refer to compounds obtained by modifying the chemical structures of drugs. These compounds exhibit no or little activity in vitro, and are converted in vivo, either enzymatically or non-enzymatically, to release the active drugs, thereby producing therapeutic effects. The metabolites in the present disclosure refer to intermediate metabolites and final metabolites obtained by metabolism of compounds in animal individuals. In the present disclosure, the term “effective amount” in the phrase “prophylactically / therapeutically / amelioratively effective amount” refers to a dose that falls between the minimum effective amount and the maximum dose of a medication and that can produce a significant effect on the body without causing a toxic response. In the present disclosure, the term “individual” in the phrase “individual in need thereof” refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. The mammal includes, but is not limited to, livestock (e.g., cattle), pets (e.g., cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human. In the present disclosure, the term “combination” refers to administration of two or more pharmaceutical components. The pharmaceutical components may be prepared compound formulations, or combination therapies in which two or more individual active ingredients are administered separately. The timing of combination administration depends in part on the combination administered. Combination administration is intended to include simultaneous or sequential administration of components. The components of the present disclosure may be administered alone or in combination to a patient. The components described in the present disclosure may be used in combination with each other or with other active agents known to be suitable for the treatment of cancer. In the present disclosure, the term “pharmaceutical composition” refers to two or more pharmaceutical components that are mixed to prepare a compound formulation, or that are present as single-active ingredient formulations for use in combination. When present as single-active ingredient formulations for use in combination, they may be administered alone or in combination to a patient. Compared to the prior art, the present disclosure has the following beneficial effects: Through experiments such as cell survival rate tests, flow cytometry cycle assays, flow cytometry apoptosis assays, cell viability tests, and tests for assessing anti-tumor efficacy in a CDX model of human pancreatic cancer, the present disclosure has demonstrated that: using chiauranib, a representative Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor, in combination of 5-fluorouracil and gemcitabine, representative DNA synthesis blockers, can synergistically inhibit the survival of PANC1 human pancreatic cancer cells, synergistically induce the cycle inhibition and apoptosis of PANC1 human pancreatic cancer cells, inhibit the viability of pancreatic cancer cells, inhibit tumor growth in animals, and so on. The experimental results show that the pharmaceutical composition of the present disclosure has a synergistic function, can well treat pancreatic cancer, and provides a better option for the treatment of pancreatic cancer. The present disclosure further provides clinical trial data on the use of chiauranib in combination with paclitaxel and gemcitabine in the treatment of patients with locally advanced or metastatic pancreatic ductal adenocarcinoma. The clinical trial results show that the combination of chiauranib, paclitaxel protein-bound, and gemcitabine exhibited a good therapeutic effect in the first-line treatment of locally advanced or metastatic pancreatic ductal adenocarcinoma, with an overall response rate (ORR) of 57% (4 / 7) and a disease control rate (DCR) of 100% (7 / 7). In comparison, the existing treatment regimen (paclitaxel protein-bound plus gemcitabine) exhibits an overall response rate (ORR) of 11.11% and a DCR of 46.67%[1]. The technical solution provided in the present disclosure significantly improved patient benefit, achieved an unexpected technical effect compared to the prior art, and showed a synergy among the drugs. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the results of an experiment for assessing the inhibitory effect of chiauranib alone on the viability of PANC1 cells. FIG. 2 shows the results of an experiment for assessing the inhibitory effect of 5-fluorouracil alone on the viability of PANC1 cells. FIG. 3 shows the results of an experiment for assessing the inhibitory effects of combinations of chiauranib and 5-fluorouracil on the viability of PANC1 cells. FIG. 4 shows the results of an experiment for assessing the effect of chiauranib and / or 5-fluorouracil on the cell cycle of PANC1 cells in Example 2. FIG. 5 shows the results of an experiment for assessing the apoptosis-inducing effect of chiauranib and / or 5-fluorouracil on PANC1 cells in Example 3. FIG. 6 shows tumor volume changes recorded in an experiment for assessing the antitumor efficacy of chiauranib and / or gemcitabine in a CDX model of SW1990 human pancreatic cancer in Example 5. FIG. 7 shows the results of the measurement of tumor weight in an experiment for assessing the efficacy of chiauranib and / or gemcitabine in a CDX model of SW1990 human pancreatic cancer in Example 5. FIG. 8 shows mouse body weight changes recorded in an experiment for assessing the anti-tumor efficacy of chiauranib and / or gemcitabine in a CDX model of SW1990 human pancreatic cancer in Example 5. In the drawings, Chiau. refers to chiauranib, and 5Fu refers to 5-fluorouracil. DETAILED DESCRIPTION The present disclosure discloses a drug for treating pancreatic cancer and use thereof. Those skilled in the art can refer to the disclosure herein and appropriately improve process parameters to achieve the intended effects. It should be particularly noted that all similar substitutions and modifications will be apparent to those skilled in the art and are considered to be included in the present disclosure. The drug for treating pancreatic cancer and the use thereof described in the present disclosure have been described through preferred examples. Obviously, those related to the art can make modifications or appropriate changes to and combine the use and the pharmaceutical composition described herein without departing from the content, spirit, or scope of the present disclosure, to implement and apply the technology of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art. Experimental materials The PANC1 human pancreatic cancer cell line was purchased from the American Type Culture Collection (ATCC) (CRL-1469TM) and cultured in a DMEM culture medium (Hyclone) containing 1% double antibiotic solution (penicillin-streptomycin, Hyclone) and 10% fetal bovine serum (Gibco). Chiauranib (Chiau.) was from Shenzhen Chipscreen Biosciences Co., Ltd., and 5-fluorouracil (5FU) was purchased from MCE (Cat. No. HY-90006). The two were separately dissolved in dimethyl sulfoxide (DMSO; purchased from Sangon Biotech (Shanghai) Co., Ltd. (hereinafter referred to as “Shanghai Sangon”), Cat. No. DN3039A) to prepare 30 mM stock solutions, and the stock solutions were stored in a freezer at -20 °C for later use. Before use, working solutions with corresponding final concentrations were prepared according to the needs of each experiment. Main experimental reagents, instruments, and devices alamarBlueTM Cell Viability Reagent (Invitrogen, DAL1100) Propidium iodide (PI; Shanghai Sangon, A601112) Ribonuclease A (RNase A; Shanghai Sangon, B500474) TritonX-100 (Shanghai Sangon, A110694) Annexin V-FITC / PI apoptosis detection kit (Yeasen Biotechnology (Shanghai) Co., Ltd., 40302ES20) Super clean bench (Airtech) CO2 cell incubator (RS Biotech, Galaxy S) Inverted microscope (Guangzhou Mshot Technology Co., Ltd.) Denovix CellDrop™ FL cell counter Tecan Spark™ multimode microplate reader Refrigerated high-speed centrifuge (Eppendorf) BD FACSCelestaTM flow cytometer Example 1. Tests for Assessing Effects of Drugs or Pharmaceutical Combinations on Cell Viability Experimental method: PANC1 cells in the logarithmic growth phase were digested, collected, and seeded into a 96-well cell culture plate at 4000 cells / well (the seeding volume was 190 pL when separate drugs were tested, and the seeding volume was 180 pL when pharmaceutical combinations were tested), and BLANK wells containing no cells were set (only the same volume of the culture medium was added). The cells were cultured overnight at 37 °C in 5% CO2. After the cells adhered to walls, the drugs were added. Before drug addition, chiauranib or 5FU was first diluted with DMSO to a concentration that was 1000 times the final concentration in each well, and then the dilution of chiauranib or 5FU in DMSO was diluted with the culture medium in a 1:50 ratio. When chiauranib was tested alone for its effect on cell viability, dilutions of chiauranib in DMSO corresponding to final concentrations of 0 pM, 1 pM, 2 pM, 4 pM, 8 pM, and 16 pM were added at 10 pL / well. When 5FU was tested alone, dilutions of 5FU in DMSO corresponding to final concentrations of 0 pM, 0.01 pM, 0.03 pM, 0.1 pM, 0.3 pM, 1 pM, 3 pM, 10 pM, and 30 pM were added at 10 pL / well. When pharmaceutical combinations were tested, according to the test results for the separate drugs, dilutions of chiauranib in DMSO corresponding to final concentrations of 0 pM, 4 pM, and 8 pM and dilutions of 5FU in DMSO corresponding to final concentrations of 0 pM, 1.25 pM, 2.5 pM, and 5 pM were added at 10 pL / well to form different dose combinations of the two drugs in the cell culture plate. After 120 h of drug treatment, the culture medium in the 96-well culture plate was removed using a pipette, and 100 pL of a detection solution (containing 90 pL of PBS and 10 pL of alamarBlueTM Cell Viability Reagent) was added to each well. The plate was incubated at 37 °C for 1-2 h, and the absorbance in each well (Ex544 / Em590) was measured with a Tecan Spark™ multimode microplate reader. Data processing and analysis: The test for each of the drug or pharmaceutical combination doses described above was repeated 3 times. The average ODBLK (background value) was calculated based on the readings of the BLANK wells, and the ODBLK was subtracted from the reading of each well to obtain the ODT of each drug treatment well and the ODT0 of the negative control wells (cells and the culture medium were added to these wells, but no drug was added). The average of the ODT0 values of the negative control wells, ODT0-A, was calculated, and the relative cell survival rate of each drug treatment well was calculated using the formula: relative cell survival rate (%) = (ODt - ODto-a) x 100%. Experimental results and analysis: The experimental results of Example 1 are shown in FIGs. 1-3. As shown in FIG. 1, chiauranib alone exhibited a certain inhibitory effect on the viability of PANC1 human pancreatic cancer cells, with the viability inhibition rates of 4 liM chiauranib and 8 gM chiauranib against PANC1 cells being close to 20% and 50%, respectively. As shown in FIG. 2, 5FU alone exhibited a certain inhibitory effect on the viability of PANC1 human pancreatic cancer cells; a dose of 5FU of just 1 lM or lower could affect the viability of PANC1 cells, and 3 lM 5FU inhibited the viability of PANC1 cells by nearly 50%. As shown in FIG. 3, 4 lM chiauranib and 8 lM chiauranib were used in combination with 1.25 lM 5FU, 2.5 lM 5FU, and 5 lM 5FU to treat PANC1 cells, and the relative cell viability data measured show that the viability inhibition rate of each dose combination of the two drugs against PANC1 cells was higher than the inhibition rates of the corresponding doses of the separate drugs. Especially, when 4 lM chiauranib was used in combination with 1.25 lM 5FU to treat PANC1 cells, the average inhibition rate was about 43.9%, while in this experiment, the inhibition rate of 4 lM chiauranib alone was about 17.7%, and the inhibition rate of 1.25 lM 5FU alone was about 9.3%; the inhibitory effect of the combination on PANC1 cells was significantly stronger than the sum of the effects of the two separate drugs. In summary, the experimental results of Example 1 show that: chiauranib and 5FU exhibited a synergistic inhibitory effect on PANC1 human pancreatic cancer cells. Example 2. Flow Cytometry Assay for Assessing Effects of Drugs or Pharmaceutical Combinations on Cell Cycle Experimental method: PANC1 cells in the logarithmic growth phase were digested, collected, seeded into six-well plates at 15% area / 1.8 mL per well, and cultured overnight under normal conditions before drug treatment. Solutions of chiauranib or 5FU were prepared according to Example 1 and added such that the final concentration of chiauranib in each well was 0 pM, 4 pM, or 8 pM, the final concentration of 5FU in each well was 0 pM, 0.25 pM, or 0.5 pM, and different dose combinations of the two drugs were formed. After 48 h of compound treatment, the culture medium was transferred to labeled 15 mL centrifuge tubes. The adherent cells in the wells were gently washed once with PBS, and the wash solutions were transferred to the corresponding 15 mL centrifuge tubes. 500 pL of trypsin digestion solution was added to the adherent cells left in the culture plates, and the plates were incubated at 37 °C for 5 min. After the cells were fully dispersed, a culture medium containing 10% FBS was added to stop the digestion reactions, and the cells were resuspended and then transferred to the corresponding 15 mL centrifuge tubes. After 5 min of centrifugation at room temperature at 1000 rpm, the supernatants were removed, and 1 mL of PBS was added to wash the cells. After 5 min of centrifugation at 4 °C at 1000 rpm, the supernatants were removed, and 300 pL of PBS was added to resuspend the cells. The suspensions were added dropwise to 1.5 mL centrifuge tubes containing 700 pL of pre-cooled absolute ethanol, and then the centrifuge tubes were gently inverted several times for thorough mixing. At this point, the cells had been collected and fixed. The samples were left to stand at 4 °C for at least 12 h. PBS, a 20 mg / mL PI stock solution, a 10 mg / mL RNase A solution, and 10% Triton X-100 were mixed in a 1000:2.5:2:10 ratio to prepare a DNA staining solution. The fixed cell samples were centrifuged at 4 °C at 1300 rpm for 10 min. The supernatants were removed using a pipette, and the cells were washed twice with PBS; each washing step involved 10 min of centrifugation at 4 °C at 1300 rpm followed by supernatant removal. The cells in each tube were resuspended in 500 pL of the staining solution described above. The suspensions were incubated at 37 °C for 30 min in a dark place and then centrifuged at 1300 rpm for 5 min, and the supernatants were removed. The cells were resuspended in 200 pL of PBS and then filtered using a 200-mesh stainless steel mesh. The filtrates were loaded into a flow cytometer for cell cycle analysis (red fluorescence was measured at an excitation wavelength of 488 nm, and light scattering was also measured; 10,000 cells were counted for each sample). Data processing and statistical analysis: The test for each of the drug or pharmaceutical combination doses described above was repeated twice. Cellular DNA content analysis and light scattering analysis were performed using FlowJo software to obtain cycle distribution data for each sample. Experimental results and analysis: The experimental results of Example 2 are shown in FIG. 4. Compared to the blank control, 4 pM chiauranib alone resulted in a certain increase in the proportion of G2 / M phase cells among PANC1 cells, and 8 pM chiauranib alone resulted in a significant increase in the proportion of polyploid cells among PANC1 cells. Compared to the blank control, 0.25 pM 5FU alone and 0.5 pM 5FU alone resulted in certain increases in the proportion of S phase cells among PANC1 cells, which were related to the mechanism by which 5FU blocks DNA synthesis (in the S phase, 5FU was incorporated into newly synthesized DNA during DNA synthesis, and such incorporation blocked DNA synthesis, causing the cell cycle to stop at the S phase). When the above doses of chiauranib were used in combination with 5FU to treat PANC1 cells, there were significant increases in the proportion of S phase cells compared to when 5FU was used alone, and there was a significant chiauranib dose-dependence. In summary, the experimental results of Example 2 show that chiauranib exhibited a synergistic sensitizing effect on the mechanism of action of 5FU. Example 3. Flow Cytometry Assay for Assessing Apoptosis-Inducing Effects of Drugs or Pharmaceutical Combinations Experimental method: Cells were seeded and treated with drugs according to Example 2. The drugs were added such that the final concentration of chiauranib in each well was 0 pM or 8 pM, the final concentration of 5FU in each well was 0 pM or 0.5 pM, and different dose combinations of the two drugs were formed. According to the instructions of the Annexin V-FITC / PI apoptosis detection kit, the cells were digested with EDTA-free trypsin, collected, and centrifuged at 4 °C at 300 g for 5 min. After the supernatants were removed, the cells were washed twice with precooled PBS; each washing step involved 5 min of centrifugation at 4 °C at 300 g followed by supernatant removal. 100 pL of 1x Binding Buffer was added to resuspend the cells, and then 5 pL of Annexin V-FITC and 10 pL of PI Staining Solution were added to each tube and gently mixed well. The mixtures were incubated at room temperature for 10-15 min in a dark place. 400 pL of 1x Binding Buffer was added. After thorough mixing, the mixtures were placed on ice. Flow cytometry analysis was immediately performed through the FL1 and FL2 channels, and apoptosis was analyzed using FlowJo software. Experimental results and analysis: The experimental results of Example 3 are shown in FIG. 5. Compared to the blank control, 0.5 pM 5FU alone did not induce more apoptosis of PANC1 human pancreatic cancer cells, and 8 pM chiauranib alone increased the proportion of apoptotic cells among PANC1 cells from a background value of 8.18% to 18.8%; in comparison, the proportion of apoptotic cells increased to 22.3% when the two drugs were used in combination. The experimental results of Example 3 show that although 5FU alone did not induce apoptosis of PANC1 cells, it synergistically enhanced the apoptosis-inducing effect of chiauranib. Example 4. Test for Assessing Effects of Combinations of Chiauranib and Gemcitabine on Viability of Human Pancreatic Cancer Cells Experimental materials: The PANC-1 human pancreatic cancer cell line was purchased from Nanjing Cobioer Biosciences Co., Ltd. (CBP60545) and cultured in a DMEM culture medium (Gibco) containing 10% fetal bovine serum (Gibco). The MIA PaCa-2 human pancreatic cancer cell line was purchased from Wuhan Procell Life Science & Technology Co., Ltd. (CL-0627) and cultured in a MIA PaCa-2 cell-specific culture medium (Procell, CM-0627, DMEM + 10% FBS + 2.5% HS + 1% P / S). Chiauranib (Chiau.) was from Shenzhen Chipscreen Biosciences Co., Ltd., and gemcitabine (GEM) was purchased from MCE (HY-17026). The two were separately dissolved in dimethyl sulfoxide (DMSO; purchased from Sigma, D2650-100ML) to prepare 10 mM stock solutions, and the stock solutions were stored in a freezer at -20 °C for later use. Before use, working solutions with corresponding final concentrations were prepared according to the needs of each experiment. Main experimental reagents, instruments, and devices CellTiter-Glo® Luminescent Cell Viability Assay (Promega, G7572) Tecan Spark™ multimode microplate reader Experimental method: PANC-1 and MIA PaCa-2 cells in the logarithmic growth phase were digested, collected, seeded into 96-well cell culture plates at 900 cells / well and 400 cells / well, respectively, and cultured overnight at 37 °C in 5% CO2. After the cells adhered to walls, a drug was added. The cells were treated with chiauranib for 120 h, with the final concentrations being 0 pM, 2.1 pM, 3.2 pM, 4.7 pM, 7.1 pM, 10.7 pM, and 16 pM. The 96-well plates were sealed with sealing films and centrifuged at 1000 rpm for 5 min. The culture media in the 96-well culture plates were slowly removed using a pipette, and 90 pL of complete culture medium was added to each well. Subsequently, 10 pL of gemcitabine was added. The cells were treated with gemcitabine for 120 h, with the final concentrations being 0 pM, 0.04 pM, 0.08 pM, 0.16 pM, and 0.32 pM. Two replicate wells were set for each concentration. In addition, control wells containing DMSO at the same concentration (0.5%, 6 replicate wells) were set. The cell proliferation inhibition rate of each drug treatment well was calculated using the formula: inhibition rate (%) = (1 - (RLUt - RLUbg) / (RLUnc - RLUbg)) x 100, where RLUT represents the luminescence value of a drug treatment well, RLUBG represents the culture medium background luminescence value, and RLUNC represents the luminescence value of the DMSO control wells. Experimental results and analysis: The experimental results of Example 4 are shown in Tables 1 to 2. The results in Table 1 show that when used alone to treat PANC-1 human pancreatic cancer cells, both chiauranib and gemcitabine exhibited certain inhibitory effects on the viability of PANC-1 cells. When used in combination, the two exhibited unexpected synergistic inhibitory effects. Compared to the separate drugs, their combinations exhibited significantly improved inhibitory effects on the viability of PANC-1 human pancreatic cancer cells. Table 1. The proliferation inhibition rates (%) of combinations of chiauranib and gemcitabine against PANC-1 cells Chiauranib (gM) Gemcitabine^ (gM)     \ 0 2.1 3.2 4.7 7.1 10.7 16.0 0 11.08± 0.87 17.16± 0.11 20.94± 2.19 32.56± 2.17 54.73± 9.63 82.57± 1.28 84.05± 2.21 0.04 21.81± 1.37 35.20± 1.04 38.79± 4.25 47.24± 3.65 65.99± 10.77 86.29± 0.59 87.61± 0.70 0.08 35.42± 0.95 41.59± 5.85 48.23± 3.39 53.82± 0.66 75.27± 3.95 86.47± 0.65 87.33± 0.39 0.16 43.92± 2.03 51.80± 4.27 58.79± 0.44 62.84± 0.75 78.48± 2.83 88.74± 0.42 88.98± 1.52 0.32 49.25± 0.58 54.31± 1.17 59.65± 1.66 66.92± 2.39 81.54± 0.51 89.36± 1.32 89.75± 0.11 The results in Table 2 show that when used alone to treat MIA PaCa-2 human pancreatic cancer cells, both chiauranib and gemcitabine exhibited certain inhibitory effects on the viability of MIA PaCa-2 cells. When used in combination, the two exhibited unexpected synergistic inhibitory effects. Compared to the separate drugs, their combinations exhibited significantly improved inhibitory effects on the viability of MIA PaCa-2 human pancreatic cancer cells. Table 2. The proliferation inhibition rates (%) of combinations of chiauranib and gemcitabine against MIA PaCa-2 cells Chiauranib (gM) Gemcitabine-. (gM)     \ 0 2.1 3.2 4.7 7.1 10.7 16.0 0 2.05± 2.64 3.96± 6.85 -0.53± 0.03 -1.27± 1.98 62.93± 7.48 96.29± 1.44 94.39± 1.12 0.04 -0.82± 11.47± 8.60± 24.57± 94.08± 99.12± 98.50± 4.45 0.46 3.35 18.31 4.30 0.02 0.14 0.08 14.51± 40.32± 44.80± 84.83± 97.62± 99.08± 98.83± 3.49 1.67 8.25 3.94 0.54 0.35 0.56 0.16 38.22± 77.67± 83.21± 90.68± 97.63± 99.08± 99.14± 2.47 4.42 0.13 0.47 0.67 0.28 0.06 0.32 64.74± 78.96± 85.21± 90.74± 97.49± 98.80± 98.87± 0.28 1.22 0.99 0.17 0.99 0.08 0.22 In conclusion, the experimental results of Example 4 show that: the combinations of chiauranib and gemcitabine exhibited unexpected synergistic inhibitory effects on PANC-1 and MIA PaCa-2 human pancreatic cancer cells, indicating that they can be used for preparing drugs related to pancreatic cancer. Example 5. Test for Assessing Anti-Tumor Efficacy of Combination of Chiauranib and Gemcitabine in CDX Model of SW1990 Human Pancreatic Cancer Experimental materials: The SW1990 human pancreatic cancer cell line was purchased from Nanjing Cobioer Biosciences Co., Ltd. (CBP60691) and cultured in an MEM culture medium (Gibco) containing 10% fetal bovine serum (Gibco), 1% NEAA (Gibco), and 1 mM sodium pyruvate (Gibco). Chiauranib (Chiau.) was from Shenzhen Chipscreen Biosciences Co., Ltd., and was suspended in a 0.2% aqueous CMC-Na solution containing 0.1% Tween 80 to prepare a 0.5 mg / mL suspension before administration. Gemcitabine (GEM) was purchased from MCE (HY-B0003), and was dissolved in PBS (Beyotime, C0221A) to prepare a 2.5 mg / mL solution before administration. Experimental method: SW1990 cells in the logarithmic growth phase were digested, collected, and counted, and then the cell density was adjusted to 4 x 107 cells / mL using a 1:1 serum-free culture medium and Matrigel. NOD / SCID mice weighing 18-20 g (Beijing Huafukang Biotechnology Co., Ltd.) were each subcutaneously inoculated with 100 gL of the cell suspension. On day 10 post-inoculation, animals with tumor volumes reaching 100-200 mm3 were randomly divided into 4 groups (N = 7): a control group, a gemcitabine monotherapy group, a chiauranib monotherapy group, and a combination therapy group. Gemcitabine was injected intraperitoneally at 25 mg / kg once every three days, and chiauranib was orally administered at 5 mg / kg once daily. Gemcitabine and chiauranib were administered simultaneously to the combination therapy group, and their dosing regimens were identical to those for the monotherapy groups. After the animals were inoculated with SW1990 cells, body weight and tumor volume were measured every Monday, Wednesday, and Friday. Tumor volume was calculated using the formula: length x width2 x 0.5. One day after the last dose was administered, the mice were euthanized and dissected, and tumors were collected and weighed. The tumor growth inhibition (TGI) rates of each treatment group were calculated using the formulas: TGI (tumor volume) was calculated using the following formula: TGITV = 1 - ((VTt -VT0) / (VCt - VC0)) x 100%, where VTt represents the tumor volume of a treatment group at the time of each measurement, and VT0 represents the tumor volume of a treatment group measured at the time of grouping; VCt represents the tumor volume of the control group at the time of each measurement, and VC0 represents the tumor volume of the control group measured at the time of grouping; TGI (tumor weight) was calculated using the following formula: TGITW = 1 - (WT / WC) x 100%, where WT represents the tumor weight of a treatment group at the end of administration, and WC represents the tumor weight of the control group at the end of administration. Data were statistically analyzed using GraphPad Prism 9.0 software and expressed as Mean ± SEM (standard error). The pairwise comparison between each treatment group and the control group used one-way analysis of variance (ANOVA). For homogeneity of variance, the Brown-Forsythe method was used. For heterogeneity of variance, the Dunnett’s T3 method was used. Experimental results and analysis: The experimental results of Example 5 are shown in FIGs. 6 and 7. After 25 days of treatment with 5 mg / kg chiauranib, there were significant decreases in tumor volume (P < 0.01) and tumor weight (P < 0.01), with the tumor growth inhibition rates calculated by tumor volume and tumor weight being about 69% and 65%, respectively. For 25 mg / kg gemcitabine, the tumor growth inhibition rates calculated by tumor volume and tumor weight were 51% and 48%, respectively. The anti-tumor effect of the combination of chiauranib and gemcitabine was significantly superior to that of each monotherapy group. Compared to the monotherapy groups, there were significant decreases in tumor volume (P < 0.001) and tumor weight (P < 0.001), with the tumor growth inhibition rates being 90% and 82%, respectively, indicating that the combination of chiauranib and gemcitabine exhibited a synergistic effect in terms of anti-tumor efficacy. As shown in FIG. 8, during the experiment, there was an overall upward trend in mouse body weight, and there was no significant difference in body weight between the treatment groups and the control group, indicating that the tested doses were well tolerated by mice. In summary, the experimental results of Example 5 show that: in the CDX model of SW1990 human pancreatic cancer, chiauranib exhibited a relatively good anti-tumor effect, and the combination of chiauranib and gemcitabine was effective and safe against tumors and exhibited a synergistic effect in terms of efficacy. Example 6. Single-Arm, Open-Label, Multi-Center Phase II Clinical Study of Combination of Chiauranib, Paclitaxel Protein-Bound, and Gemcitabine in First-Line Treatment of Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma in Patients 1. Inclusion criteria: (1) age: 18-75 years; (2) histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC); (3) no prior first-line systemic therapy; and (4) ECOG PS of 0 or 1. 2. Drugs and dosing regimen: The trial used a combination dosing regimen. The treatment groups are shown below: Chiauranib (from Shenzhen Chipscreen Biosciences Co., Ltd.): 35 mg or 50 mg, oral administration, qd. Paclitaxel protein-bound (CSPC OuYi Pharmaceutical Co., Ltd.): 125 mg / m2, IV, D1, 8, and 15, q4w. Gemcitabine (Nanjing Chia-Tai Tianqing Pharmaceutical Co., Ltd.): 1000 mg / m2, IV, D1, 8, and 15, q4w. 3. Trial process and response evaluation: The trial was divided into two stages: a dose escalation stage and a dose expansion stage. In the dose escalation stage, 4 subjects were enrolled in the chiauranib 35 mg group and 3 in the 50 mg group. In the dose expansion stage, the trial enrolled a total of 28 subjects, who were dosed according to the chiauranib 50 mg group. Primary endpoint of trial: investigator-assessed PFS (RECIST v1.1); secondary endpoints: ORR, DOR, DCR, TTR, OS, safety, and PK profile. Response evaluation: Tumor response was evaluated according to RECIST v1.1. As of March 25, 2025, 7 subjects had undergone at least one response evaluation. 4. Trial results (1) DLT evaluation: In the dose escalation stage, one subject in the chiauranib 35 mg group was deemed unevaluable due to receiving less than 75% of the chemotherapy dose during the DLT observation period (this subject had been replaced with a new one), and all the other 6 subjects (3 in the 35 mg group and 3 in the 50 mg group, including the replacement) completed DLT observation with no DLT events reported. (2) Response evaluation: As of March 25, 2025, 7 subjects had undergone at least one response evaluation. Among them, 4 achieved PR (2 of them had been confirmed), and 3 achieved SD. Conclusion: The clinical trial results show that the combination of chiauranib, paclitaxel protein-bound, and gemcitabine exhibited a good therapeutic effect in the first-line treatment of locally advanced or metastatic pancreatic ductal adenocarcinoma, with an overall response rate (ORR) of 57% (4 / 7) and a disease control rate (DCR) of 100% (7 / 7). In comparison, the existing treatment regimen (paclitaxel protein-bound plus gemcitabine) exhibits an overall response rate (ORR) of 11.11% and a DCR of 46.67%[1]. The technical solution provided in the present disclosure significantly improved patient benefit, achieved an unexpected technical effect compared to the prior art, and showed a synergy among the drugs. [1] Analysis of Efficacy of Combination of Gemcitabine, Paclitaxel Protein-Bound, and PD-1 Monoclonal Antibody Against Unresectable Pancreatic Cancer, Yongjun Li, Guizhou Medical University, DOI: 10.27045 / d.cnki.ggyyc.2022.000411. The present disclosure has been described in detail above, and the principles and embodiments of the present disclosure have been illustrated herein using specific examples. The description of the above examples is only used to help understand the method of the present disclosure and its core ideas, including the best embodiments, and also to enable any person skilled in the art to practice the present disclosure. It should be noted that those of ordinary skill in the art can make several improvements and modifications to the present disclosure without departing from the principles of the present disclosure, and these improvements and modifications also fall within the scope of protection of the claims of the present disclosure. The scope of protection of the present disclosure is defined by the claims and may include other examples that would occur to those skilled in the art. If these other examples contain structural elements that are not different from the textual description of the claims, or if they include equivalent structural elements that do not differ substantially from the textual description of the claims, then these other examples should also fall within the scope of the claims.

Claims

1. A pharmaceutical composition for first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer, comprising a DNA synthesis blocker and an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor, wherein:preferably, the DNA synthesis blocker is selected from a pyrimidine drug, including a uracil drug, a cytosine drug, or a T thymine drug;preferably, the DNA synthesis blocker is selected from a uracil drug and a cytosine drug; preferably, the DNA synthesis blocker is selected from a uracil drug;preferably, the DNA synthesis blocker is selected from a fluorouracil drug;preferably, the DNA synthesis blocker is selected from 5-fluorouracil, tegafur, tegafur-gimeracil-oteracil, cytarabine, capecitabine, gemcitabine, maribavir, fexinidazole, miriplatin, miriplatin hydrate, metronidazole, benzoylmetronidazole, losoxantrone hydrochloride, clofarabine, oxaliplatin, levofolinate calcium, ciclopirox, metronidazole hydrochloride, secnidazole, cisplatin, bleomycin sulfate, bleomycin hydrochloride, azathioprine, thiotepa, glyfosfin, metronidazole disodium phosphate, and nimorazole, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the DNA synthesis blocker is selected from 5-fluorouracil, cytarabine, gemcitabine, tegafur, and tegafur-gimeracil-oteracil, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the DNA blocker is selected from 5-fluorouracil and gemcitabine, and crystalline forms thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, prodrugs thereof, and metabolites thereof;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the DNA blocker is selected from 5-fluorouracil;or preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the DNA synthesis blocker is selected from gemcitabine;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from: chiauranib, apatinib, bevacizumab, barasertib (AZD1152), ZM-447439, GSK-1070916, AT9283, PHA-739358, MK0457 (VX-680), MK0475, ENMD-2076, CY-116, hesperadin, SN-314, R763 / AS703569, BI811283, and AMG 900, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drug;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib;preferably, the pancreatic cancer is locally advanced or metastatic pancreatic cancer; preferably, the pancreatic cancer is pancreatic ductal adenocarcinoma;more preferably,the pharmaceutical composition further comprises a tubulin inhibitor;preferably, the tubulin inhibitor is selected from a paclitaxel compound and a vincristine compound;preferably, the tubulin inhibitor is selected from utidelone, docetaxel, eribulin, cabazitaxel, vinflunine tartrate, ixabepilone, paclitaxel protein-bound, BNC-105P, OXI-4503, CPC634, ortataxel, SCB-01A, verubulin, NSC-631570, colchicine,paclitaxel, podofilox, vindesine sulfate, griseofulvin, vinblastine, sabizabulin, albuminbound docetaxel, paclitaxel poliglumex, paclitaxel-hyaluronic acid, paclitide, ARC-100, crolibulin, combretastatin A4 phosphate disodium salt, isofludelone, fluorapacin, MAP-4343, JJH-201601, larotaxel, ModraPac005 / r, patupilone, salutaxel, aqitasai, ARC-01, BT-1769, and CAP-6, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs; preferably, the tubulin inhibitor is selected from docetaxel, paclitaxel protein-bound, colchicine, paclitaxel, vinblastine, albumin-bound docetaxel, paclitaxel poliglumex, and paclitaxel-hyaluronic acid, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the tubulin inhibitor is selected from paclitaxel protein-bound, paclitaxel, paclitaxel poliglumex, and paclitaxel-hyaluronic acid;preferably, the tubulin inhibitor is selected from paclitaxel protein-bound.

2. The pharmaceutical composition according to claim 1, wherein the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the chiauranib is about 1-100 mg, preferably about 5-80 mg, more preferably about 10-50 mg, and most preferably about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg, as calculated based on chiauranib.

3. The pharmaceutical composition according to any one of claims 1-2, wherein the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the 5-fluorouracil is 10-500 mg, preferably 25-300 mg, and most preferably 50 mg, 125 mg, or 250 mg, as calculated based on 5-fluorouracil.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the DNA blocker is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the gemcitabine is 100-2000 mg, preferably 200-1000 mg, and most preferably 200 mg or 1000 mg, as calculated based on gemcitabine.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the tubulin inhibitor is selected from paclitaxel, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the paclitaxel is 20 mg, 50 mg, 100 mg, 500 mg, 1 g, or 2 g, as calculated based on paclitaxel.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition is used for first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer;preferably, the pancreatic cancer is locally advanced or metastatic pancreatic cancer; preferably, the pancreatic cancer is pancreatic ductal adenocarcinoma.

7. A kit, comprising the pharmaceutical composition according to any one of claims 15, wherein the DNA synthesis blocker, the tubulin inhibitor, and the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor are unit formulations with identical or different strengths, and the DNA synthesis blocker, the tubulin inhibitor, and the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor are placed in the same container or are placed in different containers, respectively;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is in a dosage form for gastrointestinal administration, preferably an oral formulation; the DNA synthesis blocker is in a dosage form for gastrointestinal administration or parenteral administration, preferably an oral formulation or an injectable formulation; the tubulin inhibitor is in a dosage form for gastrointestinal administration or parenteral administration, preferably an oral formulation or an injectable formulation, and more preferably an injectable formulation.

8. A method for first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer, comprising administering to a patient in need thereof a prophylactically and / or therapeutically and / or amelioratively effective amount of the pharmaceutical composition according to any one of claims 1-5; preferably, the pancreatic cancer is locally advanced or metastatic pancreatic cancer; preferably, the pancreatic cancer is pancreatic ductal adenocarcinoma;preferably, the DNA synthesis blocker, the tubulin inhibitor, and the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor are administeredsimultaneously, separately, or sequentially.

9. Use of an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor in combination with a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer, and / or in the preparation of a medicament for use in combination with a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer, wherein:preferably, the DNA synthesis blocker is selected from a pyrimidine drug, including a uracil drug, a cytosine drug, or a T thymine drug;preferably, the DNA synthesis blocker is selected from a uracil drug and a cytosine drug; preferably, the DNA synthesis blocker is selected from a uracil drug;preferably, the DNA synthesis blocker is selected from a fluorouracil drug;preferably, the DNA synthesis blocker is selected from 5-fluorouracil, tegafur, tegafur-gimeracil-oteracil, cytarabine, capecitabine, gemcitabine, maribavir, fexinidazole, miriplatin, miriplatin hydrate, metronidazole, benzoylmetronidazole, losoxantrone hydrochloride, clofarabine, oxaliplatin, levofolinate calcium, ciclopirox, metronidazole hydrochloride, secnidazole, cisplatin, bleomycin sulfate, bleomycin hydrochloride, azathioprine, thiotepa, glyfosfin, metronidazole disodium phosphate, and nimorazole, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the DNA synthesis blocker is selected from 5-fluorouracil, cytarabine, gemcitabine, tegafur, and tegafur-gimeracil-oteracil, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the DNA blocker is selected from 5-fluorouracil and gemcitabine, and crystalline forms thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, prodrugs thereof, and metabolites thereof;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the DNA blocker is selected from 5-fluorouracil;or preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the DNA synthesis blocker is selected from gemcitabine;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from: chiauranib, apatinib, bevacizumab, barasertib (AZD1152), ZM-447439, GSK-1070916, AT9283, PHA-739358, MK0457 (VX-680), MK0475, ENMD-2076, CY-116, hesperadin, SN-314, R763 / AS703569, BI811283, and AMG 900, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drug;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the chiauranib is about 1-100 mg, preferably about 5-80 mg, more preferably about 10-50 mg, and most preferably about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg, as calculated based on chiauranib;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the 5-fluorouracil is 10-500 mg, preferably 25-300 mg, and most preferably 50 mg, 125 mg, or 250 mg, as calculated based on 5-fluorouracil;preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the gemcitabine is 100-2000 mg, preferably 200-1000 mg, and most preferably 200 mg or 1000 mg, as calculated based on gemcitabine;preferably, the pancreatic cancer is locally advanced or metastatic pancreatic cancer; preferably, the pancreatic cancer is pancreatic ductal adenocarcinoma.

10. Use of an Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor in combination with a tubulin inhibitor and a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer, and / or in the preparation of a medicament for use in combination with a tubulin inhibitor and a DNA synthesis blocker in first-line, second-line, third-line, and later-line prevention and / or treatment and / or amelioration of pancreatic cancer, wherein:preferably, the DNA synthesis blocker is selected from a pyrimidine drug, including a uracil drug, a cytosine drug, or a T thymine drug;preferably, the DNA synthesis blocker is selected from a uracil drug and a cytosine drug; preferably, the DNA synthesis blocker is selected from a uracil drug;preferably, the DNA synthesis blocker is selected from a fluorouracil drug;preferably, the DNA synthesis blocker is selected from 5-fluorouracil, tegafur, tegafur-gimeracil-oteracil, cytarabine, capecitabine, gemcitabine, maribavir, fexinidazole, miriplatin, miriplatin hydrate, metronidazole, benzoylmetronidazole, losoxantrone hydrochloride, clofarabine, oxaliplatin, levofolinate calcium, ciclopirox, metronidazole hydrochloride, secnidazole, cisplatin, bleomycin sulfate, bleomycin hydrochloride, azathioprine, thiotepa, glyfosfin, metronidazole disodium phosphate, and nimorazole, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the DNA synthesis blocker is selected from 5-fluorouracil, cytarabine, gemcitabine, tegafur, and tegafur-gimeracil-oteracil, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the DNA blocker is selected from 5-fluorouracil and gemcitabine, and crystalline forms thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, prodrugs thereof, and metabolites thereof;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the DNA blocker is selected from 5-fluorouracil;or preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the DNA synthesis blocker is selected from gemcitabine;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from: chiauranib, apatinib, bevacizumab, barasertib (AZD1152), ZM-447439, GSK-1070916, AT9283, PHA-739358, MK0457 (VX-680), MK0475, ENMD-2076, CY-116, hesperadin, SN-314, R763 / AS703569, BI811283, and AMG 900, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drug;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, and a metabolite thereof;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor isselected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib;preferably, the tubulin inhibitor is selected from a paclitaxel compound and a vincristine compound;preferably, the tubulin inhibitor is selected from utidelone, docetaxel, eribulin, cabazitaxel, vinflunine tartrate, ixabepilone, paclitaxel protein-bound, BNC-105P, OXI-4503, CPC634, ortataxel, SCB-01A, verubulin, NSC-631570, colchicine, paclitaxel, podofilox, vindesine sulfate, griseofulvin, vinblastine, sabizabulin, albuminbound docetaxel, paclitaxel poliglumex, paclitaxel-hyaluronic acid, paclitide, ARC-100, crolibulin, combretastatin A4 phosphate disodium salt, isofludelone, fluorapacin, MAP-4343, JJH-201601, larotaxel, ModraPac005 / r, patupilone, salutaxel, aqitasai, ARC-01, BT-1769, and CAP-6, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs; preferably, the tubulin inhibitor is selected from docetaxel, paclitaxel protein-bound, colchicine, paclitaxel, vinblastine, albumin-bound docetaxel, paclitaxel poliglumex, and paclitaxel-hyaluronic acid, and crystalline forms, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and metabolites of the aforementioned drugs;preferably, the tubulin inhibitor is selected from paclitaxel protein-bound, paclitaxel, paclitaxel poliglumex, and paclitaxel-hyaluronic acid;preferably, the tubulin inhibitor is selected from paclitaxel protein-bound;preferably, the Aurora B / VEGFR / PDGFR / c-Kit / CSF1R multi-target kinase inhibitor is selected from chiauranib, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the chiauranib is about 1-100 mg, preferably about 5-80 mg, more preferably about 10-50 mg, and most preferably about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg, as calculated based on chiauranib;preferably, the DNA blocker is selected from 5-fluorouracil, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the 5-fluorouracilis 10-500 mg, preferably 25-300 mg, and most preferably 50 mg, 125 mg, or 250 mg, as calculated based on 5-fluorouracil;preferably, the DNA blocker is selected from gemcitabine, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the gemcitabine is 100-2000 mg, preferably 200-1000 mg, and most preferably 200 mg or 1000 mg, as calculated based on gemcitabine;preferably, the tubulin inhibitor is selected from paclitaxel, and a crystalline form thereof and a pharmaceutically acceptable salt thereof; a unit dose of the paclitaxel is 20 mg, 50 mg, 100 mg, 500 mg, 1 g, or 2 g, as calculated based on paclitaxel;preferably, the pancreatic cancer is locally advanced or metastatic pancreatic cancer; preferably, the pancreatic cancer is pancreatic ductal adenocarcinoma.

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