WO2021014812A1 - Treatment for fibroblastic or myofibroblastic tumor and disease - Google Patents

Abstract

The present invention addresses the problem of providing a new therapeutic strategy for fibroblastic or myofibroblastic tumor and disease such as desmoid-type fibromatosis. Provided is a therapeutic agent for fibroblastic or myofibroblastic tumor and disease, the therapeutic agent containing, as an active ingredient, auranofin which is successfully identified by a drug repositioning strategy, or a pharmaceutically acceptable salt thereof.

Description

Treatment of fibroblastic or myofibroblastic tumors / diseases

The present invention relates to a therapeutic agent for fibroblastic or myofibroblastic tumors / diseases (for example, desmoid fibromatosis) and its use. This application claims priority based on Japanese Patent Application No. 2019-135877 filed on July 24, 2019, and the entire contents of the patent application are incorporated by reference.

Desmoid fibromatosis (DF) is a myofibroblastic tumor that is highly locally invasive but does not metastasize distantly. Although there are predominant sites such as shoulders, chest wall, back, limbs, and head and neck, it can basically occur from any part of the body, and it is necessary to change the treatment policy according to the site of onset. Previously, surgery was central to the treatment of DF, but due to the very high local recurrence rate, conservative treatment is recommended worldwide. However, no drug is covered by insurance for DF. The effectiveness of anti-cancer drug treatment centered on methotrexate, vinblastine, and doxorubicin has been reported (see, for example, Non-Patent Document 1). Recently, the effectiveness of sorafenib and pazopanib, which are molecular-targeted therapeutic agents, has been reported (see, for example, Non-Patent Document 2).

Since DF is a benign and malignant intermediate tumor, there are problems that strong side effects such as anticancer agents and molecular-targeted therapeutic agents are strong and very expensive. If there are few side effects and there is a drug that controls the proliferation of myofibroblasts, it will be of great benefit to DF patients and can be expected to contribute to the medical economy. This also applies to benign or benign (intermediate) fibroblastic or myofibroblastic tumors / diseases other than DF.
Therefore, the main problem of the present invention is to find a new therapeutic agent for fibroblastic or myofibroblastic tumors / diseases and to solve the problems of existing therapeutic agents (anticancer agents, molecular targeted therapeutic agents, etc.). To do.

In order to solve the above problems, the present inventors emphasized the ease of clinical application, and applied a drug repositioning strategy to fibroblastic or myofibroblastic tumors / diseases such as DF. Attempts have been made to identify effective drugs. As a result of detailed examination, it was found that a drug known as an anti-rheumatic drug has an effect of efficiently suppressing the proliferation of DF cells. The drug significantly reduced the number of tumors that developed in the DF mouse model, and also reduced the cell density of the tumors that developed, and exerted an excellent antitumor effect on DF. In addition to this finding, we also obtained information on the mechanism of action that would be useful in advancing clinical applications. On the other hand, based on the effects of the successfully identified drug (particularly the effect of suppressing growth in fibroblast-like cell growth suppression experiments), the drug is a fibroblastic or myofibroblast tumor other than DF. It was speculated that it could be applied to diseases.
The following invention is based on the above findings and considerations.
[1] A therapeutic agent for fibroblastic or myofibroblastic tumors / diseases containing auranofin or a pharmaceutically acceptable salt thereof as an active ingredient.
[2] Fibroblastic or myofibroblastic tumors / diseases include fibroma, superficial fibromatosis, deep fibromatosis, sporadic fibroblastic tumor, inflammatory myofibroblastic tumor , The therapeutic agent according to [1], which is hypertrophic scar, keloid or organ fibrosis.
[3] The therapeutic agent according to [1], wherein the fibroblastic or myofibroblastic tumor / disease is desmoid fibromatosis.
[4] Fibroblastic or myofibroblasts comprising the step of administering a therapeutically effective amount of auranofin or a pharmaceutically acceptable salt thereof to a patient with a fibroblastic or myofibroblastic tumor / disease. Treatment of blastic tumors and diseases.
[5] Use of auranofin or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for fibroblastic or myofibroblastic tumors / diseases.

Growth inhibitory effect of auranofin on DF cultured cells at each concentration. A. WT strain, B. S45F mutant strain. ** p <0.01 Changes in Caspase 3/7 activity of DF cultured cells according to each gene mutation type by administration of each drug. Changes in the expression level of each gene in DF cultured cells due to administration of each drug. A. WT strain, B. T41A mutant strain, C. S45F mutant strain. * P <0.05, ** p <0.01 Results of Apc1638N desmoid spontaneous mouse experiment. A. Auranofin administration protocol, B. Typical subcutaneous tumor, C. Typical muscle, fascial tumor. Antitumor effect of auranofin on Apc1638N mice. A. Number of tumors (* p <0.05), B. Weight. Histological image of excised tumor in spontaneously developing desmoid mice. Left: Auranofin administration group, Right: Control group (only solvent without drug added).

The present invention relates to a medicine for fibroblastic or myofibroblastic tumor / disease, that is, a therapeutic agent for fibroblastic or myofibroblastic tumor / disease (hereinafter, also referred to as "therapeutic agent of the present invention"). The therapeutic agent of the present invention contains auranofin or a pharmaceutically acceptable salt thereof as an active ingredient. Auranofin is a compound with the chemical name (2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranosato) (triethylphosphine) gold and is used as an active ingredient in anti-rheumatic drugs. It has a track record (specifically, RA remission inducer, auranofin tablet 3 mg "Sawai", RA remission inducer "Ridola tablet (registered trademark) 3 mg").

A pharmacologically acceptable salt of auranofin may be used as the active ingredient of the therapeutic agent of the present invention. The "pharmacologically acceptable salt" is not particularly limited, and the use of various salts such as acid addition salts and amino acid addition salts is assumed. Examples of acid addition salts include hydrochlorides, sulfates, nitrates, phosphates, inorganic acid salts such as hydrobromide, acetates, maleates, fumarates, citrates, benzenesulfonates, Examples include organic acid salts such as benzoate, malate, oxalate, methanesulfonate and tartrate. Examples of amino acid addition salts include glycine addition salt, phenylalanine addition salt, lysine addition salt, aspartic acid addition salt, and glutamic acid addition salt.

The therapeutic agent of the present invention can be applied to the treatment or prevention of fibroblastic or myofibroblastic tumors / diseases. "Therapeutic agent" refers to a drug that exhibits a therapeutic or prophylactic effect on a target disease or condition. The therapeutic effect includes alleviating (mitigating) the symptom or associated symptom characteristic of the target disease / pathological condition, preventing or delaying the exacerbation of the symptom, and the like. The latter can be regarded as one of the preventive effects in terms of preventing aggravation. Thus, therapeutic and prophylactic effects are partially overlapping concepts, which are difficult to distinguish and capture, and the practical benefits of doing so are small. A typical prophylactic effect is to prevent or delay the recurrence of symptoms characteristic of the target disease / condition. As long as it shows some therapeutic effect or preventive effect on the target disease / pathological condition, or both, it corresponds to a therapeutic agent for the target disease / pathological condition.

"Fibroblastic or myofibroblastic tumor / disease" is a disease in which excessive (that is, deviating from the normal state) proliferation of fibroblasts and / or myofibroblasts is observed, in other words, fibers. A disease in which the proliferation of blasts / myofibroblasts underlies or forms the pathology. In particular, benign or benign (intermediate type) fibroblastic or benign (intermediate type) fibroblastic or malignant (intermediate type) fibroblastic or malignant (intermediate type) fibroblastic or malignant (intermediate type) fibroblastic or malignant (intermediate) type The therapeutic agent of the present invention is suitable for the treatment of myofibroblastic tumors / diseases. Examples of fibroblastic or myofibroblastic tumors / diseases that can be treated by the therapeutic agent of the present invention include soft fibroma, elastofibroma, and sclerotic fibroma. , Fibroma such as dermatofibroma, superficial fibroma such as palm fibroma (dupuytran contraction), sole fibroma, desmoid fibroma which is deep fibroma , Sporadic fibroma, inflammatory myofibroblastoma, hypertrophic scar, keloid, organ fibrosis (pulmonary fibrosis, renal fibrosis, etc.).

One of the suitable treatment / prevention targets for the therapeutic agent of the present invention is desmoid fibromatosis. Aggressive fibromatosis is also called aggressive fibromatosis. As described above, treatment with anticancer agents, molecular-targeted therapeutic agents, and the like has been attempted for desmoid fibromatosis, but there are problems of side effects and costs. The therapeutic agent of the present invention exerts a therapeutic effect by a mechanism of action different from those of these therapeutic agents, and provides a new therapeutic strategy.

The therapeutic agent of the present invention can be formulated according to a conventional method. When formulated, other ingredients allowed in the formulation (eg, carriers, excipients, disintegrants, buffers, emulsifiers, suspensions, soothing agents, stabilizers, preservatives, preservatives, physiology (Saline, etc.) can be contained. As the excipient, lactose, starch, sorbitol, D-mannitol, white sugar and the like can be used. As the disintegrant, starch, carboxymethyl cellulose, calcium carbonate and the like can be used. As the buffer, phosphate, citrate, acetate and the like can be used. As the emulsifier, gum arabic, sodium alginate, tragant and the like can be used. As the suspending agent, glycerin monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used. As the pain-relieving agent, benzyl alcohol, chlorobutanol, sorbitol and the like can be used. Propylene glycol, ascorbic acid and the like can be used as the stabilizer. As the preservative, phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben and the like can be used. As the preservative, benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.

The dosage form when formulating is not particularly limited. Examples of dosage forms are tablets, powders, fine granules, granules, capsules, syrups, injections, topical agents, and suppositories. The therapeutic agent of the present invention is targeted by oral administration or parenteral administration (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, or intraperitoneal injection, transdermal, nasal, transmucosal, etc.) depending on the dosage form. Applies to. Systemic and topical administrations are also indicated by the subject. These administration routes are not mutually exclusive, and two or more arbitrarily selected administration routes can be used in combination (for example, intravenous injection or the like at the same time as oral administration or after a lapse of a predetermined time). The therapeutic agent of the present invention contains an amount of the active ingredient necessary for obtaining the expected therapeutic effect (that is, a therapeutically effective amount). The amount of the active ingredient in the therapeutic agent of the present invention generally varies depending on the dosage form, but the amount of the active ingredient is set in the range of, for example, about 0.1% by weight to about 99% by weight so that a desired dose can be achieved.

The dose of the therapeutic agent of the present invention is set so as to obtain the expected therapeutic effect. Symptoms, patient age, gender, weight, etc. are generally taken into account when setting therapeutically effective doses. Those skilled in the art can set an appropriate dose in consideration of these matters. For example, the dose can be set so that the daily amount of the active ingredient is 0.1 mg to 50 mg, preferably 1 mg to 30 mg, and particularly preferably 2 mg to 20 mg for an adult (body weight of about 60 kg). As the administration schedule, for example, once to several times a day (for example, twice, three times, four times), once every two days, or once every three days can be adopted. In preparing the administration schedule, the patient's medical condition and the duration of effect of the active ingredient can be taken into consideration.

In parallel with the treatment with the therapeutic agent of the present invention, treatment with another drug (for example, an existing therapeutic agent) may be performed, or the treatment with the therapeutic agent of the present invention may be combined with an existing therapeutic procedure (for example, surgical excision). You may.

As is clear from the above description, the present application also provides a therapeutic method characterized by administering a therapeutically effective amount of the therapeutic agent of the present invention to a patient with a fibroblastic or myofibroblastic tumor / disease. To do.

We aimed to identify new drugs that are effective for desmoid fibromatosis (DF), etc. by exploring new indications of existing drugs and expanding their application, that is, by drug repositioning strategy. Specifically, we attempted to select a drug that efficiently suppresses the proliferation of DF cells, and evaluated the efficacy of the selected drug in a DF-onset mouse model.

1. 1. Drug Repositioning Drug Search For each drug in Prestwick Chemicals' 1,186 FDA-approved drug library, DF cultured cells (from desmoid tumors to gene mutation-free cell lines (WT) and CTNNB1 gene Exxon 3) Two strains of cell lines with point mutations (S45F) were prepared) and their growth inhibitory activity was comparatively evaluated by the MTS assay. Twenty-five drugs were selected by setting their own evaluation criteria. Next, by narrowing down to 5 drugs based on criteria such as suitability for clinical application in Japan and safe long-term administration, and comparing their cell growth inhibitory activity with Meloxicam, excellent cell growth inhibitory activity is shown. The drug "Auranofin" was selected as the final candidate.

2. 2. Evaluation of selected drug 2-1. Materials and methods (1) Tumor cultured cells Tumor tissue of wild-type (WT) of DF and each CTNNB1 gene mutant (T41A, S45F) histologically pathologically diagnosed are fragmented into 0.2 mg / mL proteinase. The tumor was allowed to stand at 37 ° C. for 3 hours in Dulbecco's modified Eagle's culture medium (DMEM) to be dissolved. The isolated cells were then placed in DMEM containing 10% fetal bovine serum (FBS) supplemented with 100 U / mL penicillin and 100 mg / mL streptomycin at 37 ° C. and 5% CO ₂ concentrations. Cultivation was performed in the environment. Cultures were changed every 3-4 days and were trypsinized and subcultured before reaching confluet. The 5th to 15th passage DF cultured cells thus obtained were used in the experiment.

(2) Cell proliferation evaluation assay DF cultured cells were seeded on a 96-well plate at a concentration of 5 × 10 ³ / well in a medium containing 10% FBS, and stored for 12 hours for adhesion. Then, it was replaced with DMSO or a medium containing 10% FBS containing auranophin (dissolved in DMSO) at each concentration of 0.2 to 10 μM, and cell proliferation after 24 hours was measured with the MTS assay kit (CellTiter 96® AQueous Assay). , Promega), and the absorbance was measured with a microplate reader, Rainbow RC (Tecan Japan), according to the attached instructions.

(3) Apoptosis evaluation assay DF cultured cells were seeded on a 96-well plate at a concentration of 5 × 10 ³ / well in a medium containing 10% FBS, and stored for 12 hours for adhesion. Then, it was replaced with a medium containing DMSO or 10% FBS containing Felodipine, Meloxicam or auranophin at a concentration of 5 μM, and the activity of Caspase 3/7, which is an index of apoptosis-inducing ability after 24 hours, was expressed in the Caspase assay kit (Caspase). -Glo (registered trademark) 3/7 Assay, Promega) was used to measure the luminescence with a microplate reader PowerScan4 (DS Pharma Biomedical) according to the attached instructions.

(4) mRNA expression analysis (RT-PCR)
In order to evaluate the inhibitory ability of each drug against the Wnt / β-catenin signaling pathway, the mRNA expression of Axin-2, Cyclin-D, C-myc and Cox-2, which have been reported as downstream genes, was measured. WT, T41A and S45F mutant DF cultured cells were seeded on a 96-well plate at a concentration of 1 × 10 ⁴ / well in a medium containing 10% FBS and stored for 12 hours for adhesion. The cells were cultured in a medium containing 5 μM of each drug for 6 hours, and Total cellular RNA was extracted using RNeasy Mini Kit (Qiagen) according to the attached instructions. The cDNA obtained by reverse transcription polymerase chain reaction (RT-PCR) was subjected to real-time RT-PCR reaction using LightCycler (Roche Diagnostics). The mRNA expression level of each gene was evaluated as a relative value based on the Gapdh expression level used as an internal control. The primers for Axin-2, Cyclin-D, C-myc and Cox-2 are as follows.
Axin-2 Sense Primer: 5'-CAACAGATCATCCCATCCAACA-3'(SEQ ID NO: 1), Antisense Primer: 5'-ATTGGGTAGGTGTAAGGAGAC-3' (SEQ ID NO: 2) (estimated size of PCR product is 80 bp)
Cyclin-D Sense Primer: 5'-ACCAGCTCCTGTGCTGCGAAGTG-3'(SEQ ID NO: 3), Antisense Primer: 5'-GACGGCAGGACCTCCTTCTGCACA-3' (SEQ ID NO: 4) (estimated PCR product size is 157 bp)
C-myc sense primer: 5'-CAGCACCTTCTCATGCATC-3'(SEQ ID NO: 5), antisense primer: 5'-AGGATAGTCCTTCCGAGTGG-3' (SEQ ID NO: 6) (estimated size of PCR product is 126 bp)
Cox-2 sense primer: 5'-TGCATTCTTTGCCCAGCAC-3'(SEQ ID NO: 7), antisense primer: 5'-TGCATTCTTTGCCCAGCAC-3' (SEQ ID NO: 8) (estimated size of PCR product is 146 bp)
Gapdh sense primer: 5'-AGGTCGGAGTCAACGGATTTG-3'(SEQ ID NO: 9), antisense primer: 5'-TGTAAACCATGTAGTTGAGGTCA-3' (SEQ ID NO: 10) (estimated size of PCR product is 123 bp).

(5) Mouse model As a mouse model that develops DF, a Ctnnb1 mutation model (Sato S. et al. Cell Rep. 16 (4): 917) in which Ng2 / Cspg4-CreER mice were mated with Ctnnb1 ^{lox (ex3)} mice. -927 2016) and the Apc1638N mouse model as an Apc mutation model (Smits R. et al. Gastroenterology, 114 (2): 275-83 1998) have been reported. The former is a mouse that expresses the enzyme Cre in cells expressing NG2 in the presence of tamoxifen and can delete the exon 3 of the β-catenin gene (CTNNB1) sandwiched between loxP. The latter are mice with a mutation in APC, the causative gene of familial adenomatous polyposis. The causes of the onset of desmoid are roughly divided into two cases, one is when the exon 3 of the CTNNB1 gene is mutated and the other is when the APC gene is mutated. Although the sites of occurrence are often different, it has been reported that behavior and responsiveness to drugs are similar (Heinrich MC et al, J Clin Oncol, 24 (29): 4674-74 2006) (Nishida Y). et al, Int J Clin Oncol, 20 (6): 1211-7 2015). As a result of confirming the formation of DF in both models in the preliminary test, no obvious DF formation was observed in the Ctnnb1 mutation model, so the Apc mutation model was used in this study. It is said that APC and β-catenin form a complex, and each mutation inhibits the degradation of β-catenin, so that the accumulated β-catenin translocates into the nucleus and desmoids are generated. Therefore, it is considered appropriate to evaluate the efficacy of APC mutant mice from the viewpoint of the mechanism of desmoid development. These mice were fed a diet so that the dose of auranofin was l mg / kg / day from 1 month (5 weeks of age) after birth. When lmg / kg / day is administered to mice, the human equivalent dose is 12.3, so the dose in humans is about 0.08 mg / kg / day. The amount of auranofin normally used in humans is 6 mg / day, and when the body weight is 60 kg, it is 0.1 mg / kg / day, which is considered to be the same dose as the dose to mice this time. The number of tumors, tumor diameter, and body weight at 6 months of age were compared between the administration group and the control group (solvent only). Since the number of desmoids generated in females of the Apc mutation model is small (Poon R, et al, PLoS One. 2012; 7 (5): e37940.), We decided to use male mice suitable for evaluation. As the number of tumors, the number of tumors developed subcutaneously and intramuscularly was counted, and the maximum tumor diameter was measured macroscopically. In the statistical significance test, the difference between the two groups was analyzed by the Student-t test.

2-2. Results (1) Cell growth inhibitory effect The growth inhibitory effect of auranofin on DF cultured cells was evaluated in the WT strain and the S45F strain. In the WT strain, auranofin showed a slight growth-promoting effect of 16 to 18% at a concentration of 0.5 to 1.0 μM, and a strong concentration-dependent suppression was observed at a high concentration of 5 μM or more (Fig. 1A). At 10 μM, about 80% suppression was observed compared to the control (5 μM vs l0 μM, p = 0.0012). On the other hand, in the S45F mutant strain, no significant growth promotion was observed at a concentration of 0.5 to l.0 μM of auranofin, but statistically significant suppression was observed at a high concentration of 5 μM or more, which was compared with the control. A suppression of about 60% was observed (Fig. 1B).

(2) Apoptosis-inducing effect The apoptosis-inducing effect of each mutant strain on DF cultured cells was evaluated by measuring Caspase 3/7 activity. As a result, none of felodipine, meloxicam and auranofin showed a significant increase in Caspase 3/7 activity as compared with the control, suggesting no clear apoptosis-inducing effect (Fig. 2).

(3) Transcription factor expression inhibitory effect By administration of felodipine, meloxicam or auranofin, the expression of Axin-2, Cyclin-D, C-myc and Cox-2, which are downstream genes of Wnt / β-catenin signal, is increased, respectively. Different fluctuations were observed (FIGS. 3A-C). In WT cells and T41A mutant cells, the variation in expression was observed for each gene as with other drugs by administration of auranofin, but the expression of Cyclin-D was uniformly suppressed (FIGS. 3A and 3B). ). On the other hand, in the S45F mutant strain, unlike the other two agents, auranofin showed an expression-suppressing effect on all four genes, and in particular, the expression of Cyclin-D, C-myc and Cox-2 was strongly suppressed (Fig.). 3C).

(4) Evaluation of auranofin drug efficacy in desmoid-onset mouse model From 5 weeks of age of desmoid-onset mouse model Apc1638N mouse, auranofin-free diet (non-administration group) or auranofin mixed diet (oranofin administration group) ) Was ingested (Fig. 4A). In the 6-month-old evaluation of the mice in the non-administration group, gross tumors were observed subcutaneously and in the muscles and fascia (Figs. 4B and C), and the number of tumors was 39 in the non-administration group (n =). 5) There were 28 tumors (n = 10) in the oranofin-administered group, and a statistically significant decrease in the number of tumors was observed in the pomalidomide-administered group (Fig. 5A, p <0.05). Regarding the average body weight, there was no significant difference between the auranofin-administered group and the non-administered group (Fig. 5B). Histological evaluation showed that the cell density was low in the auranofin-administered group (Fig. 6). In desmoids, not only the reduction in size but also the decrease in cell density is considered to indicate the degree of tumor growth. Therefore, the decrease in cell density has a tumor-suppressing effect.

3. 3. Discussion Auranofin found by the drug repositioning strategy exerted a medicinal effect on DF in cell-level and animal-level experiments. Not only reducing the number of tumors, but also reducing the cell density in the tissue means that there is little increasing activity when it occurs. This fact indicates that auranofin is promising for the treatment of DF. In addition, considering the characteristics and pathophysiology of DF and commonality with other diseases, auranofin is a type of fibroma (soft fibroma, elastic fibroma, sclerosing fibroma, cutaneous fibroma, etc.), table. Intrinsic fibromatosis (palm fibromatosis, sole fibromatosis, etc.) Organs such as sporadic fibroma, inflammatory myofibroblastic tumor, hypertrophic scar, keloid, pulmonary fibrosis / renal fibrosis Its application is expected to be widely applied to fibroblastic or myofibroblastic tumors / diseases such as fibrosis.

The therapeutic agent of the present invention contains the approved drug auranofin or a pharmaceutically acceptable salt thereof as an active ingredient. Auranofin has been used as an active ingredient in anti-rheumatic drugs, and its safety has been established, including optimal dosage, side effects, and contraindications. This fact is a great merit in clinical application of the therapeutic agent of the present invention containing auranofin as an active ingredient. The therapeutic agent of the present invention exhibits a growth inhibitory effect on fibroblasts / myofibroblasts, and is applied not only to DF but also to the treatment of other fibroblastic or myofibroblastic tumors / diseases. Is highly expected.

The present invention is not limited to the description of the embodiments and examples of the above invention. Various modifications are also included in the present invention as long as those skilled in the art can easily conceive without departing from the description of the scope of claims. The contents of the papers, published patent gazettes, patent gazettes, etc. specified in this specification shall be cited by reference in their entirety.

SEQ ID NO: 1-10: Description of artificial sequence: Primer

Claims (5)

1. A therapeutic agent for fibroblastic or myofibroblastic tumors / diseases containing auranofin or a pharmaceutically acceptable salt thereof as an active ingredient.
2. Fibroblastic or myofibroblastic tumors / diseases are fibroma, superficial fibromatosis, deep fibromatosis, sporadic fibroblastic tumor, inflammatory myofibroblastic tumor, hypertrophic The therapeutic agent according to claim 1, which is scar, keloid or organ fibrosis.
3. The therapeutic agent according to claim 1, wherein the fibroblastic or myofibroblastic tumor / disease is desmoid fibromatosis.
4. Fibroblastic or myofibroblastic, including the step of administering auranofin or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient with a fibroblastic or myofibroblastic tumor / disease. Treatment of tumors and diseases.
5. Use of auranofin or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for fibroblastic or myofibroblastic tumors / diseases.

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