# US 2013/0156795 A1 · Methods for inhibition of cell proliferation, synergistic transcription modules and uses thereof

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- Number: US 2013/0156795 A1
- Document ID: US20130156795A1
- Status: Published application
- Kind: A1
- Application number: 13/409,998
- Filed: 2012-03-01
- Published: 2013-06-20
- Earliest claimed: 2009-09-01
- Inventors: Antonio Iavarone; Andrea Califano
- Web page: https://patentgrep.com/patent/US20130156795A1

## CPC

- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/381: having five-membered rings
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4166: having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
- A61K 31/424: condensed with heterocyclic ring systems, e.g. clavulanic acid
- A61K 31/4245: Oxadiazoles
- A61K 31/426: 1,3-Thiazoles
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/4741: condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/515: Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5395: having two or more nitrogen atoms in the same ring, e.g. oxadiazines
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/45: Transferases (2)
- C12Q 1/6837: using probe arrays or probe chips (C12Q1/6874 takes precedence)
- C12Q 1/686: Polymerase chain reaction [PCR]
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- C12Q 1/6897: involving reporter genes operably linked to promoters
- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- G16B 35/00: ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
- G16C 20/60: In silico combinatorial chemistry
- G16C 20/64: Screening of libraries
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/158: Expression markers
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE

## Abstract

The invention provides for methods for treating nervous system cancers in a subject. The invention further provides methods for treating nervous system tumor cell invasion, migration, proliferation, and angiogenesis associated with nervous system tumors.

## Claims

### Claim 1

A method for treating nervous system cancer in a subject in need thereof comprising administering to the subject a compound that inhibits a MGES protein.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of etoposide, 5-fluorouracil, Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound is selected from the group consisting of 5-fluorouracil, Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the compound is selected from the group consisting of Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the MGES protein is C/EPB or Stat3.

### Claim 6 (depends on 1)

The method of claim 1, wherein the cancer is glioma or meningioma.

### Claim 7 (depends on 1)

The method of claim 1, wherein the cancer is astrocytoma, Glioblastoma Multiforme, oligodentroglioma, ependymoma or meningioma.

### Claim 8 (depends on 1)

The method of claim 1, wherein the cancer is cerebellar astrocytoma, medulloblastoma, ependymona, brain stem glioma, optic nerve glioma, acoustic neuromas, nerve sheath tumors, or germinoma.

### Claim 9

A method for decreasing MGES protein activity in a subject having a nervous system cancer, the method comprising administering to the subject a compound that inhibits a MGES protein.

### Claim 10 (depends on 9)

The method of claim 9, wherein the compound is selected from the group consisting of etoposide, 5-fluorouracil, Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the compound is selected from the group consisting of 5-fluorouracil, Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein the compound is selected from the group consisting of Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 13 (depends on 9)

The method of claim 9, wherein the MGES protein is C/EPB or Stat3.

### Claim 14 (depends on 9)

The method of claim 9, wherein the cancer is glioma or meningioma.

### Claim 15 (depends on 9)

The method of claim 9, wherein the cancer is astrocytoma, Glioblastoma Multiforme, oligodentroglioma, ependymoma or meningioma.

### Claim 16 (depends on 9)

The method of claim 9, wherein the cancer is cerebellar astrocytoma, medulloblastoma, ependymona, brain stem glioma, optic nerve glioma, acoustic neuromas, nerve sheath tumors, or germinoma.

### Claim 17

A method for inhibiting a MGES protein comprising contacting said protein with an effective amount of a compound selected from the group consisting of etoposide, 5-fluorouracil, Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein the compound is selected from the group consisting of 5-fluorouracil, Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 19 (depends on 18)

The method of claim 18, wherein the compound is selected from the group consisting of Clostridium difficile Toxin B,
and pharmaceutically acceptable salts thereof.

### Claim 20 (depends on 17)

The method of claim 17, wherein the MGES protein is C/EPB or Stat3.

### Claim 21

A method for detecting the presence of or a predisposition to a nervous system cancer in a human subject, the method comprising:
(a) obtaining a biological sample from a subject; and
(b) detecting whether or not there is an alteration in the expression of a Mesenchymal-Gene-Expression-Signature (MGES) gene in the subject as compared to a subject not afflicted with a nervous system cancer.

### Claim 22 (depends on 21)

The method of claim 21, wherein the MGES gene comprises Stat3, C/EBPβ, C/EBPδ, RunX1, FosL2, bHLH-B2, ZNF238, or a combination thereof.

### Claim 23 (depends on 21)

The method of claim 21, wherein the detecting comprises detecting in the sample whether there is an increase in a MGES mRNA, a MGES polypeptide, or a combination thereof.

### Claim 24 (depends on 23)

The method of claim 23, wherein the MGES gene comprises Stat3, C/EBPβ, C/EBPδ, RunX1, FosL2, bHLH-B2, or a combination thereof.

### Claim 25 (depends on 21)

The method of claim 21, wherein the detecting comprises detecting in the sample whether there is a decrease in a MGES mRNA, a MGES polypeptide, or a combination thereof.

### Claim 26 (depends on 25)

The method of claim 25, wherein the MGES gene comprises ZNF238.

### Claim 27 (depends on 21)

The method of claim 21, wherein the nervous system cancer comprises a glioma.

### Claim 28 (depends on 27)

The method of claim 27, wherein the glioma comprises an astrocytoma, a Glioblastoma Multiforme, an oligodendroglioma, an ependymoma, or a combination thereof.

### Claim 29

A method for inhibiting proliferation of a nervous system tumor cell or for promoting differentiation of a nervous system tumor cell, the method comprising decreasing the expression of a Mesenchymal-Gene-Expression-Signature (MGES) molecule in a nervous system tumor cell, thereby inhibiting proliferation or promoting differentiation.

### Claim 30 (depends on 29)

The method of claim 29, wherein the proliferation comprises cell invasion, cell migration, or a combination thereof.

### Claim 31

A method for inhibiting angiogenesis in a nervous system tumor, the method comprising decreasing the expression of a Mesenchymal-Gene-Expression-Signature (MGES) molecule in a nervous system tumor cell, thereby inhibiting angiogenesis.

### Claim 32

A method for treating a nervous system tumor in a subject, the method comprising administering to a nervous system tumor cell in the subject an effective amount of a composition that decreases the expression of a Mesenchymal-Gene-Expression-Signature (MGES) molecule in a nervous system tumor cell, thereby treating nervous system tumor in the subject.

### Claim 33

A method for identifying a compound that binds to a Mesenchymal-Gene-Expression-Signature (MGES) protein, the method comprising:
a) providing an electronic library of test compounds;
b) providing atomic coordinates for at least 20 amino acid residues for the binding pocket of the MGES protein, wherein the coordinates have a root mean square deviation therefrom, with respect to at least 50% of Cα atoms, of not greater than about 5 Å, in a computer readable format;
c) converting the atomic coordinates into electrical signals readable by a computer processor to generate a three dimensional model of the MGES protein;
d) performing a data processing method, wherein electronic test compounds from the library are superimposed upon the three dimensional model of the MGES protein; and
e) determining which test compound fits into the binding pocket of the three dimensional model of the MGES protein,
thereby identifying which compound binds to the Mesenchymal-Gene-Expression-Signature (MGES) protein.

### Claim 34 (depends on 33)

The method of claim 33, further comprising:
f) obtaining or synthesizing the compound determined to bind to the Mesenchymal-Gene-Expression-Signature (MGES) protein or to modulate MGES protein activity;
g) contacting the MGES protein with the compound under a condition suitable for binding; and
h) determining whether the compound modulates MGES protein activity using a diagnostic assay.

### Claim 35 (depends on 33)

The method of claim 33, wherein the MGES protein comprises Stat3, C/EBPβ, C/EBPδ, RunX1, FosL2, bHLH-B2, ZNF238

### Claim 36 (depends on 33)

The method of claim 33, wherein the compound is a MGES antagonist or MGES agonist.

### Claim 37 (depends on 36)

The method of claim 36, wherein the antagonist decreases MGES protein or RNA expression or MGES activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100%.

### Claim 38 (depends on 36)

The method of claim 36, wherein the antagonist is directed to Stat3, C/EBPβ, C/EBPδ, RunX1, FosL2, bHLH-B2 or a combination thereof.

### Claim 39 (depends on 36)

The method of claim 36, wherein the agonist increases MGES protein or RNA expression or MGES activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100%.

### Claim 40 (depends on 36)

The method of claim 36, wherein the agonist is directed to ZNF238.

### Claim 41 (depends on 33)

A compound identified by the method of claim 33, wherein the compound binds to the active site of MGES.

### Claim 42

A method for decreasing MGES gene expression in a subject having a nervous system cancer, the method comprising:
a) administering to the subject an effective amount of a composition comprising a MGES inhibitor compound,
thereby decreasing MGES expression in the subject.

### Claim 43 (depends on 33, 42)

The method of claim 33 or claim 42, wherein the compound comprises an antibody that specifically binds to a MGES protein or a fragment thereof; an antisense RNA or antisense DNA that inhibits expression of MGES polypeptide; a siRNA that specifically targets a MGES gene; a shRNA that specifically targets a MGES gene; or a combination thereof.

### Claim 44

A diagnostic kit for determining whether a sample from a subject exhibits increased or decreased expression of at least 2 or more MGES genes, the kit comprising nucleic acid primers that specifically hybridize to an MGES gene, wherein the primer will prime a polymerase reaction only when a nucleic acid sequence comprising any one of SEQ ID NOS: 232, 234, 236, 238, 240, 242, or 244 is present.

### Claim 45 (depends on 44)

The kit of claim 44, wherein the MGES gene is Stat3, C/EBPβ, C/EBPδ, RunX1, FosL2, bHLH-B2, ZNF238, or a combination thereof.