# US 10,479,997 B2 · Compositions and methods for diagnosis and treatment of prostate cancer

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- Number: US 10,479,997 B2
- Document ID: US10479997B2
- Status: Granted
- Kind: B2
- Application number: 15/532,087
- Filed: 2015-12-01
- Published: 2017-10-05
- Granted: 2019-11-19
- Earliest claimed: 2014-12-01
- Assignees: Novartis AG
- Applicants: Zineb Mounir; Raymond Pal Pagliarini
- Inventors: Zineb Mounir; Raymond Pal Pagliarini
- Web page: https://patentgrep.com/patent/US10479997B2

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61P 35/00: Antineoplastic agents
- A61K 2039/5158: {Antigen-pulsed cells, e.g. T-cells}
- C12N 2310/10: Type of nucleic acid
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/20: involving clustered regularly interspaced short palindromic repeats [CRISPR]
- C12N 2320/10: in screening processes
- C12N 2320/31: Combination therapy
- 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

## Abstract

The invention provides novel personalized therapies, kits, transmittable forms of information and methods for use in treating subjects having TMPRSS2:ERG positive prostate cancer, which we show is amenable to therapeutic treatment with a PRMT5 inhibitor. Kits, methods of screening for candidate PRMT5 inhibitors, and associated methods of treatment are also provided.

## Claims

### Claim 1

A method of determining if a subject afflicted with prostate cancer will respond to therapeutic treatment with a PRMT5 inhibitor comprising
(a) evaluating a test sample obtained from the subject for TMPRSS2:ERG positivity by at least detecting of the methylation of R761 of the Androgen Receptor, wherein TMPRSS2:ERG positivity indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor;
(b) determining the level and/or activity of PRMT5 in the subject, wherein (a) and (b) can be performed in any order; and (c) administering a therapeutically effective amount of a PRMT5 inhibitor to the subject, wherein the PRMT5 inhibitor is selected from the group consisting of a RNAi agent, a CRISPR, a TALEN, a zinc finger nuclease, an mRNA, an antibody or derivative thereof, an antibody-drug conjugate, a chimeric antigen receptor T cell (CART) or a low molecular weight compound.

### Claim 2 (depends on 1)

The method of claim 1, wherein the PRMT5 inhibitor is a RNAi agent.

### Claim 3 (depends on 1)

The method of claim 1, wherein the method further comprises the step of administering to a subject a second therapeutic agent.

### Claim 4 (depends on 3)

The method of claim 3, wherein the second therapeutic agent is an anti-cancer agent, anti-allergic agent, anti-nausea agent or anti-emetic agent, pain reliever, cytoprotective agent.

### Claim 5 (depends on 3)

The method of claim 3, wherein the second therapeutic agent is an anti-cancer agent selected from the list consisting of: an Androgen Receptor antagonist, abiraterone, enzalutamide, bicalutamide, flutamide, HDAC inhibitor, fluorouracil (5-FU) irinotecan, a HDM2 inhibitor, a purine analogue, 6-thioguanine, 6-mercaptopurine, a CDK4 inhibitor, and LEE011, and inhibitors of HDM2i, PI3K/mTOR-I, MAPKi, RTKi, EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi.

### Claim 6 (depends on 1)

The method of claim 1, further comprising determining the level and/or activity of PRMT5 in the subject following step (c), wherein a decrease in the level and/or activity of PRMT5 is correlated with the inhibition of the proliferation of the cancer.

### Claim 7 (depends on 1)

The method of claim 1, wherein methylation of R761 of the Androgen Receptor is monomethylation.

### Claim 8 (depends on 1)

The method of claim 1, wherein methylation of R761 of the Androgen Receptor is dimethylation.

### Claim 9 (depends on 1)

The method of claim 1, wherein the Androgen Receptor comprises an amino acid sequence of SEQ ID NO: 1478.

### Claim 10 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of a ERG inhibitor.