# US 2013/0156776 A1 · Compositions and methods for treating cancer and modulating stress granule formation

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- Number: US 2013/0156776 A1
- Document ID: US20130156776A1
- Status: Published application
- Kind: A1
- Application number: 13/435,932
- Filed: 2012-03-30
- Published: 2013-06-20
- Earliest claimed: 2009-06-26
- Assignees: Massachusetts Institute of Technology
- Inventors: Paul Chang; Sejal . Vyas; Anthony Leung; Phillip A. Sharp
- Web page: https://patentgrep.com/patent/US20130156776A1

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/45: Transferases (2)
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 35/00: Antineoplastic agents
- C07H 21/02: with ribosyl as saccharide radical
- C07K 16/40: against enzymes
- 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)
- G01N 33/6893: {related to diseases not provided for elsewhere}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2320/12: in functional genomics, i.e. for the determination of gene function
- G01N 2333/91142: Pentosyltransferases (2.4.2)
- G01N 2500/02: Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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)
- 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)

## Abstract

The invention provides methods for treating or decreasing the likelihood of developing a stress-granule related disorder and/or cancer by administering one or more poly-ADP-ribose polymerase (PARP) inhibitors, one or more PARP activators, one or more poly-ADP-ribose glycosylase (PARG) activators, and/or one or more poly-ADP-ribose glycohydrolase ARH3 activators. The invention also provides corresponding methods of decreasing stress granule formation and/or proliferation in a cell or a population of cells. The invention further provides methods of increasing the number of stress granules and proliferation in a cell or a population of cells by administering one or more PARP activators, one or more PARP inhibitors, one or more PARG inhibitors, and/or one or more ARH3 inhibitors. The invention also provides methods for screening for agents for treating or decreasing the likelihood of developing a stress granule-related disorder or cancer, and methods for determining the propensity for developing a stress granule-related disorder or cancer, as well as compositions and kits containing one or more PARP inhibitors, one or more PARP activators, one or more PARG activators, and one or more ARH3 activators.

## Claims

### Claim 1

A method of treating or decreasing the likelihood of developing a stress granule-related disorder in a subject comprising administering to said subject a therapeutically effective amount of one or more poly-ADP-ribose polymerase (PARP) inhibitor(s), one or more poly-ADP ribose glycolase (PARG) activators, and/or one or more PARP11 activators.

### Claim 2 (depends on 1)

The method of claim 1, wherein said one or more PARP inhibitor(s) selectively decrease the expression and/or one or more activities of one or more PARP(s) selected from the group consisting of PARP5a, PARP12, PARP13 isoform 1 (PARP13.1), PARP13 isoform 2 (PARP13.2), and PARP15.

### Claim 3 (depends on 2)

The method of claim 2, wherein:
(a) said decrease in expression is a decrease in the level of one or more nucleic acid(s) comprising a nucleic acid sequence having at least 95% sequence identity to PARP5a (SEQ ID NO: 8 or 9), PARP5b (SEQ ID NO: 10), PARP13.1 (SEQ ID NO: 19), PARP13.2 (SEQ ID NO: 20), or PARP15 (SEQ ID NOS: 22 or 23), or in the level of one or more polypeptide(s) encoded by said one or more nucleic acid(s); or
(b) said one or more activities of said one or more PARP(s) is (i) poly-ADP-ribosylation of a target protein localized in a stress granule or a target protein involved in the formation or disassembly of a stress granule, or (ii) the formation or nucleation of a stress granule.

### Claim 4 (depends on 1)

The method of claim 1, wherein said one or more PARG activators selectively increases the expression and/or one or more activities of PARG protein or poly-ADP-ribose glycohydrolase ARH3.

### Claim 5 (depends on 4)

The method of claim 4, wherein:
(a) said increase in expression is an increase in the level of one or more nucleic acid(s) comprising a nucleic acid sequence having at least 95% sequence identity to PARG (SEQ ID NO: 42) or ARH3 (SEQ ID NO: 41), or in the level of one or more polypeptide(s) encoded by said one or more nucleic acid(s); or
(b) said one or more activities of PARG or ARH3 is (i) hydrolysis of poly-ADP-ribose, or (ii) the prevention of the assembly of a stress granule or disassembly of a stress granule.

### Claim 6 (depends on 1)

The method of claim 1, wherein said one or more PARP11 activators selectively increases the expression and/or one or more activities of PARP11.

### Claim 7 (depends on 6)

The method of claim 6, wherein:
(a) said increase in expression is an increase in the level of one or more nucleic acid(s) comprising a nucleic acid sequence having at least 95% sequence identity to PARP11 (SEQ ID NO: 17), or in the level of one or more polypeptide(s) encoded by said one or more nucleic acid(s); or
(b) said one or more activities of PARP11 is (i) poly-ADP-ribosylation of a target protein localized in a stress granule or a target protein involved in the formation or disassembly of a stress granule, or (ii) the prevention of the assembly of a stress granule or disassembly of a stress granule.

### Claim 8 (depends on 1)

The method of claim 1, wherein:
(a) said one or more PARP inhibitors is (i) an antibody or an antibody fragment that selectively binds one or more of PARP5a, PARP12, PARP13.1, PARP13.2, and PARP15 polypeptide, or (ii) an RNA aptamer;
(b) said one or more PARG activators is one or more nucleic acid(s) comprising a nucleic acid sequence having at least 95% sequence identity to PARG (SEQ ID NO: 42) or ARH3 (SEQ ID NO: 41); or
(c) said one or more PARP11 activators is one or more nucleic acid(s) comprising a nucleic acid sequence having at least 95% sequence identity to PARP11 (SEQ ID NO: 17).

### Claim 9 (depends on 1)

The method of claim 1, wherein said stress granule-related disorder is a cardiovascular disorder, an inflammatory disorder, a neurological disorder, or ischemic reperfusion injury.

### Claim 10 (depends on 9)

The method of claim 9, wherein:
(a) said cardiovascular disorder is selected from the group consisting of an aneurysm, angina, atherosclerosis, stroke, cerebrovascular disease, congestive heart failure, coronary artery disease, myocardial disease, peripheral vascular disease, granulomatous myocarditis, chronic myocarditis, myocardial infarction, and primary hypertrophic cardiomyopathy;
(b) said inflammatory disorder is selected from the group consisting of autoimmune diseases, asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, cirrhosis, Crohn's disease, ulcerative colitis, diabetes, hemolytic anemia, inflammatory dermatosis, inflammatory bowel disorder, systemic lupus erythamatosus, psoriasis, rheumatoid arthritis, Wegener's granulomatosis, Hashimoto's thyroiditis, chronic pancreatitis, and reactive lymphoid hyperplasia; or
(c) said neurological disorder is selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, retinosa pigmentosum, macular degeneration, traumatic brain injury, stroke, and peripheral neuropathy.

### Claim 11

A method of treating or decreasing the likelihood of developing cancer in a subject comprising administering to said subject a therapeutically effective amount of one or more poly-ADP-ribose polymerase (PARP) inhibitor(s).

### Claim 12 (depends on 11)

The method of claim 11, wherein said one or more PARP inhibitor(s) selectively decrease the expression and/or one or more activities of one or more PARP(s) selected from the group consisting of PARP1, PARP2, PARP5A, PARP5B, PARP7, PARP8, PARP14, and PARP16.

### Claim 13 (depends on 12)

The method of claim 12, wherein said decrease in expression is a decrease in the level of one or more nucleic acid(s) comprising a nucleic acid sequence having at least 95% sequence identity to PARP1 (SEQ ID NO: 1 or 2), PARP2 (SEQ ID NO: 3), PARP5A (SEQ ID NO: 8 or 9), PARP5B (SEQ ID NO: 10), PARP7 (SEQ ID NO: 12), PARP8 (SEQ ID NO: 13), PARP14 (SEQ ID NO: 21), or PARP16 (SEQ ID NO: 24), or in the level of one or more polypeptide(s) encoded by said one or more nucleic acid(s).

### Claim 14 (depends on 11)

The method of claim 11, wherein said cancer is selected from the group consisting of colon adenocarcinoma, esophagus adenocarcinoma, liver hepatocellular carcinoma, squamous cell carcinoma, pancreas adenocarcinoma, islet cell tumor, rectum adenocarcinoma, gastrointestinal stromal tumor, stomach adenocarcinoma, adrenal cortical carcinoma, follicular carcinoma, papillary carcinoma, breast cancer, ductal carcinoma, lobular carcinoma, intraductal carcinoma, mucinous carcinoma, phyllodes tumor, Ewing's sarcoma, ovarian adenocarcinoma, endometrium adenocarcinoma, granulose cell tumor, mucinous cystadenocarcinoma, cervix adenocarcinoma, vulva squamous cell carcinoma, basal cell carcinoma, prostate adenocarcinoma, giant cell tumor of bone, bone osteosarcoma, larynx carcinoma, lung adenocarcinoma, kidney carcinoma, urinary bladder carcinoma, Wilm's tumor, lymphoma, and non-Hodgkin's lymphoma.

### Claim 15

A pharmaceutical composition comprising one or more PARP inhibitor(s), one or more PARG activators, and/or one or more PARP11 activators, wherein said one or more PARP inhibitor(s) selectively decrease the expression and/or one or more activities of one or more PARP(s) selected from the group consisting of PARP5A, PARP12, PARP13 isoform 1 (PARP13.1), PARP13 isoform 2 (PARP13.2), and PARP15.

### Claim 16 (depends on 15)

A kit comprising one or more pharmaceutical compositions of claim 15 and instructions for administering the one or more compositions to a subject diagnosed with a stress granule-related disorder or diagnosed as having a propensity to develop a stress granule-related disorder.

### Claim 17

A pharmaceutical composition comprising one or more PARP inhibitors, wherein said one or more PARP inhibitor(s) selectively decrease the expression and/or one or more activities of one or more PARP(s) selected from the group consisting of PARP1, PARP2, PARP5A, PARP5B, PARP7, PARP8, PARP14, and PARP16.

### Claim 18 (depends on 17)

A kit comprising one or more pharmaceutical compositions of claim 17 and instructions for administering the one or more compositions to a subject diagnosed with cancer or diagnosed as having a propensity to develop a cancer.

### Claim 19

A method for determining the propensity of a subject to develop a stress granule-related disorder comprising determining the expression and/or one or more activities of one or more of PARP5A, PARP11, PARP12, PARP13.1, PARP13.2, PARP15, PARG, and ARH3 in a subject, wherein an increase in the expression and/or one or more activities of one or more of PARP5A, PARP12, PARP13.1, PARP13.2, and PARP15, and/or a decrease in the expression or one or more activities of PARP11, PARG, or ARH3 indicates an increased propensity to develop a stress granule-related disorder.

### Claim 20

A method for determining the propensity of a subject to develop cancer comprising determining the expression and/or one or more activities of one or more of PARP1, PARP2, PARP5A, PARP5B, PARP7, PARP8, PARP14, and PARP16 in a subject, wherein an increase in the expression and/or one or more activities of one or more of PARP1, PARP2, PARP5A, PARP5B, PARP7, PARP8, PARP14, and PARP16 indicates an increased propensity to develop cancer.