U.S. patent application number 15/979287 was filed with the patent office on 2018-09-13 for multiple myeloma 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 | 20180256521 15/979287 |
Document ID | / |
Family ID | 51492478 |
Filed Date | 2018-09-13 |
United States Patent
Application |
20180256521 |
Kind Code |
A1 |
Polymeropoulos; Mihael H. ;
et al. |
September 13, 2018 |
MULTIPLE MYELOMA TREATMENT
Abstract
The invention relates generally to the treatment of multiple
myeloma. One embodiment of the invention provides a method of
treating multiple myeloma (MM) 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: |
51492478 |
Appl. No.: |
15/979287 |
Filed: |
May 14, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14912078 |
Feb 12, 2016 |
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PCT/US2014/052216 |
Aug 22, 2014 |
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15979287 |
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61869039 |
Aug 22, 2013 |
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61870747 |
Aug 27, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61P 35/00 20180101; G01N 2800/52 20130101; A61K 31/165 20130101;
A61K 9/0053 20130101; G01N 33/5743 20130101; G01N 2333/4739
20130101 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of treating multiple myeloma (MM) 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 expression of at least one gene in the
individual, the at least one gene being selected from a group
consisting of: CCNB1, AURKB, CDC2, BIRC5, KIF11, KIF2C, TOP2A,
ASPM, CKS1B, and WEE1.
3. The method of claim 2, wherein the effective amount is an amount
sufficient to decrease expression of either or both of CCNB1 and
AURKB in the individual.
4. The method of claim 2, wherein the effective amount is an amount
sufficient to decrease expression of either or both of CKS1B and
WEE1.
5. The method of claim 2, wherein the effective amount is an amount
sufficient to decrease expression of each of CCNB1, AURKB, CDC2,
BIRC5, KIF11, KIF2C, TOP2A, ASPM, CKS1B, and WEE1.
6. The method of claim 1, wherein the effective amount is between
about 0.01 mg/kg/day and about 100 mg/kg/day.
7. The method of claim 1, wherein the effective amount is between
about 0.1 mg/kg/day and about 10 mg/kg/day.
8. The method of claim 7, wherein the effective amount is between
about 0.5 mg/kg/day and about 5 mg/kg/day.
9. The method of claim 1, wherein administering includes orally
administering.
10. The method of claim 1, wherein administering includes
intravenously administering.
11. A method of treating multiple myeloma (MM) in an individual,
the method comprising: determining, from a biological sample
obtained from the individual's body, a level of expression of one
or more gene in the individual, the one or more gene selected from
a group consisting of: CCNB1, AURKB, CDC2, BIRC5, KIF11, KIF2C,
TOP2A, ASPM, CKS1B, and WEE1; and in the case that the level of
expression of the one or more gene is indicative of overexpression,
administering to the individual an effective amount of trichostatin
A (TSA).
12. The method of claim 11, wherein the effective amount is an
amount sufficient to decrease expression of at least one gene in
the individual, the at least one gene being selected from a group
consisting of: CCNB1, AURKB, CDC2, BIRC5, KIF11, KIF2C, TOP2A,
ASPM, CKS1B, and WEE1.
13. The method of claim 12, wherein the effective amount is an
amount sufficient to decrease expression of either or both of CCNB1
and AURKB in the individual.
14. The method of claim 12, wherein the effective amount is an
amount sufficient to decrease expression of either or both of CKS1B
and WEE1.
15. The method of claim 12, wherein the effective amount is an
amount sufficient to decrease expression of each of CCNB1, AURKB,
CDC2, BIRC5, KIF11, KIF2C, TOP2A, ASPM, CKS1B, and WEE1.
16. The method of claim 11, wherein the effective amount is between
about 0.01 mg/kg/day and about 100 mg/kg/day.
17. The method of claim 16, wherein the effective amount is between
about 0.1 mg/kg/day and about 10 mg/kg/day.
18. The method of claim 17, wherein the effective amount is between
about 0.5 mg/kg/day and about 5 mg/kg/day.
19. The method of claim 11, wherein administering includes orally
administering.
20. The method of claim 11, wherein administering includes
intravenously administering.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of co-pending
U.S. patent application Ser. No. 14/912,078, filed 12 Feb. 2016,
which is the US National Phase of PCT/US14/52216, filed 22 Aug.
2014, which claims priority to then-co-pending US Provisional
Patent Application Ser. No. 61/869,039, filed 22 Aug. 2013 and
61/870,747, filed 27 Aug. 2013, each of which is incorporated
herein.
BACKGROUND
[0002] Multiple myeloma (MM), sometimes referred to as plasma cell
myeloma, is a multifocal plasma cell cancer of the osseous system,
generally affecting elderly individuals. Most individuals are
symptomatic when diagnosed, with diagnosis typically made by one or
more of serum protein electrophoresis, serum free kappa/lambda
light chain assay, urine protein electrophoresis (99% of patients
with MM exhibit increased levels of one of the immunoglobulin (Ig)
classes in the blood and/or light chains in the urine), bone marrow
examination, or X-ray analysis. Although MM generally responds to
chemotherapy, recurrence is common, since such treatment does not
target cancer stem cells.
[0003] Nara et al. have recently identified a number of candidate
genes for targeting MM tumor-initiating subpopulation (SP) cells,
i.e., cancer stem cells. These include a number of genes coding for
proteins associated with cell cycle and mitosis, all of which were
found to be upregulated in MM cells. These include cyclin B1
(CCNB1), cell division cycle 2 (CDC2), baculoviral IAP
repeat-containing 5 (BIRC5), abnormal spindle homolog,
microcephaly-associated (ASPM), topoisomerase (DNA) II alpha 170
kDa (TOP2A), aurora kinase B (AURKB), kinesin family member 11
(KIF11), and kinesin family member 2c (KIF2C).
[0004] Similarly, Shaughnessy et al. report a 70-gene high-risk
profile for multiple myeloma. Two of the genes upregulated in this
high-risk profile are CDC28 protein kinase regulatory subunit 1B
(CKS1B) and WEE1 homolog (S. pombe) (WEE1).
SUMMARY
[0005] One embodiment of the invention provides a method of
treating multiple myeloma (MM) in an individual, the method
comprising: administering to the individual an effective amount of
trichostatin A (TSA).
[0006] In another embodiment, the invention provides a method of
treating multiple myeloma (MM) in an individual, the method
comprising: determining, from a biological sample obtained from the
individual's body, a level of expression of at least one gene
selected from a group consisting of: CCNB1, AURKB, CDC2, BIRC5,
KIF11, KIF2C, TOP2A, ASPM, CKS1B, and WEE1; and in the case that
the level of expression of the at least one gene is indicative of
overexpression, administering to the individual an effective amount
of trichostatin A (TSA).
[0007] In yet another embodiment, the invention provides a method
of treating multiple myeloma (MM) in an individual, the method
comprising: diagnosing or having diagnosed the individual with MM;
and administering to the individual an effective amount of
trichostatin A (TSA).
[0008] In still yet another embodiment, the invention provides a
pharmaceutical composition comprising: trichostatin A (TSA) as a
sole or primary inhibitor of CCNB1, AURKB, CDC2, BIRC5, KIF11,
KIF2C, TOP2A, ASPM, CKS1B, or WEE1; and a
pharmaceutically-acceptable excipient or carrier.
[0009] In still other embodiments of the invention, treatment with
TSA is combined with one or more other multiple myeloma treatments.
Such other treatments may include, for example, small molecule
inhibition.
DETAILED DESCRIPTION
[0010] Trichostatin A (TSA or
7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienami-
de), is an antifungal antibiotic. The structure of TSA is shown in
Formula I below.
##STR00001##
[0011] Applicants have surprisingly found that TSA, although
previously known as a class I and II histone deacetylase (HDAC)
inhibitor, is also capable of inhibiting expression of CCNB1,
AURKB, CDC2, BIRC5, KIF11, KIF2C, TOP2A, ASPM, CKS1B, and WEE1.
Accordingly, TSA may be used as a primary or sole inhibitor of one
or more such genes in the treatment of MM.
[0012] 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 expression
of CCNB1, AURKB, CDC2, BIRC5, KIF11, KIF2C, TOP2A, ASPM, CKS1B, and
WEE1 is shown below in Table 1, and indicates significant
downregulation of the expression of each gene.
TABLE-US-00001 TABLE 1 Instance ID Probe Rank Fold Expression
.DELTA. Gene 10005542 219918_s_at 22283 -69.97232079 ASPM 10005533
219918_s_at 22282 -54.61735261 ASPM 10005532 219918_s_at 22261
-23.24977266 ASPM 10005542 209464_at 22190 -11.52858083 AURKB
10005533 209464_at 22185 -11.04347695 AURKB 10005542 202095_s_at
22270 -24.2000252 BIRC5 10005533 202095_s_at 22256 -23.02258123
BIRC5 10005533 202094_at 22251 -20.74385736 BIRC5 10005532
202095_s_at 22252 -19.95557418 BIRC5 10005542 202094_at 22227
-14.71770993 BIRC5 10005532 202094_at 22219 -14.42912247 BIRC5
10005533 214710_s_at 22267 -26.45555632 CCNB1 10005532 214710_s_at
22267 -26.32053821 CCNB1 10005542 214710_s_at 22251 -20.15506664
CCNB1 10005532 203213_at 22270 -27.14720991 CDC2 10005533 203213_at
22260 -23.81235655 CDC2 10005542 203213_at 22253 -20.26528442 CDC2
10005533 210559_s_at 22199 -12.07146825 CDC2 10005532 210559_s_at
22192 -11.92448867 CDC2 10005533 203214_x_at 22194 -11.8262682 CDC2
10005542 204444_at 22213 -13.12379506 KIF11 10005532 204444_at
22187 -11.4579544 KIF11 10005533 204444_at 22184 -10.96422696 KIF11
10005533 209408_at 22250 -19.89427497 KIF2C 10005532 209408_at
22248 -19.35105571 KIF2C 10005542 209408_at 22224 -14.47328923
KIF2C 10005532 201292_at 22274 -31.9462153 TOP2A 10005533
201291_s_at 22270 -28.21627346 TOP2A 10005532 201897_s_at 22279
-39.94584911 CKS1B 10005533 201897_s_at 22279 -52.93016044 CKS1B
10005542 201897_s_at 22268 -23.90194858 CKS1B 10005532 212533_at
22237 -17.0758281 WEE1 10005533 212533_at 22248 -19.46663938 WEE1
10005542 212533_at 22265 -23.63054187 WEE1
[0013] These results support the use of TSA in the treatment of MM.
For example, an individual may be treated for MM by administering
to the individual an effective amount of TSA, wherein the effective
amount is an amount sufficient to inhibit expression of one or more
of CCNB1, AURKB, CDC2, BIRC5, KIF11, KIF2C, TOP2A, ASPM, CKS1B, and
WEE1 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 0.01 mg/kg/day and
about 100 mg/kg/day, e.g., 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.
[0014] In some embodiments, treating the individual may further
comprise determining, from a biological sample obtained from the
individual's body, a level of expression of one or more of CCNB1,
AURKB, CDC2, BIRC5, KIF11, KIF2C, TOP2A, ASPM, CKS1B, or WEE1. 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.
[0015] In other embodiments of the invention, treating the
individual may include diagnosing or having diagnosed the
individual with MM prior to administering TSA to the individual.
Such diagnosing may include one or more technique or method for
making such a diagnosis, including, for example, serum protein
electrophoresis, serum free kappa/lambda light chain assay, urine
protein electrophoresis, bone marrow examination, or X-ray
analysis.
[0016] 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.
[0017] 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).
[0018] Solid compositions for oral administration can be formulated
in a unit dosage form, each dosage containing from about 0.1 mg to
about 5000 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
0.1-5000 mg of active in addition to excipients.
[0019] 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.
[0020] In some embodiments of the invention, TSA is provided in a
liquid form and administered to an individual intravenously.
According to some embodiments of the invention, TSA is provided in
a sustained or controlled release formulation.
[0021] 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.
* * * * *