U.S. patent application number 14/912077 was filed with the patent office on 2016-07-14 for cancer treatment.
The applicant listed for this patent is Vanda Pharmaceuticals, Inc.. Invention is credited to Christian Lavedan, Louis William Licamele, Mihael H. Polymeropoulos.
Application Number | 20160199323 14/912077 |
Document ID | / |
Family ID | 51794948 |
Filed Date | 2016-07-14 |
United States Patent
Application |
20160199323 |
Kind Code |
A1 |
Polymeropoulos; Mihael H. ;
et al. |
July 14, 2016 |
CANCER TREATMENT
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).
Inventors: |
Polymeropoulos; Mihael H.;
(Potomac, MD) ; Licamele; Louis William; (Potomac,
MD) ; Lavedan; Christian; (Potomac, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vanda Pharmaceuticals, Inc. |
Washington |
DC |
US |
|
|
Family ID: |
51794948 |
Appl. No.: |
14/912077 |
Filed: |
August 22, 2014 |
PCT Filed: |
August 22, 2014 |
PCT NO: |
PCT/US2014/052209 |
371 Date: |
February 12, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61869039 |
Aug 22, 2013 |
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|
Current U.S.
Class: |
514/575 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61P 35/00 20180101; A61K 9/0095 20130101; C07K 16/2866 20130101;
A61P 35/02 20180101; A61P 43/00 20180101; C07K 2317/76 20130101;
C07K 2317/21 20130101; A61K 9/08 20130101; A61K 2039/505 20130101;
A61K 9/48 20130101; A61K 9/10 20130101; A61K 9/0053 20130101; C07K
2317/565 20130101; A61K 9/107 20130101; A61K 38/00 20130101; A61K
31/165 20130101 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of treating cancer in an individual, the method
comprising: administering to the individual an effective amount of
trichostatin A (TSA).
2. The method of claim 1, wherein the effective amount is an amount
sufficient to decrease an aurora kinase A (AURKA) level in the
individual.
3. The method of claim 1, wherein the effective amount is an amount
sufficient to inhibit histone deacetylase (HDAC) activity and
decrease an aurora kinase A (AURKA) level in the individual.
4. The method of claim 1, wherein the effective amount is between
about 0.1 mg/kg/day and about 10 mg/kg/day.
5. The method of claim 4, wherein the effective amount is between
about 0.5 mg/kg/day and about 5 mg/kg/day.
6. The method of claim 5, wherein TSA is the only AURKA inhibitor
administered to the individual.
7. The method 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, hematological
cancer, skin cancer, and malignancies.
8. The method of claim 1, wherein administering includes orally
administering.
9. The method of claim 1, wherein administering includes
intravenously administering.
10. 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).
11. The method of claim 10, wherein the effective amount is an
amount sufficient to decrease an aurora kinase A (AURKA) level in
the individual.
12. The method of claim 10, wherein the effective amount is an
amount sufficient to inhibit histone deacetylase (HDAC) activity
and decrease an aurora kinase A (AURKA) level in the
individual.
13. The method of claim 10, wherein the effective amount is between
about 0.1 mg/kg/day and about 10 mg/kg/day.
14. The method of claim 13, wherein the effective amount is between
about 0.5 mg/kg/day and about 5 mg/kg/day.
15. The method of claim 10, wherein TSA is the only AURKA inhibitor
administered to the individual.
16. The method of claim 10, 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.
17. The method of claim 10, wherein administering includes orally
administering.
18. The method of claim 10, wherein administering includes
intravenously administering.
19. A pharmaceutical composition comprising: trichostatin A (TSA)
as a sole or primary aurora kinase A (AURKA) inhibitor; and a
pharmaceutically-acceptable excipient or carrier.
20. The pharmaceutical composition of claim 19 formulated for oral
administration.
21. The pharmaceutical composition of claim 19 formulated for
intravenous administration.
22. The pharmaceutical composition of claim 19, comprising TSA in
an amount between about 1 mg and about 500 mg.
23. The pharmaceutical composition of claim 22, wherein the amount
of TSA is equivalent to a dose between about 0.1 mg/kg/day and
about 10 mg/kg/day.
24. The pharmaceutical composition of claim 23, wherein the amount
of TSA is equivalent to a dose between about 0.5 mg/kg/day and
about 5 mg/kg/day.
25. The pharmaceutical composition of claim 22, wherein the amount
of TSA is effective to inhibit histone deacetylase (HDAC) activity.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of co-pending U.S.
Provisional Patent Application Ser. No. 61/869,039, filed 22 Aug.
2013, which is hereby incorporated herein.
BACKGROUND
[0002] 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 HCl, PCI-34051, Tacedinaline (CI994), and
Panobiostat (LBH589, NVP-LBH589).
[0003] 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).
[0004] 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
[0005] 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).
[0006] 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.
[0007] In another embodiment, the invention provides 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 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 combined treatment may, in some cases, decrease
the
DETAILED DESCRIPTION
[0009] Trichostatin A (TSA or
7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienami-
de), is an antifungal antibiotic and a known class I and II HDAC
inhibitor. The structure of TSA is shown in Formula I below.
##STR00001##
[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 of the
invention include, 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-US-00001 TABLE 1 InstanceID Probe Rank Fold expression change
GeneName Gene 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 of
the invention, 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 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) 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 of the invention, TSA is provided in a
liquid form and administered to an individual intravenously.
[0019] While this invention has been described in conjunction with
the specific embodiments outlined 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 of the invention 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. All patents, patent
application, scientific articles and other published documents
cited herein are hereby incorporated in their entirety for the
substance of their disclosures.
* * * * *