NZ716668B2 - Cancer treatment - Google Patents
Cancer treatment Download PDFInfo
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- NZ716668B2 NZ716668B2 NZ716668A NZ71666814A NZ716668B2 NZ 716668 B2 NZ716668 B2 NZ 716668B2 NZ 716668 A NZ716668 A NZ 716668A NZ 71666814 A NZ71666814 A NZ 71666814A NZ 716668 B2 NZ716668 B2 NZ 716668B2
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- cancer
- aurka
- tsa
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Abstract
The invention relates generally to the treatment of cancer. One embodiment of the invention provides a method of treating cancer in an individual, the method comprising: administering to the individual an effective amount of trichostatin A (TSA).
Description
CANCER TREATMENT
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of co-pending US Provisional Patent Application
Serial No. 61/869,039, filed 22 August 2013, which is hereby incorporated herein.
BACKGROUND
Histone deacetylase (HDAC) tors have been igated for their use in cancer
therapies due to their ability to inhibit tumor cell growth with atively little toxicity.
Known HDAC inhibitors include, for example, rocilinostat (ACY-1215), Zolinza (vorinostat),
abexinostat hydrochloride (PCI-24781), suberoylanilide amic acid , ic acid
(VPA), Pracinostat ), PCI-24781 (CRA-024781), JNJ-26481585, Mocetinostat
(MGCD0103, M60103), Droxinostat, MC1568, Givinostat (ITF2357), Tubastatin A HCl, PCI-
34051, Tacedinaline (CI994), and ostat (LBH589, NVP-LBH589).
Aurora Kinase A (AURKA) is one member of a serine and threonine kinase family
known to be important in maintaining normal mitotic chromosomal segregation. |ts 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 , 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 le inhibition. Known AURKA inhibitors
include, for example, VE465, rtib (VX-680), MK-0457, MK-5108, Alisertib (MLN8237).
Due to the efficacy of HDAC inhibitors and AURKA inhibitors in blocking cancer
progression on their own, studies have evaluated the effect r 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. rly, 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 aken since even though the dual HDAC and
AURKA ng effect was desirable in the ent of cancer, no single entity is generally
known to have this dual effect.
SUMMARY
One embodiment ofthe invention provides a method oftreating cancer in an individual,
the method comprising: administering to the individual an effective amount of trichostatin A
(TSA).
Another embodiment of the invention provides a pharmaceutical composition
comprising: trichostatin A (TSA) as a sole or primary aurora kinase A (AURKA) inhibitor; and a
pharmaceutically-acceptable excipient or carrier.
In another embodiment, the invention provides a method oftreating a cancer in an
individual, the method sing: 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
ive amount of trichostatin A (TSA).
In still other ments of the invention, 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 ed treatment may, in some cases, decrease the
AURKA level to near zero.
DETAILED DESCRIPTION
Trichostatin A (TSA or 7-[4-(dimethylamino)phenyl]—N-hydroxy-4,6-dimethyl
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.
Formula I
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
y or sole AURKA inhibitor in the treatment of cancers. Cancers that may be treated
ing to embodiments of the invention e, for example, breast cancer, c
cancer, colon cancer, rectal cancer, bladder cancer, pancreatic cancer, ovarian cancer,
prostate cancer, lung cancer, hematological cancer, skin cancer, and malignancies.
A human retinal pigment epithelial cell line was treated with statin or vehicle for
24 hours and gene sion 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
m—MM
10005532 204092_s_at 22227 -15.79825298 AURKA
10005542 204092_s_at 22222 -14.33801143 AURKA
42 208079_s_at 22221 -14.19814583 AURKA
These results support the use of TSA in the treatment of cancer. For example, an
dual 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 t HDAC activity in the
individual. In some embodiments of the invention, the effective amount is between about
0.1 mg/kg/day and about 10 day, e.g., between about 0.5 mg/kg/day and about 5
mg/kg/dav-
In some embodiments, treating the individual may further comprise determining, from
a tumor sample obtained from the dual’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 d nucleotide probes,
etc.
TSA may be administered to the dual to be d in the form of a pharmaceutical
composition. Pharmaceutical compositions to be used according to various embodiments of
the invention 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) f, 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.
Administration may be oral but other routes of administration may also be employed,
e.g., parenteral, nasal, buccal, transdermal, sublingual, uscular, intravenous, rectal,
vaginal, etc. Solid dosage forms for oral stration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the compound is admixed with at least
one inert ceutically-acceptable excipient such as (a) s or extenders, as for
example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for
example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, e, and
acacia, (c) humectants, as for e, glycerol, (d) disintegrating agents, as for example,
agar-agar, m carbonate, potato or tapioca starch, alginic acid, certain complex silicates,
and sodium carbonate, (e) solution retarders, as for example in, (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 s, 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, , capsules, pills, and granules also can be prepared with gs 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 ofthe intestinal tract in a delayed manner.
Examples of embedding compositions which can be used are polymeric nces 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).
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 y dosages for human
subjects and other s, each unit containing a predetermined quantity of active
ingredient calculated to e 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.
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 ts, solubilizing agents and emulsifiers, as for example, ethyl
alcohol, isopropyl l, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propyleneglycol, 1,3-butyleneglycol, ylformamide, oils, in particular, cottonseed oil,
groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, ydrofurfuryl
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 , sweetening, flavoring, and perfuming agents.
In some embodiments of the invention, TSA is provided in a liquid form and
administered to an individual enously.
While this invention has been described in conjunction with the specific embodiments
outlined above, it is evident that many alternatives, cations and variations will be
apparent to those skilled in the art or are otherwise ed to be embraced. Accordingly,
the embodiments of the invention as set forth above are intended to be illustrative, not
ng. Various changes may be made without departing from the spirit and scope of the
ion as defined in the following claims. All patents, patent application, scientific articles
and other published documents cited herein are hereby incorporated in their entirety for the
substance of their disclosures.
Claims (6)
1. Use of statin A (TSA) in the manufacture of a medicament for the treatment of a cancer in a human, the ent comprising: determination, from a tumor sample obtained from the human’s body, of a level of aurora kinase A (AURKA) expression; and in the case that the level of AURKA expression is indicative of overexpression, administration of an amount of TSA to the human to decrease the AURKA level in the human.
2. The use of claim 1, wherein the TSA r inhibits histone ylase (HDAC) activity.
3. The use of claim 1, wherein the amount of TSA to decrease the AURKA level in the human 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. The use of claim 1, wherein TSA is the only AURKA inhibitor administered to the human.
5. The use of 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, logical cancer, skin cancer, and malignancies.
6. The use of claim 1, wherein the stration of TSA is oral or intravenous.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361869039P | 2013-08-22 | 2013-08-22 | |
US61/869,039 | 2013-08-22 | ||
PCT/US2014/052209 WO2015027121A2 (en) | 2013-08-22 | 2014-08-22 | Cancer treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ716668A NZ716668A (en) | 2021-02-26 |
NZ716668B2 true NZ716668B2 (en) | 2021-05-27 |
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