Pharmaceutical composition for treating lymphoma comprising BCL-2 inhibitor, selective nuclear export protein inhibitor, and elf4a inhibitor

Abstract

The present invention relates to a pharmaceutical composition for treating cancer in which an elF4A inhibitor and at least one of a BCL-2 inhibitor or a selective export protein (XPO-1) inhibitor are used in a combination regimen. The present invention relates to a pharmaceutical composition for treating cancer, wherein the elF4A inhibitor is one selected from the group consisting of silvestrol, CR-1-3B, zotatifin, rohinitib, didesmethylrocaglamide, and episylvestrol, and used in a combination regimen with at least one of a BCL-2 inhibitor or a selective nuclear export protein inhibitor.

Description

A pharmaceutical composition for treating lymphoma comprising a BCL-2 inhibitor, a selective nuclear export protein inhibitor, and an EIF4A inhibitor

[0001] The present invention provides a pharmaceutical composition for treating cancer using a BCL-2 inhibitor and an elF4A inhibitor, Selinexor, and a combination of an elF4A inhibitor, a BCL-2 inhibitor, and Selinexor.

[0002]

[0003] Among the most common types of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), patients with MYC / BCL-2 double-gene abnormality diffuse large B-cell lymphoma (DHL) have a very poor prognosis because the commonly used R-CHOP immunotherapy is ineffective. In particular, the MYC oncogene is an important oncogene that increases early tumorigenesis by playing a role in evading various immune checkpoint mechanisms, and is known as an undruggable target that is difficult to attack with drugs that are difficult to directly inhibit. The importance of MYC targeting in diffuse large B-cell lymphoma continues to be emphasized, and considering the incidence of lymphoma, research that can directly or indirectly inhibit the function of MYC is essential in Korea as well.

[0004] Since it is difficult to attempt direct inhibition targeting MYC, research is being conducted to indirectly target MYC with the concept of synthetic lethality that approaches by blocking the cell signaling circuit with various interactions. In particular, the present invention suggests the possibility of a new anticancer treatment by confirming the cell killing effect by treating B-cell lymphoma cell lines and T-cell lymphoma with venetoclax, a BCL-2 inhibitor, Silvestrol, Zotatifin, Rohinitib, Didesmethylrocaglamide (DDR), and CR-1-31B, which are elF4A inhibitors that can control MYC expression with synthetic lethality, and selinexor, a selective nuclear export protein 1 (XPO-1) inhibitor, alone or in combination.

[0005]

[0006] The purpose of the present invention is to provide a composition for treating cancer using a combination of at least one of an elF4A inhibitor, a BCL-2 inhibitor, and a selective nuclear export protein inhibitor.

[0007] Another object of the present invention is to provide a composition for treating cancer by using at least one of an elF4A inhibitor, a BCL-2 inhibitor, and a selective nuclear export protein inhibitor in a combination regimen, either sequentially or discontinuously.

[0008] Another object of the present invention is to provide a pharmaceutical composition for treating cancer using a combination of a BCL-2 inhibitor and a selective nuclear export protein (XPO-1) inhibitor.

[0009] The technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0010]

[0011] Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, various specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, certain embodiments may be practiced with one or more of these specific details, or without them, or in conjunction with other known methods and configurations. In other instances, well-known processes and manufacturing techniques have not been described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0012]

[0013] As used herein, the term 'elF4A inhibitor' refers to a compound or drug that inhibits the activity of the eIF4A (Eukaryotic Initiation Factor 4A) protein. eIF4A is an RNA helicase that plays an important role in eukaryotic protein translation, and functions to unwind double-stranded mRNA during the process of binding the 5' cap region of mRNA to the ribosome. Therefore, eIF4A inhibitors inhibit the activity of eIF4A, which unwinds double-stranded mRNA, thereby interfering with the initiation process of protein synthesis, which prevents cells from producing specific proteins, thereby inhibiting the protein synthesis process that is abnormally activated in cancer cells in particular, and thus can be used to inhibit the growth of cancer cells.

[0014] The above elF4A inhibitors may include, but are not limited to, silvestrol, CR-1-3B, zotatipine, rohinitib, didesmethyllocaglamide, and episilvestrol.

[0015] The term "silvestrol" used herein refers to a natural plant-derived compound, specifically extracted from the Aglaia genus. Silvestrol possesses anticancer properties and is being studied as a potential treatment for various cancer types, particularly acute leukemia, lymphoma, and neuroblastoma. As an inhibitor of eIF4A, silvestrol inhibits protein synthesis and thus inhibits cancer cell growth.

[0016] The term "CR-1-31B" in this specification refers to a synthetic compound structurally similar to silvestrol and possesses anticancer properties. Specifically, it inhibits protein synthesis as an inhibitor of eIF4A, thereby inhibiting cancer cell growth. CR-1-31B is an analog of silvestrol, developed with the goal of higher efficacy and lower toxicity.

[0017] The term "zotatipine" used herein refers to an anticancer agent that inhibits protein synthesis and thus inhibits cancer cell growth as an eIF4A inhibitor. Clinical trials are currently underway for various cancers, including breast cancer and non-small cell lung cancer.

[0018] The term "rohinitiv" in this specification refers to an inhibitor of eIF4A, which inhibits protein synthesis and thus inhibits cancer cell growth. It is a potent and specific eIF4A inhibitor that induces apoptosis in acute myeloid leukemia (AML) cell lines, thereby reducing the leukemic burden in AML xenograft models.

[0019] The term "didesmethyllocaglamide" used herein refers to a potent elF4A inhibitor with a mechanism of action similar to silvestrol. Didesmethyllocaglamide inhibits elF4A activity, thereby interfering with protein synthesis in cancer cells. Its effects are being studied, particularly in leukemia and lymphoma, and it shares structural similarities with silvestrol.

[0020] As used herein, the term "episilbestrol" refers to a compound that acts as an elF4A inhibitor, similar to silvestrol. Episilbestrol inhibits the helicase activity of elF4A, thereby blocking protein synthesis and hindering cancer cell growth. While episilbestrol exhibits some structural differences from silvestrol, its mechanism of action is identical, exerting its anticancer effects by inhibiting protein synthesis.

[0021] As used herein, the term "BCL-2 inhibitor" refers to a compound or drug that inhibits the function of the BCL-2 (B-cell lymphoma 2) protein. BCL-2 is an anti-apoptotic protein that suppresses apoptosis within cells and is known to be overexpressed, particularly in cancer cells. BCL-2 inhibitors bind to BCL-2, preventing cancer cells from further evading apoptosis.

[0022] The above BCL-2 inhibitors may include, but are not limited to, venetoclax, navitoclax, obatoclax, and sonorotoclax.

[0023] The term "venetoclax" used herein refers to a BCL-2 inhibitor, a drug that binds to and blocks the action of the BCL-2 protein, thereby inducing cancer cell apoptosis. It is primarily used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (AML).

[0024] The term "sonorotoclax" used herein refers to a next-generation BCL-2 inhibitor, currently being studied for its effectiveness in treating various blood cancers, particularly chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Similar to venetoclax, sonorotoclax promotes apoptosis by inhibiting the BCL-2 protein, which allows cancer cells to evade apoptosis. In particular, sonorotoclax is attracting attention as a safe and effective treatment option, as initial studies have shown that it may have higher selectivity and efficacy than venetoclax.

[0025] The term 'exportin-1 (XPO-1) inhibitor' used herein refers to a compound or drug that inhibits the function of the XPO-1 (Exportin-1) protein. XPO-1 is an important transport protein that plays a role in transporting proteins and RNA from the nucleus to the cytoplasm, and plays an important role in evading the normal cell death process by exporting key regulatory proteins, such as tumor suppressor proteins such as p53, from the nucleus to the cytoplasm and inhibiting their function. XPO-1 inhibitors bind to XPO-1 and block the nuclear transport of tumor suppressor proteins, thereby inhibiting the survival and proliferation of cancer cells.

[0026] The term "selinexor" used herein refers to a representative XPO-1 inhibitor that has shown efficacy in various types of cancer. Selinexor promotes cancer cell death by inducing the nuclear accumulation of tumor suppressor proteins.

[0027] The term "cancer" in this specification refers to a disease characterized by uncontrolled cell proliferation, characterized by abnormal cell growth and division. Unlike normal cells, which undergo regulated growth and division and die after a certain period of time, cancer cells evade this process, continuously proliferating and capable of invading surrounding tissues or metastasizing to other organs.

[0028] The above cancers may include, but are not limited to, breast cancer, lung cancer, colon cancer, prostate cancer, liver cancer, pancreatic cancer, stomach cancer, kidney cancer, ovarian cancer, cervical cancer, oral cancer, nasopharyngeal cancer, esophageal cancer, myeloma, leukemia, lymphoma, melanoma, brain tumor, neuroblastoma, chondrosarcoma, osteosarcoma, bladder cancer, gallbladder cancer, thyroid cancer, small cell lung cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0029] The term "lymphoma" in this specification refers to a type of cancer that arises in the lymphatic system (lymph nodes, lymph vessels, lymph fluid, spleen, etc.), which is part of the immune system. Lymphocytes proliferate or become abnormal, forming tumors in the lymph nodes or other parts of the lymphatic system. The cause of lymphoma is often unknown, but some believe it's associated with viruses such as the Epstein-Barr virus and abnormal immune regulation. Congenital or acquired immunodeficiency is also a significant risk factor. Patients receiving immunosuppressive therapy after organ transplantation, as well as various autoimmune diseases such as Sjögren's syndrome, lupus erythematosus, and rheumatoid arthritis, are particularly associated with malignant lymphoma. Symptoms of lymphoma include painless, gradual enlargement of lymph nodes, flu-like symptoms, or systemic symptoms such as fever, weight loss, and night sweats. Blood tests reveal a decreased red blood cell count in cases of bone marrow invasion, and vomiting and headaches in cases of central nervous system infiltration, including the spinal cord and brain. Symptoms of malignant lymphoma vary depending on the site of origin. Lymphoma is broadly divided into two types: Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0030] The term 'Hodgkin Lymphoma' in this specification refers to a lymphoma in which a specific abnormal lymphocyte, the Reed-Sternberg cell, is characteristically found, and tends to be relatively well treated.

[0031] The term "non-Hodgkin lymphoma" in this specification encompasses various types of lymphoma that do not contain Reed-Sternberg cells, and can arise from both B and T cells. It is classified as a highly complex disease, with numerous subtypes, accounting for approximately 90% of all lymphomas.

[0032] The term "B-cell lymphoma" as used herein refers to a type of lymphoma that arises from B cells. B-cell lymphoma is the most common subtype of non-Hodgkin's lymphoma and can present in various forms.

[0033] The above B-cell lymphomas may include, but are not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma.

[0034] The term "T-cell lymphoma" in this specification refers to a type of lymphoma that arises from T cells and is a subtype of non-Hodgkin's lymphoma. T cells play a crucial role in the immune system, defending the body against infection and disease. When these T cells proliferate abnormally or become mutated, T-cell lymphoma develops. T-cell lymphoma accounts for approximately 10-15% of non-Hodgkin's lymphomas and is less common than B-cell lymphoma.

[0035] The above T-cell lymphoma may include, but is not limited to, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and adult T-cell lymphoma.

[0036] The term 'diffuse large B-cell lymphoma (DLBCL)' used herein refers to a type of non-Hodgkin's lymphoma derived from B cells, which is characterized by rapid proliferation of abnormal B cells in lymph nodes or other parts of the body, forming a mass.

[0037] The above diffuse large B-cell lymphoma can be divided into various subtypes according to molecular characteristics, and may include, but is not limited to, germinal center B-cell type (GCB) and activated B-cell type (ABC).

[0038] The term "MYC / BCL-2 double-hit diffuse large B-cell lymphoma (DHL)" used herein refers to a subtype of diffuse large B-cell lymphoma, which is a lymphoma in which mutations occur simultaneously in the MYC and BCL-2 genes. This double-hit lymphoma is caused by the translocation or overexpression of two genes (MYC and BCL-2) that promote the survival and proliferation of tumor cells, and exhibits more aggressive characteristics than typical diffuse large B-cell lymphoma (DLBCL).

[0039] As used herein, the term "combination use" refers to the simultaneous use of two or more drugs or treatments to treat a disease. This term is used when a greater therapeutic effect is expected, such as a synergistic effect, reduced side effects, or suppressed resistance, compared to when each drug is used alone.

[0040] In this specification, the term 'apoptosis' refers to the process in which a cell ceases to function and dies for a specific reason, and there are two main forms: apoptosis and necrosis.

[0041] In this specification, the term 'apoptosis' refers to the process by which cells spontaneously die in a programmed manner, and is an important mechanism for maintaining homeostasis in the body.

[0042] As used herein, the term "synergism" refers to a situation where two or more elements, when used together, produce a greater effect than the effects of each element individually. In other words, when used in combination, the effects of each element are increased beyond the simple sum of their effects.

[0043] As used herein, the term "additive effect" refers to the result of two or more elements, when used together, that is equivalent to simply adding their individual effects. In this case, the two elements do not influence each other, and their effects are expressed independently.

[0044] The term 'agent that reduces the expression level of a gene encoding an elF4A protein' used herein may include, but is not limited to, any one or more selected from the group consisting of an antisense nucleotide, a short interfering RNA (siRNA), a short hairpin RNA, and a ribozyme that complementarily bind to a gene encoding the protein, preferably a portion thereof, and may include any means that directly or indirectly acts on a gene encoding a target elF4A protein to induce an effect of inhibiting its expression, and may include all agents that can be easily derived by a known technique using a method commonly used in the art.

[0045] In this specification, the term "EoB (Excess Over Bliss)" refers to a concept for evaluating the synergistic effect between two drugs or compounds, and is a value indicating how much the combined effect of two drugs exceeds the effect predicted by the Bliss model. When the actual effect is greater than the effect predicted by the Bliss model, the EoB value is positive, indicating a synergistic effect. Conversely, when the actual effect is smaller than the effect predicted by the Bliss model, the EoB value is negative, indicating an antagonistic effect. An EoB value of 0 indicates that the effect predicted by the Bliss model and the actual effect are identical, indicating that the two drugs act independently of each other.

[0046] The term "Bliss model" used in this specification refers to a statistical model used to explain drug interactions, assuming that two or more drugs act independently. This model is used to predict the combined effect of two or more drugs when they act independently.

[0047]

[0048] In the present invention, the pharmaceutical composition may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder or beverage, and the pharmaceutical composition may be characterized as being for human use.

[0049] In the present invention, the pharmaceutical composition is not limited to these, but may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, fragrances, etc. for oral administration, and buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc. may be mixed and used for injections, and bases, excipients, lubricants, preservatives, etc. may be used for topical administration. The formulation of the pharmaceutical composition of the present invention may be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be manufactured in the form of unit dose ampoules or multiple doses. In addition, it can be formulated in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.

[0050] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0051] Routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal. Oral or parenteral administration is preferred.

[0052] The "parenteral" of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. Preferably, the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration, but is not limited thereto.

[0053] The pharmaceutical composition of the present invention may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, and severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route, and period, but may be appropriately selected by those skilled in the art, and may be administered at 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. The administration may be administered once a day or divided into several times. The dosage does not limit the scope of the present invention in any way.

[0054] The pharmaceutical composition according to the present invention can be formulated as a pill, a sugar-coated tablet, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.

[0055]

[0056] In one specific embodiment of the present invention, a pharmaceutical composition for treating cancer is provided, wherein at least one of an elF4A inhibitor, a BCL-2 inhibitor, and a selective nuclear export protein (XPO-1) inhibitor is used in combination, wherein the nuclear export protein inhibitor is Selinexor, and the BCL-2 inhibitor is any one selected from the group consisting of venetoclax, navitoclax, obatoclax, and sonorotoclax, and the elF4A inhibitor is Silvestrol, CR-1-3B, Zotatifin, Rohinitib, didesmethylrocaglamide (DDR), and A pharmaceutical composition for treating cancer is provided, wherein the pharmaceutical composition comprises one selected from the group consisting of episilvestrol.

[0057] In one specific embodiment of the present invention, the elF4A inhibitor is an agent that reduces the activity or expression level of the elF4A protein; or an agent that reduces the expression level of a gene encoding the protein, and a pharmaceutical composition for treating cancer is provided, wherein the agent that reduces the expression level of the gene is at least one selected from the group consisting of antisense nucleotides, small interfering RNAs (siRNAs), and ribozymes that complementarily bind to the elF4A gene or a portion thereof.

[0058] In one specific example of the present invention, the pharmaceutical composition for treating cancer is provided, wherein at least one of an elF4A inhibitor, a BCL-2 inhibitor, and a selective nuclear export protein inhibitor is used in a combination regimen, either sequentially or discontinuously.

[0059] In one specific embodiment of the present invention, the cancer is lymphoma, the pharmaceutical composition is provided, the lymphoma is a pharmaceutical composition comprising B-cell lymphoma or T-cell lymphoma, the B-cell lymphoma is a pharmaceutical composition comprising diffuse large B-cell lymphoma, and the diffuse large B-cell lymphoma is a pharmaceutical composition comprising bigenic diffuse large B-cell lymphoma.

[0060] In one specific embodiment of the present invention, a pharmaceutical composition is provided, wherein the elF4A inhibitor, BCL-2 inhibitor and selective nuclear export protein inhibitor are included at 0.0001 μM to 1.0 μM.

[0061] In one specific embodiment of the present invention, the pharmaceutical composition provides a pharmaceutical composition that is administered to a patient with lymphoma, wherein the patient with lymphoma includes a B-cell lymphoma patient or a T-cell lymphoma patient.

[0062] In one specific embodiment of the present invention, the pharmaceutical composition is provided in the form of an oral formulation of powder, granules, capsules, tablets, powder or aqueous suspension, an external preparation, a suppository, or a sterile injectable solution.

[0063] In one specific embodiment of the present invention, a pharmaceutical composition for treating cancer is provided, wherein a BCL-2 inhibitor and a selective nuclear export protein (XPO-1) inhibitor are used in combination, and the pharmaceutical composition provides a pharmaceutical composition for treating cancer, wherein the BCL-2 inhibitor and the selective nuclear export protein inhibitor are used in combination, either sequentially or non-sequentially.

[0064] In one specific embodiment of the present invention, a pharmaceutical composition is provided in which the BCL-2 inhibitor is any one selected from the group consisting of venetoclax, navitoclax, obatoclax, and sonorotoclax, and the selective nuclear export protein inhibitor is selinexor.

[0065]

[0066] Unless otherwise specifically defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

[0067]

[0068] The present invention confirms that when a BCL-2 inhibitor and an elF4A inhibitor are used in combination, when a nuclear export protein inhibitor, selinexor, and an elF4A inhibitor are used in combination, and when a BCL-2 inhibitor and selinexor are used in combination, a synergistic effect of high cell death is exhibited in B-cell lymphoma.

[0069] The present invention confirms that when Selinexor and an elF4A inhibitor are used in combination, a synergistic effect of high cell death is exhibited in T-cell lymphoma.

[0070] In addition, the effects of the present invention are not limited to the above-described effects, and should be understood to include all effects that can be inferred from the composition of the invention described in the detailed description or claims of the present invention.

[0071]

[0072] Figure 1 is a diagram showing the results of cell death in OCI-LY7, OCI-LY8, and OCI-LY18 cell lines treated with venetoclax and elF4A inhibitors (silvestrol and CR-1-31B) in combination.

[0073] Figure 2 is a diagram showing the results of cell death after combined treatment with venetoclax and selinexor in OCI-LY1, OCI-LY7, OCI-LY8, OCI-LY18, SUDHL6, and Toledo cell lines.

[0074] Figure 3 is a graph showing statistical analysis of the results of cell death after combined treatment with venetoclax and silvestrol in OCI-LY7, OCI-LY8, and OCI-LY18 cell lines.

[0075] Figure 4 is a graph showing statistical analysis of the results of cell death after combined treatment with venetoclax and CR-1-31B in OCI-LY7, OCI-LY8, and OCI-LY18 cell lines.

[0076] Figure 5 is a graph showing statistical analysis of the results of cell death after combined treatment with venetoclax and selinexor in OCI-LY7, OCI-LY8, and OCI-LY18 cell lines.

[0077] Figure 6 is a drawing showing the results of cell death in the HuT-78 cell line after combined treatment with selinexor and CR-1-31B.

[0078] Figure 7 is a graph showing a statistical analysis of the results of cell death in the HuT-78 cell line after combined treatment with Selinexor and CR-1-31B.

[0079] Figure 8 is a diagram showing the results of cell death in H9 cell line after combined treatment with selinexor and CR-1-31B.

[0080] Figure 9 is a graph showing a statistical analysis of the results of cell death in the H9 cell line after combined treatment with Selinexor and CR-1-31B.

[0081] Figure 10 is a diagram showing the results of cell death in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines treated with venetoclax and zotatipine together.

[0082] Figure 11 is a diagram showing the results of cell death in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines treated with venetoclax and rohinitib together.

[0083] Figure 12 is a diagram showing the results of cell death in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines treated with venetoclax and DDR together.

[0084] Figure 13 is a diagram showing the results of cell death in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines treated with venetoclax and episilbestrol together.

[0085] Figure 14 is a diagram showing the results of cell death in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines treated with venetoclax and CR-1-13B together.

[0086] Figure 15 is a graph showing statistical analysis of the results of cell death in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines treated with venetoclax and zotatipine together.

[0087] Figure 16 is a graph showing statistical analysis of the results of cell death after combined treatment with venetoclax and rohinitib in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines.

[0088] Figure 17 is a graph showing statistical analysis of the results of cell death after combined treatment with venetoclax and DDR in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines.

[0089] Figure 18 is a graph showing statistical analysis of the results of cell death in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines treated with venetoclax and episilbestrol together.

[0090] Figure 19 is a graph showing statistical analysis of the results of cell death after combined treatment with venetoclax and CR-1-13B in OCI-LY1, OCI-LY18, and SU-DHL-6 cell lines.

[0091] Figure 20 is a diagram showing the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and zotatipine.

[0092] Figure 21 is a diagram showing the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and rohinitib.

[0093] Figure 22 is a diagram showing the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and DDR.

[0094] Figure 23 is a diagram showing the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and episilbestrol.

[0095] Figure 24 is a diagram showing the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and CR-1-13B.

[0096] Figure 25 is a graph showing statistical analysis of the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and zotatipine.

[0097] Figure 26 is a graph showing statistical analysis of the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and rohinitib.

[0098] Figure 27 is a graph showing statistical analysis of the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and DDR.

[0099] Figure 28 is a graph showing statistical analysis of the results of cell death in OCL-LY1 and OCL-LY18 cell lines treated with a combination of selinexor and episilbestrol.

[0100] Figure 29 is a graph showing a statistical analysis of the results of cell death after combined treatment with selinexor and CR-1-13B in OCL-LY1 and OCL-LY18 cell lines.

[0101] Figure 30 is a diagram showing the results of cell death in HuT-78 and H9 cell lines treated with a combination of selinexor and zotatipine.

[0102] [Correction under Rule 91 11.11.2024] Figure 31 is a diagram showing the results of combined treatment with Selinexor and Rohinitiv in the HuT-78 cell line.

[0103] [Correction under Rule 91 11.11.2024] Figure 32 is a diagram showing the results of cell death in H9 cell line after combined treatment with selinexor and rohinitiv.

[0104] Figure 33 is a diagram showing the results of cell death in HuT-78 and H9 cell lines treated with a combination of selinexor and episilbestrol.

[0105] Figure 34 is a diagram showing the results of cell death in HuT-78 and H9 cell lines treated with a combination of selinexor and CR-1-13B.

[0106] Figure 35 is a graph showing a statistical analysis of the results of cell death resulting from the combined treatment with selinexor and zotatipine in HuT-78 and H9 cell lines.

[0107] Figure 36 is a graph showing statistical analysis of the results of combined treatment with selinexor and rohinitiv in HuT-78 and H9 cell lines.

[0108] Figure 37 is a graph showing statistical analysis of the results of cell death in HuT-78 and H9 cell lines treated with a combination of selinexor and episilbestrol.

[0109] Figure 38 is a graph showing statistical analysis of the results of cell death in HuT-78 and H9 cell lines treated with a combination of selinexor and episilbestrol.

[0110] Figure 39 is a graph showing statistical analysis of the results of cell death in the HuT-78 and H9 cell lines treated with a combination of Selinexor and CR-1-13B.

[0111]

[0112] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0113]

[0114] Preparation: Cell line preparation

[0115] The cell lines used in this experiment are as shown in Table 1 below, and each cell culture was cultured in the specified medium as shown in Table 1.

[0116] Before drug treatment, 1 × 10^5 / ml of cells were dispensed into each well of a 12-well plate (1 ml each). Venetoclax was prepared at 0.0025 μM, 0.005 μM, 0.01 μM, 0.02 μM; selinexor at 0.05 μM, 0.1 μM, 0.2 μM, 0.5 μM; CR-1-31B at 0.125 nM, 0.25 nM, 0.5 nM, 1 nM; and zotatipine, rohinitib, didesmethyllocaglamide, and episilbestrol at 1 nM, 2 nM, 5 nM, 10 nM, respectively, and treated alone or in combination in each well. Information on cell lines and subtypes was as shown in Table 1 below.

[0117] Cell line subtype mediumOCI-LY-10DLBCLABCIMDM (10% FBS, 1% PenStrep)SU-DHL-2DLBCLABCRPMI (10% FBS, 1% PenStrep)HBL-1DLBCLABCRPMI (10% FBS, 1% PenStrep)OCI-LY-1DLBCLGCB / DHLIMDM (20% FBS, 1% PenStrep)OCI-LY-8DLBCLGCB / DHLRPMI (10% FBS, 1% PenStrep)OCI-LY-18DLBCLGCB / DHLRPMI (10% FBS, 1% PenStrep)SU-DHL-6DLBCLGCB / DHLRPMI (10% FBS, 1% PenStrep)toledoDLBCLGCB / DHLRPMI (10% FBS, 1% PenStrep)OCI-LY-7DLBCLGCBIMDM (10% FBS, 1% PenStrep)SU-DHL-10DLBCLGCBRPMI (10% FBS, 1% PenStrep)HuT-78T cell lymphomaIMDM (10% FBS, 1% PenStrep)H9T cell lymphomaRPMI (10% FBS, 1% PenStrep)

[0118]

[0119] Example 1. Confirmation of the apoptotic effect of combined treatment with a BCL-2 inhibitor and an elF4A inhibitor in a diffuse large B-cell lymphoma cell line.

[0120] The combined effect of BCL-2 inhibitors and elF4A inhibitors was confirmed in a broad-spectrum large B-cell lymphoma cell line.

[0121] Specifically, venetoclax was prepared at concentrations of 0.0025 μM, 0.005 μM, 0.01 μM, and 0.02 μM in the cultured diffuse large B-cell lymphoma cell line in Table 1, silvestrol, an eF4A inhibitor, was prepared at concentrations of 0.0025 μM, 0.005 μM, 0.01 μM, and 0.02 μM, CR-1-31B, an eF4A inhibitor, was prepared at concentrations of 0.125 nM, 0.25 nM, 0.5 nM, and 1 nM, and zotatipine, rohinitib, didesmethyllocaglamide, and episilbestrol, which were also eF4A inhibitors, were prepared at concentrations of 1 nM, 2 nM, 5 nM, and 10 nM, respectively, and treated alone or in combination in each well. Afterwards, the cells were cultured in a 37℃, 5% CO2 incubator for 48 hours and then apoptosis was measured. After 48 hours, the cells were harvested, stained with 7-AAD and Annexin-V, and the apoptosis effect was confirmed using a flow cytometer (Fluorescence-Activated Cell Sorting, FACS).

[0122]

[0123] Example 2. Confirmation of the apoptotic effect of combined treatment with the XPO-1 inhibitor selinexor and the elF4A inhibitor in diffuse large B-cell lymphoma cell lines.

[0124] The combined effect of XPO-1 inhibitor and elF4A inhibitor was confirmed in diffuse large B-cell lymphoma cell lines.

[0125] Specifically, the cultured diffuse large B-cell lymphoma cell line in Table 1 was treated with selinexor at 0.05 μM, 0.1 μM, 0.2 μM, and 0.5 μM, the eIF4A inhibitor silvestrol at 0.0025 μM, 0.005 μM, 0.01 μM, and 0.02 μM, the eIF4A inhibitor CR-1-31B at 0.125 nM, 0.25 nM, 0.5 nM, and 1 nM, and the eIF4A inhibitors zotatipine, rohinitib, didesmethyllocaglamide, and episilbestrol at 1 nM, 2 nM, 5 nM, and 10 nM, respectively, singly or in combination in each well. Afterwards, the cells were cultured in a 37℃, 5% CO2 incubator for 48 hours, and then apoptosis was measured. After 48 hours, the cells were harvested, stained with 7-AAD and Annexin-V, and analyzed using a flow cytometer (Fluorescence-Activated Cell Sorting, FACS).

[0126]

[0127] Example 3. Confirmation of the apoptotic effect of combined treatment with a BCL-2 inhibitor and an XPO-1 inhibitor, selinexor, in a diffuse large B-cell lymphoma cell line.

[0128] The combined administration effect of selinexor, a BCL-2 inhibitor and XPO-1 inhibitor, was confirmed in diffuse large B-cell lymphoma cell lines.

[0129] Specifically, venetoclax was prepared at concentrations of 0.0025 μM, 0.005 μM, 0.01 μM, and 0.02 μM, and selinexor was prepared at concentrations of 0.05 μM, 0.1 μM, 0.2 μM, and 0.5 μM, and each well was treated alone or in combination. Afterwards, the cells were cultured in a 37°C, 5% CO2 incubator for 48 hours and apoptosis was measured. After 48 hours, the cells were harvested, and the apoptotic effect was confirmed using a flow cytometer (Fluorescence-Activated Cell Sorting, FACS) by staining the harvested cells with 7-AAD and Annexin-V.

[0130]

[0131] Example 4. Confirmation of the apoptotic effect of combined treatment with the XPO-1 inhibitor selinexor and the elF4A inhibitor in T-cell lymphoma cell lines.

[0132] The combined administration effect of XPO-1 inhibitor and elF4A inhibitor was confirmed in T-cell lymphoma cell lines.

[0133] Specifically, the cultured T-cell lymphoma cell line in Table 1 was treated with selinexor at 0.05 μM, 0.1 μM, 0.2 μM, and 0.5 μM, the elF4A inhibitor silvestrol at 0.0025 μM, 0.005 μM, 0.01 μM, and 0.02 μM, the elF4A inhibitor CR-1-31B at 0.125 nM, 0.25 nM, 0.5 nM, and 1 nM, and the elF4A inhibitors zotatipine, rohinitib, didesmethyllocaglamide, and episilbestrol at 1 nM, 2 nM, 5 nM, and 10 nM, respectively, singly or in combination in each well. Afterwards, the cells were cultured in a 37℃, 5% CO2 incubator for 48 hours, and then apoptosis was measured. After 48 hours, the cells were harvested, stained with 7-AAD and Annexin-V, and analyzed using a flow cytometer (Fluorescence-Activated Cell Sorting, FACS).

[0134]

[0135] Analysis example. Confirmation and analysis of the results of combined treatment at different concentrations in each cell line.

[0136] Synergistic effects were observed when venetoclax and an elF4A inhibitor were used in combination, when venetoclax and selinexor were used in combination, and when selinexor and an elF4A inhibitor were used in combination in diffuse large B-cell lymphoma cell lines and T-cell lymphoma cell lines. The synergistic effects were expressed through EoB values ​​(Table 2).

[0137] Inhibitors and concentrations Inhibitors and concentrations Cell lines EoB Venetoclax 0.1 μM Silvestrol 10 nMOCI-LY 7 1.73 0.05 μM 25 nMOCI-LY 8 38.49 0.1 μM 25 nMOCI-LY 18 44.55 Venetoclax 1 μM CR-1-31B 0.25 nMOCI-LY 7-13.0 30.05 μM 0.25 nMOCI-LY 8 28.90 0.02 μM 0.5 nMOCI-LY 18 29.48 0.02 μM 1 nMOCI-LY 142.79 0.02 μM 1 nMSU-DHL-63 3.94 Venetoclax 0.02 μM Zotatipine 10 nMOCI-LY 14 4.27 0.02 μM 10 n MOCI-LY 18 12.99 0.02 μM 10 n MSU-DHL-62 2.37 Venetoclax 0.02 μM Rohinitiv 5 n MOCI-LY 118.34 0.02 μM 5 n MOCI-LY 18 12.62 0.02 μM 10 n MSU-DHL-63 8.43 Venetoclax 0.02 μM MDDR 5 n MOCI-LY 115.92 0.02 μM 10 n MOCI-LY 18 30.07 0.02 μM 5 n MSU-DHL-614.78 Venetoclax 0.02 μM Episilbestrol 5 n MOCI-LY 12 3.67 0.01 μM 10 n MOCI-LY 18 48.000.02μM 5nMSU-DHL-620.14Selinexor 0.1μM Zotatipin 2nMOCI-LY 1 44.400.1μM 5nMOCI-LY 1 842.660.2μM 5nMHuT-7846.600.2μM 2nMH 9 32.38Selinexor 0.1μM Rohinitiv 2nMOCI-LY 1 29.760.1μM 5nMOCI-LY 1 856.460.2μM 2nMHuT-7818.510.1μM 2nMH 9 38.17Selinexor 0.1μMDDR 2nMOCI-LY 1 37.940.1μM 2nMOCI-LY 1 862.190.1μ M5nMHuT-7852.360.1μM2nMH931.84Selinexor0.1μMEpisilbestrol2nMOCI-LY122.820.1μM2nMOCI-LY1859.530.1μM5nMHuT-7839.780.05μM5nMH934.96Selinexor0.1μMCR-1-31B0.25nMOCI-LY147.160.1μM0.5nMOCI-LY1852.040.2μM0.5nMHuT-7851.590.2μM0.25nMH931.49Venetoclax1μMSelinexor0.05μMMOCI-LY7-2.050.02μM0.5μMOCI-LY160.000.02μM0.5μMOCI-LY847.680.01μM0.05μMOCI-LY1833.640.5μM0.05μMSU-DHL-626.070.02μM0.1μMToledo37.41.

[0138] According to Table 2 above, when venetoclax and silvestrol were used as combination therapy, the EoB value was positive in the double gene abnormality cell line among B-cell lymphoma, confirming the presence of a synergistic effect. The EoB value was the highest at 44.55 in the OCI-LY18 cell line when venetoclax was 0.1 μM and silvestrol was 0.025 nM, and was 17.78 when venetoclax was 0.05 μM and silvestrol was 0.05 nM. In the OCI-LY8 cell line, the EoB value was the highest at 38.49 when venetoclax was 0.025 μM and silvestrol was 0.025 nM, and was 7.89 when venetoclax was 0.05 μM and silvestrol was 0.05 nM.

[0139] When venetoclax and CR-1-31B were used in combination therapy, the EoB value was positive in B-cell lymphoma cell lines with double gene abnormalities, confirming the presence of a synergistic effect. The EoB value was the highest at 40.93 in the OCI-LY18 cell line when venetoclax was 0.01 μM and CR-1-31B was 1 nM, and was 29.48 when venetoclax was 0.02 μM and CR-1-31B was 0.5 nM. In the OCI-LY1 cell line, the EoB value was the highest at 45.27 when venetoclax was 0.01 μM and CR-1-31B was 1 nM, and was the second highest at 42.79 when venetoclax was 0.02 μM and CR-1-31B was 1 nM.

[0140] When venetoclax and zotatipine were used in combination therapy, the EoB value was positive in a double-gene abnormality B-cell lymphoma cell line, confirming a synergistic effect. The EoB value was highest at 38.49 in the OCI-LY18 cell line when venetoclax was 0.02 μM and zotatipine was 5 nM, and the second highest at 15.38 when venetoclax was 0.02 μM and zotatipine was 2 nM.

[0141] When venetoclax and rohinitib were used in combination therapy, the EoB value was positive in a double-gene abnormality B-cell lymphoma cell line, confirming a synergistic effect. The EoB value was highest at 41.79 in the OCI-LY18 cell line when venetoclax was 0.01 μM and rohinitib was 5 nM, and the second highest at 15.97 when venetoclax was 0.005 μM and rohinitib was 5 nM.

[0142] When venetoclax and DDR were used in combination therapy, the EoB value was positive in a double-gene abnormality B-cell lymphoma cell line, confirming a synergistic effect. The EoB value was highest at 30.07 in the OCI-LY18 cell line when venetoclax was 0.01 μM and DDR was 10 nM, and the second highest at 28.07 when venetoclax was 0.005 μM and DDR was 10 nM.

[0143] When venetoclax and episilbestrol were used in combination therapy, the EoB value was positive in double-gene abnormality B-cell lymphoma cell lines, confirming a synergistic effect. The EoB value was highest at 48.00 in the OCI-LY18 cell line when venetoclax was 0.01 μM and episilbestrol was 10 nM, and the second highest at 33.47 when venetoclax was 0.01 μM and episilbestrol was 2 nM.

[0144] When selinexor and zotatipine were used in combination therapy, positive EoB values ​​were observed in B-cell lymphoma with double genetic abnormalities and T-cell lymphoma cell lines, confirming a synergistic effect. The EoB value was highest at 63.46 in the OCI-LY18 cell line when selinexor was 0.2 μM and zotatipine was 2 nM, and the second highest at 45.67 when selinexor was 0.1 μM and zotatipine was 2 nM.

[0145] When selinexor and rohinitib were used in combination therapy, positive EoB values ​​were observed in B-cell lymphoma with double genetic abnormalities and T-cell lymphoma cell lines, confirming a synergistic effect. The EoB value was highest at 68.12 in the OCI-LY18 cell line when selinexor was 0.1 μM and rohinitib was 2 nM, and the second highest at 56.46 when selinexor was 0.1 μM and rohinitib was 5 nM.

[0146] When selinexor and DDR were used as combination therapy, the EoB value was positive in a double-gene abnormality cell line among B-cell lymphomas, confirming a synergistic effect. The EoB value was highest at 62.19 in the OCI-LY18 cell line when selinexor was 0.1 μM and DDR was 2 nM, and the second highest at 53.92 when selinexor was 0.1 μM and DDR was 5 nM.

[0147] When selinexor and CR-1-31B were used in combination therapy, the EoB values ​​were positive in B-cell lymphoma cell lines with double genetic abnormalities and T-cell lymphoma cell lines, confirming a synergistic effect. The EoB value was highest at 59.53 in the OCI-LY18 cell line when selinexor was 0.1 μM and episilbestrol was 2 nM, and the second highest at 56.89 when selinexor was 0.1 μM and episilbestrol was 5 nM.

[0148] When venetoclax and selinexor were used in combination therapy, the EoB value was positive in a double-gene abnormality B-cell lymphoma cell line, confirming a synergistic effect. The EoB value was highest at 33.64 in the OCI-LY18 cell line when selinexor was 0.05 μM and venetoclax was 0.01 μM, and the second highest at 26.48 when selinexor was 0.1 μM and venetoclax was 0.01 μM.

[0149] The results showing the presence or absence of synergistic effects depending on the cell line when each inhibitor was used in combination therapy are as shown in Table 3 below.

[0150] Cell line SubtypeVenetoclax + elF4A inhibitorSelinexor + elF4A inhibitorVenetoclax + selinexorOCI-LY-10DLBCLABCNo effectNo effectNo effectSU-DHL-2DLBCLABCNo effectNo effect-HBL-1DLBCLABCNo effectNo effect-OCI-LY-1DLBCLGCB / DHLSynergistic effectSynergistic effectOCI-LY-8DLBCLGCB / DHLSynergistic effectSynergistic effectOCI-LY-18DLBCLGCB / DHLSynergistic effectSynergistic effectSU-DHL-6DLBCLGCB / DHLSynergistic effectSynergistic effecttoledoDLBCLGCB / DHLSynergistic effectSynergistic effectOCI-LY-7DLBCLGCBNoynergistic effectNo effect None SU-DHL-10DLBCLGCB No effect No effect No effect HuT-78 T cell lymphoma No effect Synergistic effect No effect H9 T cell lymphoma No effect Synergistic effect No effect

[0151] Based on the above examples and Tables 1 to 3, the synergistic effects according to each combination of administration were summarized as shown in Table 4 below.

[0152] elF4A inhibitorBCL-2 inhibitorXPO1 inhibitorTest target cellsCells with synergistic effectSubtypes of synergistic cell linesSilbestrolVenetoclaxOCI-LY7, OCI-LY8, OCI-LY18OCI-LY8, OCI-LY18GCB / DHLCR-1-31BVenetoclaxOCI-LY1, OCI-LY18, SU-DHL-6OCI-LY7, OCI-LY8, OCI-LY18OCI-LY1, OCI-LY18, SU-DHL-6OCI-LY8, OCI-LY18GCB / DHLZotatipineVenetoclaxOCI-LY1, OCI-LY18, SU-DHL-6OCI-LY1, OCI-LY18, SU-DHL-6GCB / DHLRohinitiveVenetoclaxOCI-LY1, OCI-LY18, SU-DHL-6OCI-LY1, OCI-LY18, SU-DHL-6GCB / DHLDidesmethylocaglamideVenetoclaxOCI-LY1, OCI-LY18, SU-DHL-6OCI-LY1, OCI-LY18, SU-DHL-6GCB / DHLEpisilbestrolVenetoclaxOCI-LY1, OCI-LY18, SU-DHL-6OCI-LY1, OCI-LY18, SU-DHL-6GCB / DHLCR-1-31BSelinexorHuT-78, H9, OCI-LY1, OCI-LY18HuT-78, H9,OCI-LY1, OCI-LY18GCB / DHL, T-cell lymphoma cell lineZotatipinSelinexorHuT-78, H9,OCI-LY1, OCI-LY18HuT-78, H9,OCI-LY1, OCI-LY18GCB / DHL, T-cell lymphoma cell lineRohinitiveSelinexorHuT-78, H9,OCI-LY1, OCI-LY18HuT-78, H9,OCI-LY1, OCI-LY18GCB / DHL, T-cell lymphoma cell lineDidesmethyllocaglamideSelinexorHuT-78, H9,OCI-LY1, OCI-LY18HuT-78, H9,OCI-LY1, OCI-LY18GCB / DHL, T-cell lymphoma cell lineEpisilbestrolSelinexorHuT-78, H9,OCI-LY1, OCI-LY18HuT-78, H9,OCI-LY1, OCI-LY18GCB / DHL, T-cell lymphoma Cell lines Venetoclax Selinexor HuT-78, H9,OCI-LY7, OCI-LY8, OCI-LY18HuT-78, H9,OCI-LY8, OCI-LY18GCB / DHL, T-cell lymphoma cell lines,

[0153] GCB / DHL stands for double-gene abnormality cell line among B-cell lymphomas.

[0154]

[0155] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and are not intended to limit the scope of the present invention. Therefore, it will be apparent to those skilled in the art that various modifications and variations are possible within the scope of the technical spirit of the present invention as set forth in the claims.

Claims

1. A pharmaceutical composition for treating cancer using a combination regimen of at least one of an eLF4A inhibitor, a BCL-2 inhibitor, and a selective nuclear export protein (XPO-1) inhibitor.

2. In paragraph 1, A pharmaceutical composition wherein the above nuclear export protein inhibitor is Selinexor.

3. In paragraph 1, A pharmaceutical composition wherein the BCL-2 inhibitor is any one selected from the group consisting of venetoclax, navitoclax, obatoclax, and sonorotoclax.

4. In paragraph 1, A pharmaceutical composition wherein the elF4A inhibitor is any one selected from the group consisting of Silvestrol, CR-1-3B, Zotatifin, Rohinitib, Didesmethylrocaglamide (DDR), and Episilvestrol.

5. In paragraph 1 or paragraph 4, A pharmaceutical composition comprising, as an active ingredient, an agent that reduces the activity or expression level of the elF4A protein, or an agent that reduces the expression level of a gene encoding the protein.

6. In paragraph 5, A composition wherein the agent for reducing the expression level of the above gene is at least one selected from the group consisting of antisense nucleotides, small interfering RNAs (siRNAs), and ribozymes that complementarily bind to the elF4A gene or a portion thereof.

7. In paragraph 1, The above pharmaceutical composition for treating cancer is a pharmaceutical composition for treating cancer that uses at least one of an elF4A inhibitor, a BCL-2 inhibitor, and a selective nuclear export protein inhibitor in a combination regimen, either sequentially or discontinuously.

8. In any one of paragraphs 1 to 7, A pharmaceutical composition wherein the cancer is lymphoma.

9. In paragraph 8, A pharmaceutical composition wherein the above lymphoma comprises B-cell lymphoma or T-cell lymphoma.

10. In paragraph 9, A pharmaceutical composition, wherein the B-cell lymphoma comprises diffuse large B-cell lymphoma.

11. In paragraph 10, A pharmaceutical composition, wherein the above diffuse large B-cell lymphoma comprises a bigenic diffuse large B-cell lymphoma.

12. In paragraph 1, A pharmaceutical composition comprising the elF4A inhibitor, BCL-2 inhibitor and selective nuclear export protein inhibitor at concentrations of 0.0001 μM to 1.0 μM.

13. In paragraph 1, A pharmaceutical composition, wherein the pharmaceutical composition is administered to a patient with lymphoma.

14. A pharmaceutical composition according to claim 13, wherein the lymphoma patient comprises a B-cell lymphoma patient or a T-cell lymphoma patient.

15. In paragraph 1, The pharmaceutical composition is prepared in the form of an oral formulation of powder, granules, capsules, tablets, powder or aqueous suspension, an external preparation, a suppository, or a sterile injectable solution.

16. A pharmaceutical composition for treating cancer using a combination of a BCL-2 inhibitor and a selective nuclear export protein (XPO-1) inhibitor.

17. In paragraph 16, The above pharmaceutical composition is a pharmaceutical composition for treating cancer using a BCL-2 inhibitor and a selective nuclear export protein inhibitor in a sequential or non-sequential combination regimen.

18. In paragraph 16, A pharmaceutical composition, wherein the BCL-2 inhibitor is any one selected from the group consisting of venetoclax, navitoclax, obatoclax, and sonorotoclax.

19. In paragraph 16, A pharmaceutical composition wherein the selective nuclear export protein inhibitor is selinexor.

20. In paragraph 16, A pharmaceutical composition wherein the cancer is lymphoma.

21. In paragraph 16, A pharmaceutical composition wherein the above lymphoma comprises B-cell lymphoma or T-cell lymphoma.

22. In paragraph 16, A pharmaceutical composition, wherein the B-cell lymphoma comprises diffuse large B-cell lymphoma.

23. In paragraph 16, A pharmaceutical composition, wherein the above diffuse large B-cell lymphoma comprises a bigenic diffuse large B-cell lymphoma.

24. A method for treating cancer by administering in combination, either sequentially or non-sequentially, at least one of an elF4A inhibitor, a BCL-2 inhibitor, and a selective nuclear export protein (XPO-1) inhibitor.

25. In paragraph 24, A method for treating cancer wherein the above nuclear export protein inhibitor is Selinexor.

26. In paragraph 24, A method for treating cancer, wherein the BCL-2 inhibitor is any one selected from the group consisting of venetoclax, navitoclax, obatoclax, and sonorotoclax.

27. In paragraph 24, A method for treating cancer, wherein the elF4A inhibitor is any one selected from the group consisting of Silvestrol, CR-1-3B, Zotatifin, Rohinitib, Didesmethylrocaglamide (DDR), and Episilvestrol.

28. In paragraph 24 or paragraph 27, A method for treating cancer, wherein the elF4A inhibitor comprises as an active ingredient an agent that reduces the activity or expression level of the elF4A protein; or an agent that reduces the expression level of a gene encoding the protein.

29. In paragraph 28, A method for treating cancer, wherein the agent that reduces the expression level of the above gene is at least one selected from the group consisting of antisense nucleotides, small interfering RNAs (siRNAs), and ribozymes that complementarily bind to the elF4A gene or a portion thereof.

30. In any one of paragraphs 24 to 29, A method of treatment, wherein the cancer comprises lymphoma.

31. In paragraph 30, A treatment method, wherein the above lymphoma includes B-cell lymphoma or T-cell lymphoma.

32. In paragraph 31, A method of treatment, wherein the above B-cell lymphoma includes diffuse large B-cell lymphoma.

33. In paragraph 32, A treatment method, wherein the above diffuse large B-cell lymphoma includes bigenic diffuse large B-cell lymphoma.

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