(19)
(11)EP 3 036 007 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
09.10.2019 Bulletin 2019/41

(21)Application number: 14789436.4

(22)Date of filing:  22.08.2014
(51)International Patent Classification (IPC): 
A61K 31/165(2006.01)
A61K 9/08(2006.01)
A61K 9/48(2006.01)
A61P 35/00(2006.01)
A61K 9/00(2006.01)
A61K 9/10(2006.01)
A61K 9/107(2006.01)
(86)International application number:
PCT/US2014/052209
(87)International publication number:
WO 2015/027121 (26.02.2015 Gazette  2015/08)

(54)

CANCER TREATMENT

KREBSBEHANDLUNG

TRAITEMENT CONTRE LE CANCER


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 22.08.2013 US 201361869039 P

(43)Date of publication of application:
29.06.2016 Bulletin 2016/26

(73)Proprietor: Vanda Pharmaceuticals Inc.
Washington, DC 20037 (US)

(72)Inventors:
  • POLYMEROPOULOS, Mihael, H.
    Potomac, MD 20854 (US)
  • LICAMELE, Louis, William
    Potomac, MD 20854 (US)
  • LAVEDAN, Christian
    Potomac, MD 20854 (US)

(74)Representative: Appleyard Lees IP LLP 
15 Clare Road
Halifax HX1 2HY
Halifax HX1 2HY (GB)


(56)References cited: : 
EP-A2- 0 196 415
WO-A1-02/060430
  
  • LIMEI LIU ET AL: "Trichostatin A Affects Breast Cancer Cell Viability by Modulating Fhit and Survivin Expression", BIOMEDICAL ENGINEERING AND BIOTECHNOLOGY (ICBEB), 2012 INTERNATIONAL CONFERENCE ON, IEEE, 28 May 2012 (2012-05-28), pages 1133-1135, XP032207903, DOI: 10.1109/ICBEB.2012.457 ISBN: 978-1-4577-1987-5
  • VIGUSHIN: "Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo", CLINICAL CANCER RESEARCH, 1 January 2001 (2001-01-01), XP055152712,
  • JUNG-HYUN PARK ET AL: "Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase", JOURNAL OF MOLECULAR MEDICINE, SPRINGER, BERLIN, DE, vol. 86, no. 1, 13 September 2007 (2007-09-13), pages 117-128, XP019576405, ISSN: 1432-1440
  • X WANG ET AL: "Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation", ONCOGENE, vol. 25, no. 54, 22 May 2006 (2006-05-22), pages 7148-7158, XP055152985, ISSN: 0950-9232, DOI: 10.1038/sj.onc.1209707
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

BACKGROUND



[0001] Histone deacetylase (HDAC) inhibitors have been investigated for their use in cancer therapies due to their ability to inhibit tumor cell growth with comparatively little toxicity. Known HDAC inhibitors include, for example, rocilinostat (ACY-1215), Zolinza (vorinostat), abexinostat hydrochloride (PCI-24781), suberoylanilide hydroxamic acid (SAHA), valporic acid (VPA), Pracinostat (SB939), PCI-24781 (CRA-024781), JNJ-26481585, Mocetinostat (MGCD0103, MG0103), Droxinostat, MC1568, Givinostat (ITF2357), Tubastatin A HCI, PCI-34051, Tacedinaline (CI994), and Panobiostat (LBH589, NVP-LBH589).

[0002] Aurora Kinase A (AURKA) is one member of a serine and threonine kinase family known to be important in maintaining normal mitotic chromosomal segregation. Its protein localizes in the centrosomes of interphase cells and in the spindle of mitotic cells. AURKA overexpression has been linked with carcinogenesis in humans and has been detected in tumors of the breast, gastric tissues, colorectal tissue, bladder, pancreas, ovaries, prostate, and lung. It is possible, however, for any cancer to overexpress AURKA, which may be determined, for example, by testing a tumor for AURKA overexpression. Inhibition of AURKA expression has been shown to reduce cell invasion in vivo. As such, AURKA, too, is a cancer treatment target, typically through small molecule inhibition. Known AURKA inhibitors include, for example, VE465, tozasertib (VX-680), MK-0457, MK-5108, Alisertib (MLN8237).

[0003] Due to the efficacy of HDAC inhibitors and AURKA inhibitors in blocking cancer progression on their own, studies have evaluated the effect of their combined administration in non-human cancer models. For example, Li et al. found that co-treatment with VPA and VE465 induced more apoptosis than either compound did alone. Similarly, Okabe et al. found a synergistic inhibitory effect on the proliferation of cancer cells through the administration of either vorinostat or pracinostat in combination with tozasertib. The studies leading to the discovery of the present invention were undertaken since even though the dual HDAC and AURKA blocking effect was desirable in the treatment of cancer, no single entity is generally known to have this dual effect.

SUMMARY



[0004] The invention is defined in the appended claims.

[0005] One embodiment there is provided a method of treating cancer in an individual, the method comprising: administering to the individual an effective amount of trichostatin A (TSA).

[0006] Another embodiment there is provided a pharmaceutical composition comprising: trichostatin A (TSA) as a sole or primary aurora kinase A (AURKA) inhibitor; and a pharmaceutically-acceptable excipient or carrier.

[0007] In another embodiment, there is provided a method of treating a cancer in an individual, the method comprising: determining, from a tumor sample obtained from the individual's body, a level of aurora kinase A (AURKA) expression; and in the case that the level of AURKA expression is indicative of overexpression, administering to the individual an effective amount of trichostatin A (TSA).

[0008] In still other embodiments, treatment with TSA is combined with one or more other cancer treatments. Such other treatments may include, for example, small molecule AURKA inhibition. Such a combined treatment may, in some cases, decrease the AURKA level to near zero.

DETAILED DESCRIPTION



[0009] Trichostatin A (TSA or 7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide), is an antifungal antibiotic and a known class I and II HDAC inhibitor. The structure of TSA is shown in Formula I below.



[0010] Applicants have surprisingly found that TSA, although previously known as an HDAC inhibitor, is also capable of inhibiting AURKA expression. As such, TSA may be used as the primary or sole AURKA inhibitor in the treatment of cancers. Cancers that may be treated according to embodiments including, for example, breast cancer, gastric cancer, colon cancer, rectal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, hematological cancer, skin cancer, and malignancies.

[0011] A human retinal pigment epithelial cell line was treated with trichostatin or vehicle for 24 hours and gene expression for 22,238 probe sets covering 12,490 genes was generated using an Affymetrix instrument. The effect of trichostatin A on AURKA expression is shown below in Table 1, and indicates a clear more than ten-fold downregulation of AURKA expression.
Table 1
InstanceIDProbeRankFold expression changeGeneNameGene
10005532 208079_s_at 22253 -20.0837023 aurora kinase A AURKA
10005533 208079_s_at 22245 -18.95510102 aurora kinase A AURKA
10005533 204092_s_at 22238 -17.32256882 aurora kinase A AURKA
10005532 204092_s_at 22227 -15.79825298 aurora kinase A AURKA
10005542 204092_s_at 22222 -14.33801143 aurora kinase A AURKA
10005542 208079_s_at 22221 -14.19814583 aurora kinase A AURKA


[0012] These results support the use of TSA in the treatment of cancer. For example, an individual may be treated for cancer by administering to the individual an effective amount of TSA, wherein the effective amount is an amount sufficient to inhibit expression of AURKA in the individual. Such an amount may also be sufficient to inhibit HDAC activity in the individual. In some embodiments, the effective amount is between about 0.1 mg/kg/day and about 10 mg/kg/day, e.g., between about 0.5 mg/kg/day and about 5 mg/kg/day.

[0013] In some embodiments, treating the individual may further comprise determining, from a tumor sample obtained from the individual's body, a level of AURKA expression. Such determining may include any known or later-developed method or technique, including, for example, quantitative antigen-antibody interactions, the use of labeled nucleotide probes, etc.

[0014] TSA may be administered to the individual to be treated in the form of a pharmaceutical composition. Pharmaceutical compositions to be used according to various embodiments of comprise a therapeutically effective amount of TSA or an active metabolite of TSA, or a pharmaceutically acceptable salt or other form (e.g., a solvate) thereof, together with one or more pharmaceutically acceptable excipients or carriers. The phrase "pharmaceutical composition" refers to a composition suitable for administration in medical use. It should be appreciated that the determinations of proper dosage forms, dosage amounts, and routes of administration for a particular patient are within the level of ordinary skill in the pharmaceutical and medical arts.

[0015] Administration may be oral but other routes of administration may also be employed, e.g., parenteral, nasal, buccal, transdermal, sublingual, intramuscular, intravenous, rectal, vaginal, etc. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is admixed with at least one inert pharmaceutically-acceptable excipient such as (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, drages, capsules, pills, and granules also can be prepared with coatings and shells, such as enteric coatings and others well known in the art. The solid dosage form also may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Such solid dosage forms may generally contain from 1% to 95% (w/w) of the active compound. In certain embodiments, the active compound ranges from 5% to 70% (w/w).

[0016] Solid compositions for oral administration can be formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired effect over the course of a treatment period, in association with the required pharmaceutical carrier. TSA can be formulated, e.g., in a unit dosage form that is a capsule having 1-500 mg of active in addition to excipients.

[0017] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound or composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances. Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0018] In some embodiments, TSA is provided in a liquid form and administered to an individual intravenously.

[0019] While this invention has been described above, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art or are otherwise intended to be embraced. Accordingly, the embodiments as set forth above are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention as defined in the following claims.


Claims

1. Trichostatin A (TSA) for use in the treatment of cancer in an individual, the dosage regime comprising:

determining, from a tumor sample obtained from the individual's body, a level of aurora kinase A (AURKA) expression; and

in the case that the level of AURKA expression is indicative of overexpression, administering to the individual trichostatin A (TSA) to decrease the AURKA level in an individual.


 
2. Trichostatin A for use according to claim 1, wherein the TSA further inhibits histone deacetylase (HDAC) activity.
 
3. Trichostatin A for use according to claim 1, wherein the effective amount is between about 0.1 mg/kg/day and about 10 mg/kg/day or between about 0.5 mg/kg/day and about 5 mg/kg/day.
 
4. Trichostatin A for use according to claim 1, wherein TSA is the only AURKA inhibitor administered to the individual.
 
5. Trichostatin A for use according to claim 1, wherein the cancer includes at least one cancer selected from a group consisting of: breast cancer, gastric cancer, colon cancer, rectal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, hematological cancer, skin cancer, and malignancies.
 
6. Trichostatin A for use according to claim 1, wherein the TSA is administered orally or intravenously.
 


Ansprüche

1. Trichostatin A (TSA) zur Verwendung bei der Behandlung einer Krebserkrankung bei einem Individuum, wobei das Dosierungsregime Folgendes umfasst:

Bestimmen, anhand einer dem Körper des Individuums entnommenen Tumorprobe, eines Niveaus der Expression von Aurorakinase A (AURKA); und

falls das Niveau der AURKA-Expression eine Überexpression anzeigt, Verabreichen von Trichostatin A (TSA) an das Individuum, so dass der AURKA-Spiegel bei einem Individuum herabgesetzt wird.


 
2. Trichostatin A zur Verwendung nach Anspruch 1, wobei das TSA ferner Histon-Deacetylase(HDAC)-Aktivität hemmt.
 
3. Trichostatin A zur Verwendung nach Anspruch 1, wobei die wirksame Menge zwischen etwa 0,1 mg/kg/Tag und etwa 10 mg/kg/Tag oder zwischen etwa 0,5 mg/kg/Tag und etwa 5 mg/kg/Tag liegt.
 
4. Trichostatin A zur Verwendung nach Anspruch 1, wobei TSA der einzige AURKA-Inhibitor ist, der dem Individuum verabreicht wird.
 
5. Trichostatin A zur Verwendung nach Anspruch 1, wobei die Krebserkrankung wenigstens einen Krebs ausgewählt aus der Gruppe bestehend aus Brustkrebs, Magenkrebs, Kolonkarzinom, Rektalkarzinom, Blasenkrebs, Bauchspeicheldrüsenkrebs, Eierstockkrebs, Prostatakrebs, Lungenkrebs, hämatologischem Krebs, Hautkrebs und Malignomen umfasst.
 
6. Trichostatin A zur Verwendung nach Anspruch 1, wobei das TSA oral oder intravenös verabreicht wird.
 


Revendications

1. Trichostatine A (TSA) pour une utilisation dans le traitement du cancer chez une personne, le régime de dosage comprenant :

la détermination, à partir d'un échantillon de tumeur obtenu du corps de la personne, d'un niveau d'expression de l'aurora kinase A (AURKA) ; et

au cas où le niveau d'expression de l'AURKA est indicatif d'une surexpression, l'administration de trichostatine A (TSA) à la personne afin de diminuer le niveau de l'AURKA chez une personne.


 
2. Trichostatine A pour une utilisation selon la revendication 1, la TSA inhibant en outre l'activité de l'histone désacétylase (HDAC).
 
3. Trichostatine A pour une utilisation selon la revendication 1, la quantité efficace se situant entre environ 0,1 mg/kg/jour et environ 10 mg/kg/jour ou entre environ 0,5 mg/kg/jour et environ 5 mg/kg/jour.
 
4. Trichostatine A pour une utilisation selon la revendication 1, la TSA étant le seul inhibiteur de l'AURKA à être administré à la personne.
 
5. Trichostatine A pour une utilisation selon la revendication 1, le cancer incluant au moins un cancer choisi dans le groupe constitué par : le cancer du sein, le cancer gastrique, le cancer du côlon, le cancer rectal, le cancer de la vessie, le cancer du pancréas, le cancer des ovaires, le cancer de la prostate, le cancer du poumon, le cancer hématologique, le cancer de la peau et les tumeurs malignes.
 
6. Trichostatine A pour une utilisation selon la revendication 1, la TSA étant administrée par voie orale ou par voie intraveineuse.