# US 2014/0154303 A1 · Treating cancer by inhibiting expression of olfm4, sp5, tob1, arid1a, fbn1 or hat1

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- Number: US 2014/0154303 A1
- Document ID: US20140154303A1
- Status: Published application
- Kind: A1
- Application number: 13/984,977
- Filed: 2012-02-13
- Published: 2014-06-05
- Earliest claimed: 2011-02-11
- Assignees: Singapore Health Services Pte Ltd; National University of Singapore
- Inventors: Patrick Tan; Hue Kian Oh
- Web page: https://patentgrep.com/patent/US20140154303A1

## CPC

- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- 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 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61P 35/00: Antineoplastic agents
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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

## Abstract

The present invention in one aspect relates to a method for treating cancer or enhancing a cancer treatment, the method comprising inhibiting the expression of an oligonucleotide encoding for a protein selected from the group consisting of OLFM4, SP5, TOB1, ARID1A, FBN1 and HAT1, by administering to a mammal in need of cancer treatment an effective amount of at least one silencing oligonucleotide comprising a binding motif for binding to the oligonucleotide encoding for a protein.

## Claims

### Claim 1

A method for treating cancer or enhancing a cancer treatment, the method comprising inhibiting the expression of an oligonucleotide encoding for a protein selected from the group consisting of OLFM4, SP5, TOB1, ARID1A, FBN1 and HAT1, by administering to a mammal in need of cancer treatment an effective amount of at least one silencing oligonucleotide comprising a binding motif with a core nucleotide sequence of UCCUGUAC, or at least one silencing oligonucleotide targeting the 3′ untranslated region of the oligonucleotide encoding for a protein selected from the group consisting of OLFM4, SP5, TOB1, ARID1A, FBN1 and HAT 1.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the olignucleotide encoding for a protein is selected from the group consisting of OLFM4, SP5, TOB1 and ARID1A.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the oligonucleotide encoding for a protein is selected from the group consisting of OLFM4 and SP5.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the at least one silencing oligonucleotide targeting the 3′ untranslated region of the oligonucleotide encoding for a protein selected from the group consisting of OLFM4, SP5, TOB1, ARID1A, FBN1 and HAT1 includes a nucleotide sequence being complementary to the nucleotide sequence of the 3′ untranslated region of the oligonucleotide encoding for a protein.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the oligonucleotide encoding for a protein has at least one binding site for binding with the binding motif with a core nucleotide sequence of UCCUGUAC of the silencing oligonucleotide comprising the binding motif.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the at least one binding site is located in the 3′ untranslated region of the oligonucleotide encoding for a protein.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the oligonucleotide encoding for a protein is an oligonucleotide encoding for the OLFM4 protein.

### Claim 8 (depends on 7)

The method according to claim 7, wherein a binding site of the oligonucleotide encoding for the OLFM4 protein comprises a nucleotide sequence of SEQ ID No:3.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the silencing oligonucleotide is a mi-RNA, si-RNA, sh-RNA or a precursor thereof.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the silencing nucleotide is an mi-RNA selected from the group consisting of hsa-miR-623, hsa-miR-134, hsa-miR-181c, hsa-miR-654-5p, hsa-miR-936, hsa-miR-939, kshv-miR-K12-3, hsa-miR-550, hsa-miR-486-5p, hsa-miR-575, hcmv-miR-UL70-3p, hsa-miR-638, hsvl-miR-H1, hsa-miR-139-3p, hsa-miR-202, hsa-miR-378, hsvl-miR-LAT, hsa-miR-596, hsa-miR-188-5p, hsa-miR-28-3p, hsa-miR-30d, hsa-miR-572, hsa-miR-1225-5p, hsa-miR-345, hsa-miR-30a, hsa-miR-671-5p, hivl-miR-H1, hsa-miR-148a, hsa-miR-222, hsa-miR-10b, hsa-miR-564, hsa-miR-193b, hsa-miR-125a-3p, hsa-miR-370, hsa-miR-375, hsa-miR923, hsa-miR-513c, hsa-miR-513a-5p, hsa-miR-494 and hsa-miR-513b, hsa-miR-486-5p, hsa-let-7d*, hsa-miR-328, hsa-miR-32*, hsa-miR-1227, hsa-miR-206, hsa-miR-1229, hsa-miR-595 and hsa-miR-631, or a precursor of these mi-RNAs.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the silencing nucleotide is selected from the group consisting of hsa-miR-375, hsa-miR-148a, miR-671-5p, hsa-miR-30a, hsa-miR-1225-5p, hsa-miR-572, hsa-miR-188-5p, miR-139-3p, hsa-miR-638, hsa-miR-486-5p, hsa-miR-550, miR-939, hsa-miR-936, hsa-miR-181c, miR-134, hsa-miR-623, hsa-let-7d*, hsa-miR-328, hsa-miR-32*, hsa-miR-1227, hsa-miR-206, hsa-miR-1229, hsa-miR-595 and hsa-miR-631, or a precursor of these mi-RNAs

### Claim 12 (depends on 10)

The method according to claim 10, wherein the mi-RNA is hsa-miR-486-5p (miR-486) comprising a nucleotide sequence of SEQ ID NO:1.

### Claim 13 (depends on 11)

The method according to claim 11, wherein the precursor is a precursor of mi-486 comprising a nucleotide sequence of SEQ ID NO:2.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the cancer is selected from the group consisting of gastric cancer, colon cancer, breast cancer and lung cancer.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the cancer is gastric cancer.

### Claim 16 (depends on 1)

The method according to claim 1, wherein the silencing oligonucleotide comprises a chemical modification of one or more nucleotides.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the modification comprises a phosphate backbone modification, a modified sugar moiety, a modified nucleotide or a modified terminal.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the phosphate backbone modification is selected from the group consisting of phosphorothioate modification, methylphosphonate modification, phosphotriester modification, phosphordithionate modification and phosphoselenate modification.

### Claim 19 (depends on 1)

The method according to claim 1, wherein the silencing oligonucleotide is formulated with a delivery vehicle.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the delivery vehicle is a nanoparticle, in the form of a liposome; or a peptide; or an aptamer; or an antibody; or a polyconjugate; or microencapsulation.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the lipsome is a stable nucleic acid-lipid particle (SNALP), or dioleoyl phosphatidylcholine (DOPC)-based delivery system, or a lipoplex.

### Claim 22 (depends on 1)

The method according to claim 1, wherein the silencing oligonucleotide is formulated for systemic administration.

### Claim 23 (depends on 1)

The method according to claim 1, wherein the silencing oligonucleotide is encoded with an expression vector for expression in a mammalian cell.

### Claim 24 (depends on 23)

The method according to claim 23, wherein the expression vector is a viral vector selected from the group consisting of a retroviral, adenoviral, lentiviral and adeno-associated viral vector.

### Claim 25 (depends on 23)

The method according to claim 23, wherein the mammalian cell is a tumour cell.

### Claim 26

A method of inducing apoptosis in a mammal in need thereof, the method comprising administering to the mammal an effective amount of at least one silencing oligonucleotide comprising a binding motif of with a core nucleotide sequence of UCCUGUAC to bind and thereby inhibit an anti-apoptotic protein in the mammal.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the anti-apoptotic protein is OLFM4.

### Claim 28 (depends on 26)

The method according to claim 26, wherein the mammal in need thereof is a mammal with a cell proliferative disorder.

### Claim 29 (depends on 28)

The method according to claim 28, wherein the cell proliferative disorder is cancer.

### Claim 30 (depends on 28)

The method according to claim 28, wherein the cancer is selected from the group consisting of gastric cancer, colon cancer, breast cancer and lung cancer.

### Claim 31

A method of screening for cancer, the method comprising screening for a silencing oligonucleotide comprising a binding motif with a core nucleotide sequence of UCCUGUAC or an oligonucleotide encoding for a protein including a matching nucleotide sequence being complementary to the nucleotide sequence of UCCUGUAC.

### Claim 32 (depends on 31)

The method of screening for cancer according to claim 31, wherein the method comprises mi-RNA profiling or deep sequencing.

### Claim 33 (depends on 31)

The method of claim 31, wherein the cancer is gastric cancer.