# US 9,518,098 B2 · Uses of NANOG inhibitors and related methods

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- Number: US 9,518,098 B2
- Document ID: US9518098B2
- Status: Granted
- Kind: B2
- Application number: 14/128,882
- Filed: 2012-06-25
- Published: 2014-05-29
- Granted: 2016-12-13
- Earliest claimed: 2011-06-24
- Assignees: Universite De Geneve
- Applicants: Ariel Ruiz Altaba
- Inventors: Ariel Ruiz Altaba
- Web page: https://patentgrep.com/patent/US9518098B2

## CPC

- C07K 14/435: from animals; from humans
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/175: having the group [IMAGE cpc-sch-A61K-0950.gif] , >N—C(O)—N=N— or[IMAGE cpc-sch-A61K-0951.gif] , e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 38/17: from animals; from humans {(enzyme inhibitors A61K38/005)}
- A61K 39/39533: {against materials from animals}
- A61P 35/00: Antineoplastic agents
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to substances and compositions thereof useful in the control of cancer stem cell persistence and concomitant tumor recurrence and/or control of tumor growth. In particular, the invention relates to substances and compositions useful in the treatment of cancers and/or tumors linked to cancer stem cells, preferably brain cancers and/or tumors, in a subject.

## Claims

### Claim 1

A NANOG antagonist that is a NANOG dominant-negative polypeptide comprising a NANOG homeodomain fused to the repressor domain of a heterologous protein.

### Claim 2 (depends on 1)

The NANOG antagonist according to claim 1, wherein the NANOG homeodomain has the amino acid sequence of SEQ ID NO:5, or the NANOG homeodomain is a NANOG homeodomain of a mammalian NANOG protein that binds to the DNA consensus sequence of SEQ ID NO:34.

### Claim 3 (depends on 1)

The NANOG antagonist according to claim 1, wherein the repressor domain comprises the repressor domain of Pit-1beta (SEQ ID NO: 37), or the repressor domain of an Engrailed protein selected from SEQ ID NO: 36 or 38, the repressor domain of IRF1 (SEQ ID NO: 39), or the WRPW motif of the hairy-related protein (SEQ ID NO: 44).

### Claim 4 (depends on 1)

The NANOG antagonist according to claim 1, wherein the NANOG dominant-negative polypeptide further comprises a cell penetrating peptide for translocating the polypeptide across the cell membrane and/or a brain tumor targeting peptide and/or a tag selected from SEQ ID NO: 42 or SEQ ID NO: 43 at the N-terminus or the C-terminus of the NANOG antagonist polypeptide.

### Claim 5 (depends on 4)

The NANOG antagonist according to claim 4, wherein the cell penetrating peptide comprises penetratin from Antennapedia of SEQ ID NO: 40 and the brain tumor targeting peptide comprises a transferrin-like peptide of SEQ ID NO: 41.

### Claim 6 (depends on 1)

The NANOG antagonist according to claim 1, wherein the NANOG dominant-negative polypeptide further comprises the dimerization domain of SEQ ID NO: 35.

### Claim 7 (depends on 1)

A pharmaceutical formulation comprising a NANOG antagonist according to claim 1 and at least one pharmaceutically acceptable carrier.

### Claim 8 (depends on 7)

The pharmaceutical formulation according to claim 7 further comprising a co-agent selected from bevacizumab, temazolomide, procarbazine, carmustine, or cilengitide.

### Claim 9

A method of repressing or treating cancers linked to cancer stem cells in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a NANOG antagonist selected from:
a) a NANOG dominant-negative polypeptide comprising a NANOG homeodomain fused to the repressor domain of a heterologous protein;
b) a vector driving the expression of said NANOG antagonist; or
c) a pharmaceutical formulation comprising a) or b).

### Claim 10 (depends on 9)

The method of claim 9 wherein said cancers are brain cancers.

### Claim 11 (depends on 9)

The method according to claim 9, wherein the NANOG homeodomain has the amino acid sequence of SEQ ID NO:5, or the NANOG homeodomain is a NANOG homeodomain of a mammalian NANOG protein that binds to the DNA consensus sequence of SEQ ID NO:34.

### Claim 12 (depends on 9)

The method of claim 9, wherein the NANOG dominant-negative polypeptide further comprises a cell penetrating peptide for translocating the polypeptide across the cell membrane and/or a brain tumor targeting peptide and/or a Tag selected from FLAG of SEQ ID NO:42 and HA of SEQ ID NO:43 at the N-terminus or the C-terminus part of the NANOG antagonist.

### Claim 13 (depends on 9)

The method according to claim 9, wherein the NANOG dominant-negative polypeptide is administered systemically.

### Claim 14

A method of controlling cancer stem cell persistence and concomitant tumor recurrence in a subject comprising administering to a subject in need thereof an amount of a NANOG antagonist selected from:
a) a NANOG dominant-negative polypeptide comprising a NANOG homeodomain fused to the repressor domain of a heterologous protein;
b) a vector driving the expression of said NANOG antagonist; or
c) a pharmaceutical formulation comprising a) or b).

### Claim 15

A method of repressing or treating cancers linked to cancer stem cells in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a NANOG antagonist, wherein said NANOG antagonist is
a) a short hairpin RNA selected from:
i) shNANOG1 of nucleotide sequence SEQ ID NO:11,
ii) shNANOG2 of nucleotide sequence SEQ ID NO:12 or
iii) shNANOGP8 consisting of SEQ ID NO:13;
b) a vector driving the expression of said NANOG antagonist; or
c) a pharmaceutical formulation comprising a) or b).

### Claim 16 (depends on 15)

The method of claim 15 wherein said cancers are brain cancers.

### Claim 17

A method of controlling cancer stem cell persistence and concomitant tumor recurrence in a subject comprising administering to a subject in need thereof an amount of a NANOG antagonist, wherein said NANOG antagonist is
a) a short hairpin RNA selected from:
i) shNANOG1 of nucleotide sequence SEQ ID NO:11,
ii) shNANOG2 of nucleotide sequence SEQ ID NO:12 or
iii) shNANOGP8 consisting of SEQ ID NO:13;
b) a vector driving the expression of said NANOG antagonist; or
c) a pharmaceutical formulation comprising a) or b).