Nitroxoline for use in the treatment or prevention of plexiform neurofibroma

Abstract

The present invention relates to a composition comprising nitroxoline or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of plexiform neurofibromas.

Description

[Technical field]

[0001] The present invention relates to a new use of nitroxoline. [Background technology]

[0002] Neurofibromas are benign nerve sheath tumors in the peripheral nervous system. In 90% of cases, they are found as independent tumors, while the remainder are found in patients with the autosomal dominant genetic disorder neurofibromatosis type I (NF1). Neurofibromas can cause a variety of symptoms ranging from physical disfigurement and pain to cognitive impairment, and can transform into malignant tumors.

[0003] Plexiform neurofibromas arise early in development from cutaneous nerves or from more internal nerve bundles such as cranial nerves or proximal large peripheral nerve sheaths. Plexiform neurofibromas are composed of Schwann cells (SCs), fibroblasts, degranulated mast cells, and vascular cells (Hirota S et al.,Arch Pathol Lab Med.1993;117(10):996-9). Plexiform neurofibromas enlarge progressively and can cause lifelong morbidity and mortality, with a lifetime incidence of 10-15% transforming into malignant peripheral nerve sheath tumors.

[0004] NF1 is caused by germline mutations in the NF1 tumor suppressor gene, which encodes a protein called neurofibromin. Neurofibromin functions as a GTPase-activating (GAP) protein, inactivating the intracellular signaling protein Ras by converting the active GTP-bound form to the inactive GDP-bound form. This in turn leads to downregulation of Ras activity. Loss of neurofibromin activity increases Ras activity, which promotes the transcription of many genes required for cell growth and proliferation. Plexiform neurofibromas appear in approximately 15%-40% of NF1 patients.

[0005] Internal plexiform neurofibromas are very difficult to completely remove surgically because they extend through multiple layers of tissue and damage healthy tissue or organs when surgery is attempted. Plexiform neurofibromas can cause disfigurement, neurological deficits, and other clinical deficits, including the potential for severe clinical complications when occurring in certain areas.

[0006] Also, significant efforts have been made to identify pharmacological targets to treat plexiform neurofibromas. In particular, plexiform neurofibromas are frequently targeted for repurposing efforts and repositioning of drugs in development. Many different standards and methods have been applied to this task. In many cases, repurposing candidates have been identified primarily based on clinical pattern matching, whereas in other cases, the basic disease mechanisms have been extensively studied to identify therapeutic targets, followed by thorough preclinical validation.

[0007] Currently, surgery remains the main treatment option. However, they are difficult to remove because they are large and may cross tissue boundaries. In 2020, the FDA approved the MEK inhibitor Koselugo (selumetinib) for the treatment of NF1 pediatric patients aged 2 years and older with symptomatic, inoperable plexiform neurofibromas. However, not all patients respond to treatment, and tumors shrink only partially. Selumetinib is a selective inhibitor of mitogen-activated protein kinase kinases (MAPK kinases, MEK, MAP2K, and MAPKK), with the systematic name 6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide.

[0008] Overall, efforts to treat plexiform neurofibromas have offered some intriguing possibilities but have not achieved conclusive success despite many efforts, highlighting the need for new therapeutic approaches.

[0009] Nitroxoline has been used in humans as an antibiotic and, although not widely used, has been commercially available since the 1960s. It is used to treat or prevent biofilm infections, such as urinary tract infections. It is particularly effective at disrupting biofilms, and the cause of this action is thought to be its metal cation chelating properties. Nitroxoline is metabolized in the liver to the corresponding sulfate and glucuronide metabolites. There is evidence that both of these metabolites share antibacterial activity. It is also used in anticancer therapy via its antiproliferative effects. The systematic name for nitroxoline is 5-nitroquinolin-8-ol. Summary of the Invention

[0010] The present invention relates to a composition comprising nitroxoline or a pharma- ceutical acceptable salt thereof for use in the treatment or prevention of plexiform neurofibroma. As is evident from the in vitro data shown below, nitroxoline is effective in the treatment and prevention of plexiform neurofibroma.

[0011] A first aspect of the invention is a composition comprising nitroxoline, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of plexiform neurofibroma.

[0012] A second aspect of the invention is the use of nitroxoline, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of plexiform neurofibroma.

[0013] A third aspect of the invention provides a method of treating or preventing plexiform neurofibroma, the method comprising administering to a patient a composition comprising nitroxoline or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the dose response of nitroxoline on proliferation (top) and apoptosis (bottom) of WT and NF1-deficient Schwann cells in an in vitro assay. [Diagram 2]FIG. 1 shows the effect of nitroxoline treatment on proximal nerve volume (A) and tumor number (B) in the Postn-Cre+ Nf1fl / fl mouse model of plexiform neurofibroma (n=6, *=p-value<0.05 (Fisher's LSD test / Dunnett's test)). [Diagram 3] Graph showing tumor / nerve width and caliper measurement method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Nonmyelinating Schwann cells, which express only an inactive version of the NF1 gene (a "tumor suppressor gene") and completely lose expression of functional neurofibromin, are the origin of plexiform neurofibromas. The NF1 gene encodes a protein that regulates cell proliferation. There are two types of Schwann cells: myelinating and nonmyelinating. Myelinating Schwann cells cover large diameter (greater than 1 micrometer) peripheral nervous system (PNS) axons with myelin, whereas nonmyelinating Schwann cells surround small diameter PNS axons with cytoplasmic processes. In non-mutated non-myelinating Schwann cells, the collection of Schwann cells around the axon is called a Remak bundle. On the other hand, mutated non-myelinating Schwann cells do not form normal Remak bundles. Instead, they fail to properly surround and separate the target axon, giving rise to plexiform neurofibromas. Furthermore, non-myelinating Schwann cells begin to proliferate rapidly when their NF1 gene is inactivated.

[0016] It has been hypothesized that proliferating non-myelinating Schwann cells secrete chemoattractants that promote the migration of various cell types that are heterozygous for the NF1 gene into the hyperplastic lesions caused by the non-myelinating Schwann cells. These cell types include fibroblasts, perineurial cells, endothelial cells, and mast cells. Mast cells then secrete mitogens or survival factors that alter the developing tumor microenvironment, leading to the formation of neurofibromas.

[0017] In the present invention, nitroxoline is an effective treatment for plexiform neurofibromas because it inhibits cell proliferation and increases apoptosis in NF1-deficient Schwann cells, as demonstrated by the following in vitro data: Preferably, nitroxoline is used for the treatment or prevention of plexiform neurofibromas, and the subject has neurofibromatosis type I.

[0018] The term "treatment" or "treating" as used herein refers to a therapeutic (curative) treatment, including reducing the size of plexiform neurofibromas. A blood test for protein melanoma inhibitory activity can be used to detect the presence of neurofibromas. The term "prevention" or "preventing" as used herein refers to a "prophylactic" treatment, including administering the compositions of the present invention to patients whose non-myelinating Schwann cells are mutated (e.g., NF1-deficient) but who have not developed plexiform neurofibromas. Mutated (e.g., NF1-deficient) non-myelinating Schwann cells may begin to proliferate, such as by proliferating rapidly.

[0019] "Patient" and "subject" are used interchangeably and refer to a subject to which nitroxoline is administered. Preferably, the subject is a human. Suitably, the subject has neurofibromatosis type I. In one embodiment, the patient is a pediatric patient, preferably a pediatric patient aged 2 years or older, preferably the pediatric patient has NF1.

[0020] In one embodiment, nitroxoline is used to treat or prevent plexiform neurofibromas and the patient has undergone or will undergo surgery to remove some or all of the plexiform neurofibroma. This may be particularly advantageous when the plexiform neurofibroma is large and / or has spread beyond tissue boundaries such that it is difficult to remove all of it by surgery and / or it is desirable / beneficial to remove at least some of it quickly.

[0021] The term "surgery" has its usual meaning in the art. Surgery is an invasive technique based on physical intervention into an organ / system / tissue for diagnostic or therapeutic reasons.

[0022] As used herein, a pharma- ceutically acceptable salt is a salt with a pharma- ceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, stearic acid, benzenesulfonic acid or p-toluenesulfonic acid. Pharmaceutically acceptable bases include hydroxides of alkali metals (e.g., sodium or potassium) and alkaline earth metals (e.g., calcium or magnesium), and organic bases such as alkylamines, arylamines or heterocyclic amines.

[0023] The present invention is directed to a composition comprising nitroxoline or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of plexiform neurofibromas.

[0024] In an alternative embodiment, the present invention is directed to a composition comprising nitroxoline or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of plexiform neurofibroma, wherein nitroxoline is the only active agent in the composition. By only active agent, it is meant that the composition does not contain any other component that can be used in the treatment or prevention of plexiform neurofibroma. In an alternative embodiment, the composition further comprises a second active agent for treating plexiform neurofibroma, preferably the second active agent is selumetinib or a pharma- ceutically acceptable salt thereof.

[0025] In an alternative embodiment, the present invention is directed to a composition comprising nitroxoline, or a pharma- ceutically acceptable salt thereof, for use in combination with a second composition comprising selumetinib, or a pharma- ceutically acceptable salt thereof, wherein the two compositions are administered to a subject simultaneously, separately or sequentially.

[0026] As used herein, "separate" administration means that the drugs are administered as part of the same overall dosing regimen (which may include several days), but preferably on the same day. As used herein, "concurrently" means that the drugs are taken together or formulated as a single composition. As used herein, "sequentially" means that the drugs are administered at about the same time, preferably within about one hour of each other. Preferably, the drugs are administered simultaneously, i.e., taken together or formulated as a single composition. Most preferably, the drugs are formulated as a single composition.

[0027] The composition of the present invention may contain a pharma- ceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant any diluent or excipient, such as a filler or binder, that is compatible with other components of the composition and is not harmful to the recipient. The pharma- ceutically acceptable carrier can be selected according to standard pharmaceutical practice based on the desired route of administration.

[0028] In the present invention, the composition can be administered in various dosage forms. In one embodiment, the composition can be formulated in a form suitable for oral, rectal, parenteral, intranasal or transdermal administration, or for administration by inhalation or suppository.

[0029] The composition can be orally administered, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferably, the composition is formulated to be suitable for oral administration, for example, tablets and capsules. Tablets and capsules can be prepared using binders such as syrup, acacia, gelatin, sorbitol, tragacanth, cellulose, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, or silica, and surfactants such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as suspending agents such as sorbitol syrup, methylcellulose, sugar syrup, gelatin, carboxymethylcellulose, or edible fats, emulsifiers and surfactants such as lecithin or acacia, vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil, and preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). The liquid composition can be encapsulated, for example, in gelatin to provide a unit dosage form.

[0030] The compositions can also be administered parenterally, by subcutaneous, intravenous, intramuscular, intrasternal, transdermal or infusion techniques.

[0031] The composition can also be administered by inhalation.The advantage of inhalation is that it is delivered directly to areas with a rich blood supply, compared to many drugs taken by oral route.Therefore, absorption is very rapid, due to the enormous surface area and rich blood supply of the alveoli, and first-pass metabolism is avoided.

[0032] The invention also provides an inhalation device comprising a composition of the invention, typically a metered dose inhaler (MDI) that includes a pharma- ceutically acceptable chemical propellant to propel the medicament out of the inhaler.

[0033] The composition can also be administered by intranasal administration. The highly permeable tissue of the nasal cavity is highly receptive to drugs and absorbs them quickly and efficiently. Nasal drug delivery is less painful and invasive than injections, reducing patient anxiety. In this method, absorption is very fast and first-pass metabolism is usually avoided, thus reducing inter-patient variability. Furthermore, the present invention also provides an intranasal device comprising the composition according to the present invention.

[0034] The composition can also be administered by transdermal administration. For topical delivery, transdermal and transmucosal patches, creams, ointments, jellies, solutions or suspensions can be used. Thus, the present invention also provides a transdermal patch comprising the composition.

[0035] The composition may also be administered by sublingual administration. Accordingly, the present invention also provides a sublingual tablet comprising the composition.

[0036] The compositions may also be formulated with agents that reduce degradation of the substance by processes other than the patient's normal metabolism, such as antibacterial agents or inhibitors of protease enzymes that may be present in the patient, or in commensals or parasites living on or within the patient, and which can degrade the compound.

[0037] Liquid dispersions for oral administration may be syrups, emulsions, and suspensions.

[0038] Suspensions and emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharma- ceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol), and, if desired, an appropriate amount of lidocaine hydrochloride.

[0039] The solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.

[0040] In one embodiment of the invention, the composition is administered in an amount effective to treat or prevent plexiform neurofibromas. The effective amount will be apparent to one skilled in the art and will depend on many factors, including age, sex, and weight, and a physician will be able to determine the effective amount.

[0041] In a preferred embodiment, the composition contains 30 mg to 600 mg, preferably 50 mg to 500 mg, more preferably 100 mg to 400 mg, even more preferably 150 mg to 350 mg, and most preferably 200 mg to 300 mg of nitroxoline.

[0042] The compositions may be administered once daily, twice daily, three times daily, or four times daily.

[0043] In one embodiment of the present invention, the composition is administered at least once a day. Preferably, it is administered as a single daily dose. Preferably, the single daily dose is 90 mg to 1800 mg of nitroxoline, preferably 150 mg to 1500 mg, more preferably 300 mg to 1200 mg, even more preferably 450 mg to 1050 mg, and most preferably 600 mg to 900 mg.

[0044] In one embodiment of the invention, the composition is administered twice daily, preferably with each dose being between 45 mg and 900 mg of nitroxoline, preferably between 75 mg and 750 mg, more preferably between 150 mg and 600 mg, even more preferably between 225 mg and 525 mg, and most preferably between 300 mg and 450 mg.

[0045] In one embodiment of the invention, the composition is administered three times a day, preferably with each dose being 30 mg to 600 mg of nitroxoline, preferably 50 mg to 500 mg, more preferably 100 mg to 400 mg, even more preferably 150 mg to 350 mg, and most preferably 200 mg to 300 mg.

[0046] In one embodiment of the invention, the composition is administered four times a day, preferably with each dose being 15 mg to 500 mg of nitroxoline, preferably 50 mg to 400 mg, more preferably 100 mg to 300 mg, even more preferably 125 mg to 225 mg, and most preferably 150 mg to 200 mg.

[0047] Preferably, the dosing regimen is such that the total daily dose of nitroxoline does not exceed 1500 mg.

[0048] Suitably, the dose of nitroxoline may be 50 to 250 mg / kg, more preferably 60 to 200 mg / kg, even more preferably 80 to 170 mg / kg, for example 100 to 150 mg / kg.

[0049] Suitably, an effective amount of nitroxoline results in an intracellular concentration of 1-150 μM, preferably 10-100 μM, more preferably 25-50 μM.

[0050] Preferably, the composition comprising nitroxoline and the second composition comprising a second active agent, preferably selumetinib, are administered once a day. Preferably, the two compositions are administered simultaneously, i.e., nitroxoline and selumetinib are taken together. The compositions can also be administered sequentially, i.e., at about the same time, preferably within about one hour of each other.

[0051] In embodiments where the composition comprises selumetinib, or where the composition is used in combination with a second composition comprising selumetinib, suitably the composition comprising selumetinib comprises from 1 mg to 75 mg of selumetinib, preferably from 5 mg to 50 mg of selumetinib, more preferably from 10 mg to 35 mg of selumetinib, and most preferably from 15 mg to 30 mg of selumetinib.

[0052] Preferably, the effective amount of selumetinib administered to a subject is 1 mg / m 2 ~75mg / m 2, preferably selumetinib 5 mg / m 2 ~50mg / m 2 , more preferably selumetinib 10 mg / m 2 ~35mg / m 2 , most preferably selumetinib 15 mg / m 2 ~30mg / m 2 It is.

[0053] To treat or prevent plexiform neurofibromas, compositions containing nitroxoline are used in a chronic regimen, i.e., long-lasting, chronic treatment, preferably lasting for at least 1 month, preferably at least 2 months, for example at least 3 months.

[0054] The present invention also relates to a kit comprising (i) at least one dose of nitroxoline or a pharma- ceutically acceptable salt thereof, and optionally (ii) at least one dose of selumetinib or a pharma- ceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment or prevention of plexiform neurofibromas.

[0055] The present invention also relates to the use of nitroxoline or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment or prevention of plexiform neurofibromas. This embodiment of the invention may have any of the preferred features described above.

[0056] The present invention also relates to a method of treating or preventing plexiform neurofibromas, comprising administering to a patient a composition comprising nitroxoline or a pharma- ceutically acceptable salt thereof. This embodiment of the invention may have any of the preferred features described above. The method of administration may follow any of the routes described above.

[0057] For the avoidance of doubt, the present invention also encompasses pro-drugs which react in vivo to produce the compounds of the present invention.

[0058] Experimental Section Example 1 - In vitro drug testing with WT and NF1-deficient Schwann cells In this study, immortalized wild-type (WT) and NF1-deficient (Nf1 - / - ) Schwann cells (SCs) were utilized to examine the effectiveness of nitroxoline and its ability to decrease cell proliferation, increase apoptosis, and increase overall cell viability.

[0059] Nf1 - / - Consistent with their in vivo phenotype, SCs have increased survival and proliferation in vitro (Kim HA et al., Mol Cell Biol. 1997;17(2):862-72). In this study, WT (ipn02.3λ) and NF1 - / - (ipNF95.6) immortalized human SC line is used. Nitroxoline selectivity is confirmed by NF1 - / - cells and WT cells.

[0060] Cells were treated with serial dilutions of nitroxoline starting at 105 μM and incubated for 48 h. After the incubation period, proliferation, viability, and apoptosis assays were performed as described below. Cell proliferation was assessed using the CellTiter-Glo assay (Promega), which measures ATP consumption. - / - Cells were incubated at 37°C and 5% CO 2 Cells were plated in triplicate at a concentration of 10,000 cells / well in 96-well dishes in 100 μl of DMEM containing 1% glutamine, 10% FBS, 2% sodium bicarbonate, and 1% penicillin / streptomycin with or without nitroxoline for 48 hours in a humidified incubator. After incubation, 100 μl of CellTiterGlo reagent was added to each well. After 10 minutes, plates were read using a 96-well microplate luminometer. Cell apoptosis was assessed using the Caspase-Glo 3 / 7 kit (Promega). - / - Cells were incubated at 37°C and 5% CO 2Cells were plated in triplicate at a concentration of 10,000 cells / well in 96-well dishes in 100 μl of DMEM containing 1% glutamine, 10% FBS, 2% sodium bicarbonate, and 1% penicillin / streptomycin with or without nitroxoline for 48 hours in a humidified incubator. After incubation, 100 μl of Caspase-Glo 3 / 7 reagent was added to each well. After 10 minutes, the plates were read using a 96-well luminometer to measure caspase 3 / 7 activity.

[0061] result Nitroxoline inhibited cell proliferation and increased apoptosis in a dose-response manner, as shown in Figure 1. The antiproliferative effect was observed in WT and Nf1 - / - In Schwann cells, apoptosis was observed at concentrations above 1 μM. Induction of apoptosis was evident at concentrations above 3 μM in both SCs, but the magnitude of the increase was greater in Nf1 at concentrations above 10 μM. - / - It was significantly greater in SC.

[0062] Example 2 - In vivo drug testing in Nf1-KO mice The aim of this study was to evaluate the effect of nitroxoline in a mouse model of neurofibromatosis type 1, more specifically in a model that develops plexiform neurofibromas. This study is the same one used by AstraZeneca to approve selumetinib for pNF.

[0063] animal In this study, Postn-Cre of plexiform neurofibromas + Nf1 fl / fl A mouse model is used. Neurofibromas that develop in these mice faithfully recapitulate the human disease (Burks et al. 2019). At 4 months of age, when mice (male and female) had established plexiform neurofibromas, they were randomized into three treatment groups and gavaged with nitroxoline 120 mg / kg QD, 120 mg / kg BD, or vehicle (10% DMSO in 90% corn oil). Mice were treated for 12 weeks and then sacrificed. Mice were perfused and fixed in 10% neutral buffered formalin.

[0064] Nerve volume Whole bodies were decalcified in 5% formic acid, the spinal cord proximal nerve tree was dissected, and nerve width (including tumors formed along it) across four nerves per mouse was measured with a caliper (shown in Figure 3). Nerve volume was then calculated using the following spheroid calculation: 0.52 × (width)2w length.

[0065] Number of tumors To quantify tumor numbers, nerves were processed into paraffin blocks, sectioned, and stained for collagen using Masson's Trichrome stain. Tumor numbers were scored from these slides by a clinician.

[0066] statistical analysis Graphs and statistical analyses of the data were generated using GraphPad Prism (Ver9).

[0067] result At both dosing schedules (120 mg / kg QD and 120 mg / kg BD), mice treated with nitroxoline had smaller proximal nerve volumes compared to vehicle-treated control mice (Figure 2). Because plexiform tumors form along the proximal nerve, the reduction in proximal nerve volume can be interpreted as a reduction in the size of the plexiform tumors. In addition to the reduction in total nerve volume, a reduction in the number of tumors along the nerve was observed in nitroxoline-treated mice compared to vehicle controls (Figure 2).

[0068] conclusion Nitroxoline inhibits Nf1 in vitro - / - Inhibits cell proliferation and increases apoptosis of Schwann cells. In a mouse model of plexiform neurofibroma, nitroxoline-treated mice had smaller proximal nerve volumes and fewer tumors compared to vehicle control animals. Therefore, nitroxoline is expected to reduce, treat, and prevent plexiform neurofibroma.

[0069] References Burks CA,Rhodes SD,Bessler WK,Chen S,Smith A,Gehlhausen JR,Hawley ET,Jiang L,Li X,Yuan J,Lu Q,Jacobsen M,Sandusky GE,Jones DR,Clapp DW,Blakeley JO.Ketotifen Modulates Mast Cell Chemotaxis to Kit-Ligand,but Does Not Impact Mast Cell Numbers,Degranulation,or Tumor Behavior in Neurofibromas of Nf1-Deficient Mice.Mol Cancer Ther.2019 Dec;18(12):2321-2330。

Claims

1. A composition comprising nitroxoline or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of plexiform neurofibroma.

2. 10. The composition for use according to claim 1 in the treatment of plexiform neurofibromas.

3. The composition for use according to claim 1, wherein the subject of said treatment or prevention has neurofibromatosis type I.

4. The composition for use according to claim 1, wherein the subject of said treatment or prevention is a human.

5. 2. The composition for use according to claim 1, wherein the composition comprises 30 mg to 600 mg, preferably 50 mg to 500 mg, more preferably 100 mg to 400 mg, even more preferably 150 mg to 350 mg, and most preferably 200 mg to 300 mg of nitroxoline.

6. 2. The composition for use according to claim 1, wherein the administration is carried out in two doses per day.

7. 7. The composition for use according to claim 6, wherein the dose is between 45 mg and 900 mg of nitroxoline, preferably between 75 mg and 750 mg, more preferably between 150 mg and 600 mg, even more preferably between 225 mg and 525 mg, and most preferably between 300 mg and 450 mg.

8. 2. The composition for use according to claim 1, wherein the administration is carried out in three doses per day.

9. 9. The composition for use according to claim 8, wherein the dose is between 30 mg and 600 mg of nitroxoline, preferably between 50 mg and 500 mg, more preferably between 100 mg and 400 mg, even more preferably between 150 mg and 350 mg, and most preferably between 200 mg and 300 mg.

10. 2. The composition for use according to claim 1, wherein the administration is carried out in four doses per day.

11. 11. The composition for use according to claim 10, wherein the dose is 15 mg to 500 mg of nitroxoline, preferably 50 mg to 400 mg, more preferably 100 mg to 300 mg, even more preferably 125 mg to 225 mg, and most preferably 150 mg to 200 mg.

12. 10. The composition for use according to claim 1, which is administered orally or intravenously.

13. 10. The composition for use according to claim 1, which is administered parenterally, transdermally, sublingually, rectally or by inhalation administration.

14. 10. The composition for use of claim 1, wherein nitroxoline or a pharmaceutically acceptable salt is the only active agent in the composition.

15. 2. The composition for use according to claim 1, wherein the composition further comprises selumetinib or a pharmaceutically acceptable salt thereof.

16. 2. The composition for use according to claim 1, which is for use in combination with a second composition comprising selumetinib or a pharmaceutically acceptable salt thereof, wherein the two compositions are administered to a subject simultaneously, separately or sequentially.

17. The composition for use according to claim 15, wherein the amount of selumetinib is between 1 mg and 75 mg, preferably between 5 mg and 50 mg, more preferably between 10 mg and 35 mg, and most preferably between 15 mg and 30 mg.

18. 1. Use of nitroxoline or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment or prevention of plexiform neurofibroma.

19. Use according to claim 18, with any of the additional features according to claims 2 to 17.

20. A method for treating or preventing plexiform neurofibromas, comprising administering to a patient a composition comprising nitroxoline or a pharmaceutically acceptable salt thereof.

21. A method according to claim 20, having any of the additional features of claims 2 to 17.

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