Use of letrozole in the preparation of drugs for treating lymphoma

Abstract

This invention discloses the use of letrozole or its pharmaceutically acceptable salts, solvates, or hydrates in the preparation of medicaments for treating lymphoma. Experimental verification has shown that letrozole or its pharmaceutically acceptable salts, solvates, or hydrates can be used to treat lymphoma, particularly diffuse large B-cell lymphoma with c-MYC rearrangements.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and specifically relates to the use of aromatase inhibitor letrozole or its pharmaceutically acceptable salts, solvates or hydrates in the preparation of medicaments for the treatment of lymphoma. Background Technology

[0002] Letrozole (chemical name: 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole; English name: Letrozole) is an aromatase inhibitor. Aromatase inhibitors (AIs) specifically inactivate aromatase, blocking aromatization reactions, inhibiting estrogen production, and lowering blood estrogen levels, thereby achieving the goal of treating breast cancer. It is often used in postmenopausal patients with advanced breast cancer who have failed anti-estrogenic (tamoxifen) therapy. Letrozole is currently mainly used clinically for the treatment of breast cancer.

[0003]

[0004] c-MYC is a proto-oncogene located on chromosome 8q24, encoding a transcription factor involved in numerous processes such as cell growth, proliferation, differentiation, and apoptosis. 10%-15% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients have potential MYC translocations, leading to dysregulation of cell proliferation and apoptosis. BCL-2 is a proto-oncogene located on chromosome 18q12, encoding a protein with important anti-apoptotic effects. In DLBCL, BCL-2 overexpression not only inhibits tumor cell apoptosis but also often synergistically promotes DLBCL progression with c-MYC or other oncogenes, and mediates drug resistance in DLBCL cells. BCL-6 is a transcriptional repressor located on chromosome 3q27, primarily regulating cell proliferation, differentiation, and apoptosis. BCL-6-related gene translocations downregulate BCL-6 protein expression in normal germinal center B cells, rendering BCL-6 ineffective in inhibiting MYC and BCL-2, thus causing lymphoma development. Approximately half of patients with c-MYC translocation also have BCL-2 and / or BCL-6 translocations. In the 2016 WHO classification, DLBCL with the aforementioned recurrent gene abnormalities is defined as high-grade B-cell lymphoma (HGBCL) with MYC and BCL-2 and / or BCL-6 translocations; these patients account for approximately 8%-10% of all newly diagnosed DLBCL cases. Compared to other types of DLBCL, this type is more aggressive, often showing poor response to first-line R-CHOP therapy, and has a very poor prognosis.

[0005] Patients with c-MYC / Bcl-2 rearranged DLBCL have high-risk clinical characteristics and are prone to relapse and drug resistance. Even with high-intensity chemotherapy regimens, patients still do not achieve better prognoses. Currently, there is no consensus on the best treatment for this type of lymphoma. International research on this type of lymphoma has reached a bottleneck. How to discover new related pathways and drug targets, and ultimately provide safe, effective, and inexpensive drugs for the whole society, is a problem of great significance to both basic and applied research in my country's biomedicine. Faced with the trend of increasing investment in new drug development for corresponding targets and the increasing risk of failure in the international community, exploring new indications for existing drugs (repurposing or repositioning drugs) can effectively mitigate research and development risks, reduce research and development costs, and accelerate the pace of drug launch to quickly meet clinical needs. Therefore, it has become a strategy valued and adopted by many international pharmaceutical companies.

[0006] Comparative functional genomics breaks down the analytical barriers hindering the combined application of multi-omics data, enabling the organic integration of disease, gene, and drug. Applying this method and clinical bioinformatics strategies, it's possible to discover compounds with potential therapeutic applications for c-MYC / Bcl-2 rearranged DLBCL from a large pool of marketed compounds, significantly reducing the number of compounds required for experimental screening, saving financial and human resources, and potentially leading to better therapeutic outcomes. Currently, there are no reports on the use of letrozole in the treatment of lymphoma. Summary of the Invention

[0007] According to one aspect of the invention, an object of the invention is to provide the use of letrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof in the preparation of a medicament for treating lymphoma.

[0008] Preferably, the lymphoma is a diffuse large B-cell lymphoma with c-MYC rearrangement.

[0009] According to another aspect of the invention, another object of the invention is to provide the use of letrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with additional anticancer therapeutic agents in the preparation of a medicament for treating lymphoma. The additional anticancer therapeutic agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, and etoposide.

[0010] Preferably, the lymphoma is a diffuse large B-cell lymphoma with c-MYC rearrangement.

[0011] According to another aspect of the invention, another object of the invention is to provide the use of a pharmaceutical composition in the preparation of a medicament for treating lymphoma, said pharmaceutical composition comprising the active ingredient letrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient or carrier. Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

[0012] Preferably, the pharmaceutical composition comprises 1-99 wt% letrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof, and 1-99 wt% a pharmaceutically acceptable excipient or carrier.

[0013] Preferably, the pharmaceutical composition can be prepared into tablets, capsules, pills, powders, immediate-release dosage forms, sustained-release dosage forms, solutions, suspensions, emulsions, ointments, creams, or suppositories, etc. Tablets, capsules, pills, powders, immediate-release dosage forms, sustained-release dosage forms, solutions, and suspensions are preferred.

[0014] Preferably, the dosage of the pharmaceutical composition is determined according to the patient's age, condition, etc., and the unit dose of the formulation contains 0.05-200 mg of the letrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof. Preferably, the unit dose of the formulation contains 1 mg-100 mg of the letrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0015] Preferably, the dosage of the pharmaceutical composition is typically 0.001-100 mg / kg body weight per day, and more preferably 0.1-20 mg / kg body weight per day, taken once or in divided doses.

[0016] According to another aspect of the invention, another object of the invention is to provide a method for treating lymphoma, the method comprising administering to a patient a therapeutically effective amount of letrozole or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or the pharmaceutical composition thereof. Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement. Attached Figure Description

[0017] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0018] Figure 1To analyze the differential expression of GSE44164 double-hit lymphoma patients using volcano plot analysis of transcriptome sequencing data, 835 differentially expressed genes were identified, including 521 upregulated genes and 314 downregulated genes. Detailed Implementation

[0019] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0020] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0021] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0022] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0023] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0024] definition

[0025] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. The pharmaceutically acceptable salts of letrozole described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glycerophosphate, glucuronate, hemisulfate, heptahydrate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, lysine, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N+(C1-4 alkyl)4- salts. Representative base or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0026] The term "solvent" refers to a compound form that is typically bound to a solvent via a solvent decomposition reaction. This physical binding can include hydrogen bonds. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include stoichiometric and non-stoichiometric solvates. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. "Solvent" includes both solution phases and separable solvates. Representative solvates include hydrates, ethoxides, and methoxides.

[0027] The term "hydrate" refers to a compound that is bound to water. Typically, the number of water molecules contained in a hydrate of a compound is proportional to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0028] As used herein, the term “treatment” means the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. While not excluded, treating a disease or condition does not require the complete elimination of its associated symptoms. As used herein, the term “treatment” and similar terms can include “preventive treatment,” which refers to reducing the likelihood of the recurrence of a disease or condition or the relapse of a previously controlled disease or condition in subjects who are not at risk or are at risk of developing or being at risk of developing or experiencing a disease or condition or its recurrence. The term “treatment” and its synonyms are considered in relation to the administration of a therapeutically effective amount of the compound described herein to a subject who requires such treatment.

[0029] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For example, in the oral dosage form of this invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0030] The term "pharmaceutically acceptable excipient or carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Pharmaceutically acceptable excipients that can be used to manufacture the pharmaceutical compositions described herein include, but are not limited to, inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavoring agents, and fragrances may also be present in the composition.

[0031] Pharmaceutical compositions can be formulated for any route of administration, such as oral administration. Typically, pharmaceutical compositions are in solid dosage form. However, in some embodiments, other dosage forms, such as liquids, suspensions, or semi-solid dosage forms, may also be used.

[0032] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is combined with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or (a) filler or extender (e.g., starch, lactose, sucrose, glucose, mannitol, and silica), (b) binder (e.g., carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), (c) humectant (e.g., glycerin), (d) disintegrant (e.g., agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate), (e) inhibitor (e.g., paraffin), (f) absorption enhancer (e.g., quaternary ammonium compounds), (g) wetting agent (e.g., cetyl alcohol and glyceryl monostearate), (h) absorbent (e.g., kaolin and bentonite), and (i) lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), and mixtures thereof. For capsules, tablets, and pills, the dosage form may contain a buffer.

[0033] The terms "subject," "patient," or "object" refer to an animal, preferably a mammal, and most preferably a human, that has become the subject of treatment, observation, or experimentation. In any of the embodiments described herein, the subject may be a human.

[0034] Various dosage forms of the pharmaceutical compositions disclosed herein can be prepared according to conventional pharmaceutical methods. Each unit dose of the formulation contains 0.05-200 mg of the compound, preferably 1-100 mg of the compound.

[0035] The compounds and pharmaceutical compositions disclosed herein are for clinical use in mammals, including humans and animals, and can be administered via oral, nasal, skin, lung, or gastrointestinal routes. The optimal daily dose is 0.1-20 mg / kg body weight, administered once or in divided doses. Regardless of the method of administration, the optimal dose for a patient should be determined based on the specific treatment. Clinical trials typically begin with a low dose and gradually increase it until the most suitable dose is found.

[0036] In a common embodiment of the treatment method provided in this disclosure, the abnormal cell growth is cancer. The compounds of the present invention can be administered as a single agent or in combination with other anticancer therapeutic agents, particularly with standard of care agents applicable to specific cancers.

[0037] As used in this disclosure, the term "additional anticancer therapeutic agent" refers to any one or more therapeutic agents other than the compounds of the present invention, which are used or can be used to treat lymphoma. In some embodiments, such additional anticancer therapeutic agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxins, immunotumor agents, etc. Preferably, the additional anticancer therapeutic agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, and etoposide.

[0038] In some embodiments, administration of the compounds of the present invention is provided by any method capable of delivering the compound to the site of action. These methods include oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), local administration, and rectal administration.

[0039] The pharmaceutical composition may be in, for example, a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion; a form suitable for topical application, such as an ointment or cream; or a form suitable for rectal administration, such as a suppository. Preferably, it is in the form of tablets, capsules, pills, powders, immediate-release dosage forms, sustained-release dosage forms, solutions, or suspensions.

[0040] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0041] Example

[0042] 1. Bioinformatics screening:

[0043] 1.1 Data Sources and Screening of Differentially Expressed Genes

[0044] Data from the Gene Expression Database (GEO) was selected for the experimental group, consisting of 15 cases of high-grade B-cell lymphoma (HGBCL) with Bcl-2 / c-MYC rearrangements of the GBC subtype, specifically diffuse large B-cell lymphoma (DLBCL). Thirteen cases of normal tonsillar germinal center B cells were selected from the same study group's gene expression dataset, GSE43677, as the control group. Both datasets were compiled using the GPL96[HG-U133A]Affymetrix Human Genome U133AArray platform.

[0045] The obtained data and matrices were processed using R1.4.1717 software. After grouping, the dataset was screened for differentially expressed genes using the limma3.49.4 package, with a screening threshold of P < 0.05 and |log2FoldChange| > 0.5. The differentially expressed genes (DEGs) were plotted using the ggplot2 package.

[0046] Disease association analysis

[0047] 1.2 Drug Screening

[0048] Based on the theories of "systems biology" and "comparative functional genomics," an "integrated multi-omics analysis" algorithm was designed. This algorithm integrates and analyzes the transcriptomes of diseases or patients with those of drugs from the aforementioned data sources, establishing a clinical bioinformatics epigenomic precision medicine prediction platform (EpiMed). This platform is used to perform correlation analysis between the aforementioned DEGs (disease, disease, and genetic information) and drug transcriptome data, searching among FDA-approved clinical drugs and traditional Chinese medicines for drugs that can effectively treat monkeypox virus infection in humans. The screening criteria are a correlation coefficient >|0.1| and P < 0.05; drugs with a negative correlation are considered to have therapeutic effects.

[0049] 2. Experimental verification:

[0050] 2.1 Experimental Materials:

[0051] 2.1.1 Main reagents: PRIM 1640 culture medium (Gibco, USA), fetal bovine serum (Gibco, USA), penicillin-streptomycin-amphotericidal (100X triple antibody) (Gibco, USA), CCK-8 kit (Dojindo, Japan), letrozole (Shanghai Mairui Biochemical Technology Co., Ltd.)

[0052] 2.1.2 Main instruments: Micropipettes (2.5ul, 10ul, 20ul, 100ul, 200ul, 1000ul, 5000ul, Eppendorf, Germany), Clean bench (Thermo Fisher Scientific, USA), Cell incubator (Thermo Fisher Scientific, USA), Microplate reader (Thermo Fisher Scientific, USA)

[0053] 2.1.3 Cell line: DOHH-2 (Bcl-2 / c-MYC rearranged diffuse large B-lymphoma cell line)

[0054] 2.2 Experimental Methods:

[0055] 2.2.1 Preparation of complete cell culture medium: Take 6 ml of penicillin-streptomycin-amphotericidal (100X triple antibody) and 56 ml of fetal bovine serum, add them to 500 ml of PRIM 1640 culture medium to prepare complete culture medium, and store it at 4 degrees Celsius for later use.

[0056] 2.2.2 Cell Culture and Passage: The DOHH-2 cell line was cultured in complete culture medium and placed in a 37℃, 5% incubator.

[0057] 2.2.3 Drug Preparation: Weigh a certain dose of the drug using an electronic balance, dissolve the drug in DMSO to prepare a 10 mmol / L solution, and store at -30°C. Before use, dilute the drug in culture medium to prepare concentrations of 160 μmol / L, 120 μmol / L, 80 μmol / L, 40 μmol / L, and 20 μmol / L.

[0058] 2.2.4 CCK-8 Assay: Cells were passaged at approximately 80% confluence at a ratio of 1:3, about 3 times. After passage, cells were cultured in serum-free medium for 24 hours. Cells were then selected for the CCK-8 assay. After centrifugation, the cells were resuspended in 10 ml of culture medium. 20 μL of cells were added to 80 μL of culture medium, and 10 μL was added to a cell counting chamber to calculate the total cell count. An appropriate number of cells were selected for the experiment. 100 μL of cell suspension was seeded into each well, resulting in approximately 5 × 10⁶ cells per well. 4Each group of 96-well plates had three replicates. 100 μL of different drug concentrations were added to each well to achieve final concentrations of 80 μmol / L, 60 μmol / L, 40 μmol / L, 20 μmol / L, and 10 μmol / L. 100 μL of PBS was added to the outermost layer of the plate to reduce evaporation of the culture medium. At three time points (24h, 48h, and 72h), 20 μL of CCK-8 solution (10% concentration per well) was added to each well, and the plates were incubated for 2 hours. The OD values ​​of each well were then read at 450 nm using a microplate reader and the data were recorded.

[0059] 2.2.5 The drug killing inhibition rate is calculated as follows: Drug killing inhibition rate (%) = 1 - (mean OD of experimental group - blank OD) / (mean OD of control group - blank OD) × 100%.

[0060] 2.2.6 Statistical methods: Three independent experiments were conducted, and the average value of the results was taken.

[0061] 3. Bioinformatics screening results

[0062] 3.1 Results of differentially expressed gene screening

[0063] By analyzing transcriptome sequencing data from patients with GSE44164 double-hit lymphoma, 835 differentially expressed genes were identified. Figure 1 Differential expression analysis (volcano plot) showed that 521 genes were upregulated and 314 genes were downregulated.

[0064] 3.2 Results of Differential Gene Drug Prediction

[0065] The 835 differentially expressed genes were introduced into EpiMed and integrated with the disease or patient transcriptome and drug transcriptome for analysis. Drugs that can effectively treat this type of lymphoma were searched among FDA-approved clinical drugs and traditional Chinese medicines. The screening criteria were correlation coefficient >|0.1|, P<0.05. Drugs with negative correlation were considered to have therapeutic effects. Chutrozole was selected as a potential therapeutic drug.

[0066] 4. Experimental verification of the drug's killing effect on lymphoma cells.

[0067] 4.1 The results of differentially expressed gene drug prediction are shown in Table 2 below.

[0068] Table 2

[0069] 24h Inhibition rate 1 Inhibition rate 2 Inhibition rate 3 Average inhibition rate 80umol / L 43.73％ 39.45％ 31.61％ 38.27％ 60umol / L 30.42％ 10.68％ 14.28％ 18.46％ 40umol / L 27.89％ 15.64％ 13.72％ 19.08％ 20umol / L 20.15％ 9.58％ 21.44％ 17.06％ 10umol / L 15.79％ 5.17％ 6.93％ 9.30％ 48h Inhibition rate 1 Inhibition rate 2 Inhibition rate 3 Average inhibition rate 80umol / L 73.51％ 71.12％ 63.78％ 69.47％ 60umol / L 52.29％ 48.73％ 44.09％ 48.37％ 40umol / L 34.23％ 26.74％ 24.76％ 28.58％ 20umol / L 24.01％ 13.27％ 10.54％ 15.94％ 10umol / L 0 0 0 0 72h Inhibition rate 1 Inhibition rate 2 Inhibition rate 3 Average inhibition rate 80umol / L 85.65％ 89.07％ 85.65％ 86.79％ 60umol / L 66.37％ 72.15％ 66.37％ 68.30％ 40umol / L 40.86％ 38.55％ 40.86％ 40.09％ 20umol / L 25.91％ 35.75％ 25.91％ 29.19％ 10umol / L 5.06％ 2.07％ 5.06％ 4.07％

[0070] Inhibition rate 1, inhibition rate 2, and inhibition rate 3 were three parallel replicate experiments, and the final results were the average. After 24h, 48h, and 72h of letrozole treatment, the inhibition of lymphoma cell proliferation gradually increased with the increase of letrozole concentration, with a half-maximal inhibitory concentration of approximately 40 μmol / L, indicating a considerable inhibitory effect.

[0071] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. Use of letrozole or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lymphoma, wherein the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

2. Use of letrozole or a pharmaceutically acceptable salt thereof in combination with an additional anticancer agent in the preparation of a medicament for the treatment of lymphoma, wherein the additional anticancer agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, and etoposide, and wherein the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

3. Use of a pharmaceutical composition in the preparation of a medicament for treating lymphoma, said pharmaceutical composition comprising an active ingredient, letrozole or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier, said lymphoma being diffuse large B-cell lymphoma with c-MYC rearrangement.

4. The use according to claim 3, characterized in that, The pharmaceutical composition comprises 1-99 wt% letrozole or a pharmaceutically acceptable salt thereof, and 1-99 wt% a pharmaceutically acceptable excipient or carrier.

5. The use according to claim 3, characterized in that, The pharmaceutical composition is prepared into tablets, capsules, pills, powders, solutions, suspensions or emulsions.

6. The use according to claim 3, characterized in that, The pharmaceutical composition is prepared into an immediate-release dosage form or a sustained-release dosage form.

7. The use according to claim 3, characterized in that, The dosage of the pharmaceutical composition is determined according to the patient's age and condition, and each unit dose of the formulation contains 0.05-200 mg of the letrozole or a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, characterized in that, The formulation contains 1 mg to 100 mg of letrozole or a pharmaceutically acceptable salt thereof per unit dose.

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