Pharmaceutical composition comprising parthenolide derivative

Abstract

Disclosed is a pharmaceutical composition comprising a parthenolide derivative and a tyrosine kinase inhibitor. The pharmaceutical composition exhibits a good synergistic effect against tumors and can delay the development of drug resistance and improve efficacy and safety, thereby achieving the objective of prolonging the survival of patients.

Description

Pharmaceutical compositions containing parthenolide derivatives

[0001] Priority Statement

[0002] This disclosure claims priority to the following patent applications:

[0003] The Chinese patent application, filed on March 24, 2025, with application number 2025103576247, and entitled "Pharmaceutical Composition Containing Trichoderma lactone Derivatives".

[0004] The Chinese patent application, filed on June 20, 2025, with application number 2025108384775, and entitled "Pharmaceutical Composition Containing Trichoderma lactone Derivatives".

[0005] This disclosure incorporates the full text of the aforementioned Chinese patent application. Technical Field

[0006] This invention belongs to the field of pharmaceuticals, and specifically relates to an antitumor drug composition comprising a ternolactone derivative. Background Technology

[0007] Parthenolide (PTL) is a sesquiterpene lactone extracted from chrysanthemum. Due to its unique chemical properties and complex molecular effects on various tumor cells, it is considered a highly promising anticancer drug candidate. Studies have shown that PTL can not only effectively inhibit key transcription factors such as nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and STAT-3, but also trigger specific cell death pathways, leading to increased intracellular reactive oxygen species and alterations in Bcl-2 family proteins. Furthermore, PTL has also demonstrated specific targeting ability against cancer stem cells.

[0008] Anlotinib is a quinoline derivative tyrosine kinase inhibitor. As a multi-target tyrosine kinase inhibitor, it plays a role in influencing tumor angiogenesis and proliferation signaling. Its main targets include receptor tyrosine kinases VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), EGFR, FGFR1-4, PDGFRα and β, and stem cell factor receptors (SCFR) 7, 8, and 9. Compared with other tyrosine kinase inhibitors, anlotinib has several advantages: highly efficient and specific inhibition of VEGFR-2 and VEGFR-3, multi-target inhibition of tumor angiogenesis, and low effective dose. Currently, anlotinib is marketed as an oral capsule, with an oral bioavailability of 36.6 ± 9.7% in male rats. Furthermore, anlotinib is positively charged under physiological conditions, exhibiting high protein binding capacity, which reduces the concentration of the free drug in plasma, leading to a decrease in its effective dose within tumors and limiting its anti-tumor effect.

[0009] Multi-mechanism combination therapy is an important strategy for delaying or even avoiding the development of drug resistance in cancer. Based on current treatment strategies for non-small cell lung cancer (NSCLC) and research progress on tyrosine kinase inhibitors, multi-mechanism combination drugs for NSCLC can delay the development of drug resistance, improve efficacy and safety, thereby achieving the goal of prolonging patient survival. Summary of the Invention

[0010] This disclosure provides a pharmaceutical combination product of a parthenolide derivative and a tyrosine kinase inhibitor (TKI), and the use of the pharmaceutical composition product in the preparation of a medicament for the prevention or treatment of tumor diseases.

[0011] The pharmaceutical compositions of the present invention have the following advantages compared to individual drugs:

[0012] 1. Combination therapy enhanced the tumor-inhibiting effects of each individual drug;

[0013] 2. It delays the development of drug resistance, improves efficacy and safety, thereby achieving the goal of prolonging patient survival.

[0014] To address the technical problem of this invention, this invention provides a pharmaceutical combination product comprising:

[0015] (i) a basil lactone derivative or a pharmaceutically acceptable salt thereof, stereoisomer or isotope derivative thereof;

[0016] (ii) Tyrosine kinase inhibitors (TKIs),

[0017] The chrysanthemum lactone derivative has the following structure:

[0018] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the ternolactone derivative is selected from any one of fumarate, hydrochloride, maleate, L-malate, benzenesulfonate, p-toluenesulfonate, citrate, acetate, L-tartrate, sulfate, succinate, and benzoate.

[0019] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the chrysanthemum lactone derivative is selected from fumarate.

[0020] In a preferred embodiment of the present invention, the tyrosine kinase inhibitor targets any one or a combination of the following targets: EGFR, FGFR, PDGFR, and VEGFR.

[0021] In a preferred embodiment of the present invention, the tyrosine kinase inhibitor is a multi-target kinase inhibitor, wherein the multi-target targets include FGFR, PDGFR, and VEGFR.

[0022] In a preferred embodiment of the present invention, the tyrosine kinase inhibitor is selected from any one or a combination of anlotinib, osimertinib, sunitinib, gefitinib, erlotinib, omamolinib, icotinib, pyrotinib, dacomitinib, afatinib, neratinib, lapatinib, valritinib, tesvatinib, telitinib, ippatinib succinate, flumetinib, befotinib, rizitinib, pozizitinib, surufatinib, sunitinib, lenvatinib, and sorafenib.

[0023] In a preferred embodiment of the present invention, the tyrosine kinase inhibitor is selected from any one or a combination of anlotinib, osimertinib, sunitinib, sorafenib, and lenvatinib.

[0024] In a preferred embodiment of the present invention, (i) and (ii) are administered simultaneously, separately, or sequentially, or (i) and (ii) are present in the same dosage form.

[0025] In a preferred embodiment of the present invention, it is used to treat tumor-related diseases.

[0026] In a preferred embodiment of the present invention, the tumor-related diseases are selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, small cell lung cancer, cholangiocarcinoma, or choriocarcinoma, preferably non-small cell lung cancer. In some embodiments, the dose of the parthenolide derivative is selected from 1-100 mg, and the dose of the tyrosine kinase inhibitor is selected from 1-100 mg.

[0027] The dosage of the ternolactone derivatives described in this disclosure is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, and 49 mg. 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75m g, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg.

[0028] The dosage of the tyrosine kinase inhibitors described in this disclosure is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, and 49 mg. 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75m g, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg.

[0029] In some embodiments, the dose of the ternolactone derivative is selected from 1-100 mg, and the administration frequency may be once, twice or three times a day; the dose of the tyrosine kinase inhibitor is selected from 1-100 mg, and the administration frequency may be once, twice or three times a day.

[0030] In some embodiments, the dose of the ternolactone derivative is selected from 1-60 mg, and the administration frequency may be once or twice a day; the dose of the tyrosine kinase inhibitor is selected from 1-60 mg, and the administration frequency is once a day.

[0031] In some embodiments, the dose of the ternolactone derivative is selected from 1-20 mg, and the administration frequency may be once or twice a day; the dose of the tyrosine kinase inhibitor is selected from 1-20 mg, and the administration frequency is once a day.

[0032] In some embodiments, the dose of the ternolactone derivative is selected from 1-10 mg, and the administration frequency may be once or twice a day; the dose of the tyrosine kinase inhibitor is selected from 1-10 mg, and the administration frequency is once a day.

[0033] In some embodiments, the dose of the tyrosine kinase inhibitor is selected from 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, and 29 mg. The dosages of the tyrosine kinase inhibitors are selected from 10 mg, 20 mg, 40 mg, 60 mg, and 50 mg, and the dosing frequency is once or twice a day.

[0034] In some embodiments, the dosage of the parthenolide derivative is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, and 20 mg, and the administration frequency is once or twice a day.

[0035] In some embodiments, the dosage of the tyrosine kinase inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg, and the dosing frequency is once or twice a day; the dosage of the tyrosine kinase inhibitor is selected from 10 mg, 20 mg, 40 mg, and 60 mg, and the dosing frequency is once a day.

[0036] In some embodiments, the dosage of the tyrosine kinase inhibitor is selected from 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg, and the dosing frequency is once or twice a day; the dosage of the tyrosine kinase inhibitor is selected from 1 mg, 2.5 mg, 5 mg, and 10 mg, and the dosing frequency is once a day.

[0037] The combined routes of administration described in this invention include oral administration, parenteral administration, and transdermal administration. The parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection, with oral administration being preferred.

[0038] This invention also provides a pharmaceutical composition comprising the above-mentioned parthenolide derivative, a tyrosine kinase inhibitor, and one or more pharmaceutical carriers, excipients, and diluents. The pharmaceutical composition can be formulated into any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalers, or sprays. The pharmaceutical composition can also be formulated into the same dosage form; for example, the parthenolide derivative and the tyrosine kinase inhibitor can be formulated as compound tablets, compound capsules, compound pills, compound granules, compound solutions, compound suspensions, compound syrups, compound injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), compound suppositories, compound inhalers, or compound sprays.

[0039] The present invention also provides a method for treating tumor diseases, comprising administering to a patient an effective amount of the above-mentioned parthenolide derivative and an effective amount of the above-mentioned tyrosine kinase inhibitor.

[0040] The present invention also provides a pharmaceutical kit for use in the treatment of tumor diseases, wherein the pharmaceutical composition of the parthenolide derivative and tyrosine kinase inhibitor described herein is packaged.

[0041] This invention combines a ternolactone derivative with a tyrosine kinase inhibitor for administration, thereby enhancing the efficacy of drugs for treating tumor diseases.

[0042] The term "combination" as used in this invention refers to a route of administration that involves administering at least one dose of a parthenolide derivative and at least one dose of a tyrosine kinase inhibitor within a specified time period, wherein both substances exhibit pharmacological activity. The time period can be within a single dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. The parthenolide derivative and the tyrosine kinase inhibitor can be administered simultaneously or sequentially. This period includes treatments in which the parthenolide derivative and the tyrosine kinase inhibitor are administered via the same or different routes of administration. Attached Figure Description

[0043] Figure 1-2 Effects of compound 1 in combination with anlotinib at different concentrations on the ability of H226 cells to form cells.

[0044] Figure 3-4 Effects of compound 1 in combination with sunitinib on OS-RC-2 renal cell carcinoma cells.

[0045] Figure 5-6 shows the effect of compound 1 in combination with sunitinib on breast cancer T47D cells.

[0046] Figure 7-8 shows the effect of compound 1 in combination with osimertinib on OS-RC-2 renal cell carcinoma cells.

[0047] Figure 9-10 Effects of compound 1 in combination with osimertinib on HepG-2 hepatocellular carcinoma cells.

[0048] Figure 11-12 shows the effect of compound 1 in combination with osimertinib on breast cancer T47D cells.

[0049] Figure 13-14 Effects of compound 1 in combination with sorafenib on breast cancer MCF-7 cells.

[0050] Figures 15-16 show the effect of compound 1 in combination with lenvatinib on H1688 lung cancer cells. Detailed Implementation

[0051] The present disclosure will be explained in more detail below with reference to the embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0052] Experimental materials

[0053] The ternolactone derivative of the present invention is a fumarate having the following structure (hereinafter referred to as compound 1).

[0054] Specifications: White powder

[0055] Storage conditions: Store in a sealed container, protected from light, and at a low temperature.

[0056] Example 1: Effect of compound 1 in combination with anlotinib on the clonogenic ability of H226 cells

[0057] The H226-human lung squamous cell carcinoma cell line was purchased from Beijing Beina Chuanglian Biotechnology Co., Ltd.

[0058] The H1688 human small cell lung cancer cell line was preserved by Tianjin Shangde Pharmaceutical Technology Co., Ltd.

[0059] The MCF-7 human breast cancer cell line was preserved by Tianjin Shangde Pharmaceutical Technology Co., Ltd.

[0060] The T-47D human breast cancer cell line was preserved by Tianjin Shangde Pharmaceutical Technology Co., Ltd.

[0061] The HepG-2 human liver cancer cell line was purchased from Shanghai Chuanqiu Biotechnology Co., Ltd.

[0062] The OS-RC-2 human renal cell carcinoma line was purchased from the Chinese Academy of Sciences Type Culture Collection Committee Cell Bank / Stem Cell Bank.

[0063] Cell culture

[0064] H226, H1688, T-47D, and OS-RC-2 were cultured in 1640 medium, HepG-2 in DMEM medium, and MCF-7 in MEM medium, and were cultured in a cell culture incubator containing 5% CO2 at 37°C.

[0065] Cells were thawed and passaged using standard methods: The cryovials were removed from liquid nitrogen, thawed in a 37°C water bath, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in complete culture medium. The cells were then cultured at 37°C with 5% CO2. When the cells had covered 70-80% of the bottom of the culture dish, the culture medium was aspirated, the cells were washed with 2-3 mL of PBS buffer, and 1-2 mL of 0.25% trypsin (enough to cover the bottom of the dish) was added for digestion. The cells were incubated for a period of time until they became rounded, then complete culture medium was immediately added to stop the digestion. The digested cell suspensions were combined, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, the cells were resuspended in complete culture medium, the cells were gently dispersed, and seeded into new culture dishes for continued culture.

[0066] Collect cells in the logarithmic growth phase, digest and count them, and adjust the volume to 500 cells / well. Insert 1 mL into each well of a 12-well plate. After incubating overnight, add the drug, incubate for an appropriate time, and then stain.

[0067] Staining: Discard the culture medium, wash once with PBS, blot dry the supernatant, fix with methanol for 1 min, discard the methanol, stain with 0.5% crystal violet aqueous solution for 20 min, discard the staining solution, wash twice with pure water, air dry and take pictures, and count colonies with more than 50 cells.

[0068] Experimental results

[0069] Example 1: Effect of compound 1 in combination with anlotinib on the H226-human lung squamous cell carcinoma cell line

[0070] As shown in Figures 1 and 2, in the H226-human lung squamous cell carcinoma cell line model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and anlotinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0071] Example 2: Effect of compound 1 in combination with sunitinib on renal cell carcinoma OS-RC-2 cells

[0072] As shown in Figures 3 and 4, in the OS-RC-2 human renal cell carcinoma model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and sunitinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0073] Example 3: Effect of compound 1 in combination with sunitinib on breast cancer T-47D cells

[0074] As shown in Figures 5 and 6, in the T-47D-human breast cancer cell line model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and sunitinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0075] Example 4: Effect of compound 1 in combination with osimertinib on renal cell carcinoma OS-RC-2 cells

[0076] As shown in Figures 7 and 8, in the OS-RC-2 human renal cell carcinoma model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and osimertinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0077] Example 5: Effect of compound 1 in combination with osimertinib on HepG-2 liver cancer cells

[0078] As shown in Figures 9 and 10, in the HepG-2 human hepatocellular carcinoma cell line model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and osimertinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0079] Example 6: Effect of Compound 1 in combination with osimertinib on breast cancer T-47D cells

[0080] As shown in Figures 11-12, in the T-47D-human breast cancer cell line model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and osimertinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0081] Example 7: Effect of compound 1 in combination with sorafenib on breast cancer MCF-7 cells

[0082] As shown in Figures 13 and 14, in the MCF-7 human breast cancer cell line model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and solatinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0083] Example 8: Effect of compound 1 in combination with lenvatinib on lung cancer H1688 cells

[0084] As shown in Figures 15-16, in the H1688-human small cell lung cancer cell line model, the results showed that compound 1 inhibited tumor proliferation in a dose-dependent manner. The combination of compound 1 and lenvatinib enhanced the tumor-inhibiting effects of each drug alone. The dosage of the test drug in this experiment did not produce significant toxic side effects in the animals, indicating good safety.

[0085] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A pharmaceutical combination product comprising: (i) ternolactone derivatives or their pharmaceutically acceptable salts, stereoisomers, or isotopic derivatives; and (ii) Tyrosine kinase inhibitors (TKIs), The chrysanthemum lactone derivative has the following structure:

2. The pharmaceutical combination product according to claim 1, wherein, The pharmaceutically acceptable salts of the described ternolactone derivatives are selected from any one of fumarate, hydrochloride, maleate, L-malate, benzenesulfonate, p-toluenesulfonate, citrate, acetate, L-tartrate, sulfate, succinate, and benzoate.

3. The pharmaceutical combination product according to claim 1, wherein, The pharmaceutically acceptable salt of the chrysanthemum lactone derivative is selected from fumarate.

4. The pharmaceutical combination product according to claim 1, wherein, The tyrosine kinase inhibitors described herein target any one or a combination of the following targets: EGFR, FGFR, PDGFR, VEGFR.

5. The pharmaceutical combination product according to claim 1, wherein, The tyrosine kinase inhibitor is a multi-target kinase inhibitor, and the multi-target targets include FGFR, PDGFR, and VEGFR.

6. The pharmaceutical combination product according to claim 1, wherein, The tyrosine kinase inhibitor is selected from any one or a combination of anlotinib, osimertinib, sunitinib, gefitinib, erlotinib, omamolinib, icotinib, pyrotinib, dacomitinib, afatinib, neratinib, lapatinib, valaritinib, tesvatinib, telitinib, ippatinib succinate, flumetinib, befotinib, rizitinib, pozizitinib, surufatinib, sunitinib, lenvatinib, and sorafenib.

7. The pharmaceutical combination product according to claim 1, wherein, The tyrosine kinase inhibitor is selected from any one or a combination of anlotinib, osimertinib, sunitinib, sorafenib, and lenvatinib.

8. The pharmaceutical combination product according to claim 1, wherein, (i) and (ii) are administered simultaneously, separately, or sequentially, or (i) and (ii) are present in the same dosage form.

9. The pharmaceutical combination product according to claim 1, wherein, Used to treat tumor-related diseases.

10. The pharmaceutical combination product according to claim 1, wherein, The tumor-related diseases mentioned are selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, small cell lung cancer, bile duct cancer, or choriocarcinoma, with non-small cell lung cancer being preferred.

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