# US 2010/0166707 A1 · Extracellular matrix/metastasis modifier genes for the prevention or inhibition of metastasis or growth of tumor and for characterization of tumor

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- Number: US 2010/0166707 A1
- Document ID: US20100166707A1
- Status: Published application
- Kind: A1
- Application number: 12/280,260
- Filed: 2007-02-23
- Published: 2010-07-01
- Earliest claimed: 2006-02-24
- Assignees: Government of the United States of America, repres; The Regents of the University of California
- Inventors: Kent W. Hunter; Nigel Crawford; Douglas R. Lowy; Xiaolan Qian; Hoda Anton-Culver; Agryrios Ziogas
- Web page: https://patentgrep.com/patent/US20100166707A1

## CPC

- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K 38/1709: {from mammals}
- A61P 35/00: Antineoplastic agents
- C07K 14/47: from mammals
- G01N 33/5011: {for testing antineoplastic activity}
- 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
- 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)
- 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)

## Abstract

Disclosed are methods involving the administration of an extracellular matrix (ECM)/metastasis modifier gene, e.g., Anakin, Necdin, CentaurinD3 (CentD3), Csf1r, Brd4, Pi16, and Luc7l, for the prevention or inhibition of metastasis or of tumor growth. Further disclosed are methods of characterizing a tumor or cancer in a subject comprising detecting (i) a single nucleotide polymorphism (SNP) in an Anakin gene or a Brd4 gene of the subject, (ii) an amino acid substitution in an Anakin protein in the subject, or (iii) a level of expression of an Anakin gene or a Brd4 gene in the subject. Methods of screening a compound for anti-cancer activity and use of a compound with anti-cancer activity for the preparation of a medicament to treat or prevent cancer in a subject are also disclosed. Also disclosed is a method of inhibiting Sipa-1 in a subject.

## Claims

### Claim 1

(canceled)

### Claim 2

A pharmaceutical composition comprising (i) a nucleic acid comprising a nucleotide sequence encoding a protein, (ii) a vector comprising the nucleic acid, (iii) a host cell comprising the vector, (iv) a gene product, or (v) a combination thereof, wherein the protein or gene product are encoded by a gene selected from the group consisting of: Anakin, Necdin, and Brd4, and a pharmaceutically acceptable carrier.

### Claim 3 (depends on 2)

The pharmaceutical composition of claim 2, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 2 or 4.

### Claim 4 (depends on 2)

The pharmaceutical composition of claim 2, wherein the gene is an Anakin gene and the gene product is an Anakin protein or an Anakin mRNA.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein the Anakin protein comprises the amino acid sequence of SEQ ID NO: 1 or 3.

### Claim 6 (depends on 2)

The pharmaceutical composition of claim 2, wherein the Necdin gene comprises the nucleotide sequence of SEQ ID NO: 10, or the Necdin gene product comprises the amino acid sequence of SEQ ID NO: 9.

### Claim 7 (depends on 2)

The pharmaceutical composition of claim 2, wherein the Brd4 gene comprises the nucleotide sequence of SEQ ID NO: 108 or 110, or the Brd4 gene product comprises the amino acid sequence of SEQ ID NO: 109 or 111.

### Claim 8 (depends on 2)

A method of preventing or inhibiting metastasis of a cancer cell in a subject comprising administering to the subject the pharmaceutical composition of claim 2 in an amount that is effective to prevent or inhibit metastasis of the cancer cell in the subject.

### Claim 9

A pharmaceutical composition comprising (i) a nucleic acid comprising a nucleotide sequence encoding a protein, (ii) a vector comprising the nucleic acid, (iii) a host cell comprising the vector, (iv) a gene product, or (v) a combination thereof, wherein the protein or gene product are encoded by a gene selected from the group consisting of: CentaurinD3 (CentD3), Csf1r, Pi16, and Luc7l, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 2)

A method of preventing or inhibiting tumor growth in a subject comprising administering to the subject the pharmaceutical composition of claim 2 in an amount that is effective to prevent or inhibit tumor growth in the subject.

### Claim 11

A method of characterizing a tumor or a cancer in a subject comprising detecting (i) a single nucleotide polymorphism (SNP) in an Anakin gene or a Brd4 gene of the subject, (ii) an amino acid substitution in an Anakin protein in the subject, or (iii) an expression level of an Anakin gene or a Brd4 gene in the subject, whereupon the tumor or cancer is characterized.

### Claim 12 (depends on 11)

The method of claim 11, wherein the tumor or cancer is characterized in terms of metastatic capacity, stage, tumor grade, nodal involvement, regional metastasis, distant metastasis, sex hormone receptor status, or tumor size.

### Claim 13 (depends on 12)

The method of claim 12, wherein the sex hormone receptor is the estrogen receptor or the progesterone receptor.

### Claim 14 (depends on 11)

The method of claim 11, wherein the SNP is located within an exon of an Anakin gene and results in an amino acid substitution.

### Claim 15 (depends on 14)

The method of claim 14 wherein the amino acid substitution is a Leu substituted for a Pro at position 436 of SEQ ID NO: 1.

### Claim 16 (depends on 11)

The method of claim 11, wherein the SNP is a T→C at position 1421 of SEQ ID NO: 2.

### Claim 17 (depends on 11)

The method of claim 11, wherein the SNP is located within an intron of the Brd4 gene.

### Claim 18 (depends on 17)

The method of claim 17, wherein the SNP is an A→G at position 14290 of SEQ ID NO: 112, a G→A SNP at position 3185 of SEQ ID NO: 112, or a G→T SNP at position 13865 of SEQ ID NO: 112.

### Claim 19 (depends on 11)

The method of claim 11, wherein the subject is a mammal.

### Claim 20 (depends on 19)

The method of claim 19, wherein the mammal is a human.

### Claim 21 (depends on 11)

The method of claim 11, wherein the cancer is an epithelial cancer.

### Claim 22 (depends on 21)

The method of claim 21, wherein the epithelial cancer is breast cancer.

### Claim 23 (depends on 21)

The method of claim 21, wherein the epithelial cancer is renal cell carcinoma.

### Claim 24 (depends on 11)

The method of claim 11, wherein detecting a SNP comprises detecting a complementary SNP.

### Claim 25 (depends on 11)

The method of claim 11, wherein detecting a SNP comprises a polymerase chain reaction (PCR).

### Claim 26 (depends on 25)

The method of claim 25, wherein the PCR is carried out using primers and probes comprising the nucleotide sequences of SEQ ID NOs: 5 to 8.

### Claim 27 (depends on 11)

The method of claim 11, wherein the method is performed in vitro.

### Claim 28 (depends on 11)

The method of claim 11, wherein the method further comprises comparing (i) the nucleotide sequence of the Anakin gene or the Brd4 gene of the subject, (ii) the amino acid sequence of the Anakin protein of the subject, or (iii) the expression level of the Anakin gene or the Brd4 gene in the subject to a control.

### Claim 29

An isolated, purified, or synthetic nucleic acid comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 8.

### Claim 30

An isolated, purified, or synthetic antibody, or antigen binding portion thereof, which specifically binds to a murine Anakin protein or an Anakin allelic variant.

### Claim 31 (depends on 30)

The isolated, purified, or synthetic antibody, or antigen binding portion thereof, of claim 30, wherein the murine Anakin protein comprises the amino acid sequence of SEQ ID NO: 3.

### Claim 32 (depends on 30)

The isolated, purified, or synthetic antibody, or antigen binding portion thereof, of claim 30, wherein the Anakin allelic variant comprises the amino acid sequence of SEQ ID NO: 1 with an amino acid substitution of Leu to Pro at position 436 of SEQ ID NO: 1.

### Claim 33 (depends on 30)

The isolated, purified, or synthetic antibody, or antigen binding portion thereof, of claim 30, wherein the antibody, or antigen binding portion thereof, specifically binds to an epitope comprising Pro at position 436 of SEQ ID NO: 1 or Leu at position 436 of SEQ ID NO: 1.

### Claim 34 (depends on 30)

A kit comprising the antibody, or antigen binding portion thereof, of claim 30, or a nucleic acid which specifically hybridizes to a portion of a nucleic acid comprising a nucleotide sequence encoding an Anakin protein or Anakin allelic variant, or a combination thereof, and a set of user instructions.

### Claim 35 (depends on 34)

The kit of claim 34, wherein the nucleic acid comprising a nucleotide sequence encoding an Anakin protein comprises the nucleotide sequence of SEQ ID NO: 2 or 4.

### Claim 36 (depends on 34)

The kit of claim 34, wherein the nucleic acid comprising a nucleotide sequence encoding an Anakin allelic variant comprises the nucleotide sequence of SEQ ID NO: 2 with a T→C single nucleotide polymorphism (SNP) at position 1421 of SEQ ID NO: 2.

### Claim 37 (depends on 34)

The kit of claim 34, comprising one or more of the nucleic acids comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 8.

### Claim 38

A method for screening a compound for anti-cancer activity comprising (a) providing a cell that (i) under-expression a nucleic acid comprising a nucleotide sequence encoding an Anakin protein or a Brd4 protein or (ii) comprises an Anakin or Brd4 allelic variant, (b) contacting the cell with a compound of interest, and (c) assaying for anti-cancer activity.

### Claim 39

(canceled)

### Claim 40

A method of inhibiting Sipa-1 in a subject in need thereof comprising administering to the subject an effective amount of (i) a nucleic acid comprising a nucleotide sequence encoding an Anakin protein, (ii) a vector comprising the nucleic acid, (iii) a host cell comprising the vector, (iv) an Anakin gene product, or (v) a combination thereof.

### Claim 41 (depends on 40)

The method of claim 40, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 2 or 4.

### Claim 42 (depends on 40)

The method of claim 40, wherein the Anakin gene product is a protein or an mRNA.

### Claim 43 (depends on 42)

The method of claim 42, wherein the protein comprises the amino acid sequence of SEQ ID NO: 1 or 3.

### Claim 44 (depends on 40)

The method of claim 40, wherein the method effectively inhibits Sipa-1 GTPase activity.