# US 2013/0280264 A1 · Total and Phosphorylated IL-1 Receptor-Associated Kinase-1 and IL-1 Receptor-Associated Kinase-4 as a Biomarker for Cancer Progression and Chemotherapy Resistance

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- Number: US 2013/0280264 A1
- Document ID: US20130280264A1
- Status: Published application
- Kind: A1
- Application number: 13/804,135
- Filed: 2013-03-14
- Published: 2013-10-24
- Earliest claimed: 2012-03-22
- Assignees: University of Maryland, Baltimore
- Applicants: University of Maryland, Baltimore
- Inventors: Eduardo Davila
- Web page: https://patentgrep.com/patent/US20130280264A1

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- C07D 235/04: Benzimidazoles; Hydrogenated benzimidazoles
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/158: Expression markers
- G01N 2333/9121: with an alcohol group as acceptor (2.7.1), e.g. general tyrosine, serine or threonine kinases
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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
- 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)
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Toll-like receptors (TLR) are expressed by a variety of cancers, including melanoma and T-ALL. TLR signaling plays an important role in T cell malignancies and melanoma. The effects of stimulating or inhibiting the TLR/IL-1 receptor-associated kinases IRAK-1 and IRAK-4 in melanoma and T-ALL cells were evaluated. Pharmacological treatment with an IRAK-1,-4 inhibitor delays tumor growth and prolongs survival in vitro and in vivo, indicating that TLR signaling contributes to T-ALL and melanoma progression and interfering with this signaling is a novel therapeutic strategy to control T-ALL and melanoma proliferation.

## Claims

### Claim 1

A method comprising:
(a) identifying a subject having cancer that expresses an active form of IRAK-1 or phosphorylated IRAK-1 or a variant thereof and/or active form of IRAK-4 or phosphorylated IRAK-4 or a variant thereof; and
(b) administering to the subject a therapeutically effective amount of an IRAK-1,-4 inhibitor, in an amount that reduces or eliminates the cancer.

### Claim 2 (depends on 1)

The method of claim 1, wherein step (a) further comprises:
(i) obtaining a biological sample of the cancer from the subject,
(ii) determining if the cancer cells in the biological sample expresses an active form of IRAK-1 or phosphorylated IRAK-1 or a variant thereof and/or an active form of or phosphorylated IRAK-4 or a variant thereof, and
(iii) if the active form of IRAK-1 or phosphorylated IRAK-1 or a variant thereof and/or active form of IRAK-4 or phosphorylated IRAK-4 or a variant thereof is detected, then identifying the subject as having cancer that expresses active or phosphorylated IRAK-1 and/or active or phosphorylated IRAK-4 or a variant thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein the subject is human.

### Claim 4 (depends on 2)

The method of claim 2, wherein the cancer is selected from the group consisting of lung cancer, digestive and gastrointestinal cancers, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, stomach (gastric) cancer, esophageal cancer, gall bladder cancer, liver cancer, pancreatic cancer, appendix cancer, breast cancer, ovarian cancer, renal cancer, cancer of the central nervous system, skin cancer, lymphomas, lymphoblastic leukemias, choriocarcinomas, head and neck cancer, osteogenic sarcomas, and blood cancers.

### Claim 5 (depends on 4)

The method of claim 4, wherein the cancer is T-ALL.

### Claim 6 (depends on 4)

The method of claim 4, wherein the skin cancer is melanoma.

### Claim 7 (depends on 1)

The method of claim 1, wherein the amount of IRAK-1,-4 inhibitor ranges from 1 mg/kg to about 100 mg/kg.

### Claim 8 (depends on 7)

The method of claim 7, wherein the IRAK-1,-4 inhibitor is administered orally, by injection, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.

### Claim 9 (depends on 7)

The method of claim 7, wherein IRAK-1,-4 inhibitor is administered locally to the site of the cancer.

### Claim 10 (depends on 7)

The method of claim 7, wherein IRAK-1,-4 inhibitor is administered alone, or in combination with a chemotherapeutic drug.

### Claim 11 (depends on 10)

The method of claim 10, wherein the chemotherapeutic drug is selected from the group consisting of vinblastine, 5′-flurouracil, cisplatin, vemurafenib, ipilimumab, and BMW-663513, ABT-737, PF-04929113, 17-AAG(Geldanamycin), 17-DMAG, BIIB021, BIIB021, SNX-2112, Vinflunine Tartrate, CYT997, Vincristine Sulfate, ABT-751, Docetaxel, Epothilone A, Paclitaxel(Taxol), Vinorelbine(Navelbine), Abiraterone Acetate, BI6727, Eplerenone, KX2-391, and Irinotecan Hcl Trihydrate.

### Claim 12 (depends on 11)

The method of claim 11, wherein the chemotherapeutic drug is in an amount of about in a range of from about 3.7 mg/m2 to about 100 mg/m2.

### Claim 13

A pharmaceutical composition comprising therapeutically effective amounts of IRAK-1,-4 inhibitor in a range of from about 1 mg/kg to about 100 mg/kg.

### Claim 14

A pharmaceutical composition comprising therapeutically effective amounts of IRAK-1,-4 inhibitor in combination with one or chemotherapeutic drug.

### Claim 15 (depends on 13)

The pharmaceutical composition of claim 13, wherein the chemotherapeutic drug is selected from the group consisting of vinblastine, 5′-fluorouracil, cisplatin, vinblastine, 5′-flurouracil, cisplatin, vemurafenib, ipilimumab, and BMW-663513, ABT-737, PF-04929113, 17-AAG(Geldanamycin), 17-DMAG, BIIB021, BIIB021, SNX-2112, Vinflunine Tartrate, CYT997, Vincristine Sulfate, ABT-751, Docetaxel, Epothilone A, Paclitaxel(Taxol), Vinorelbine(Navelbine), Abiraterone Acetate, BI6727, Eplerenone, KX2-391, and Irinotecan Hcl Trihydrate.

### Claim 16 (depends on 13)

The pharmaceutical composition of claim 13, wherein the chemotherapeutic drug is in an amount of about in a range of from about 3.7 mg/m2 to about 100 mg/m2.

### Claim 17 (depends on 13)

A kit containing the pharmaceutical composition of claim 13.

### Claim 18 (depends on 14)

A kit containing the pharmaceutical composition of claim 14.

### Claim 19

A method for determining if cancer in a subject will be responsive to treatment with a IRAK-1,-4 inhibitor, comprising:
(a) obtaining a biological sample of cells from the cancer, from the subject;
(b) assaying the cells in the sample for the presence of an active form of or phosphorylated IRAK-1 or a variant thereof and/or active form of or phosphorylated IRAK-4 or a variant thereof, and;
(c) if the activated form of or phosphorylated IRAK-1 or variant thereof and/or active form of or phosphorylated IRAK-4 or variant thereof is detected in the cells, then determining that the cancer will respond to treatment with the IRAK-1,-4 inhibitor.

### Claim 20 (depends on 19)

The method of claim 19 further comprising
(d) administering a therapeutically effective amount of the IRAK-1,-4 inhibitor to the subject.

### Claim 21 (depends on 20)

The method of claim 20, wherein the cancer is melanoma.

### Claim 22 (depends on 20)

The method of claim 20, wherein the biological sample is melanoma tissue.

### Claim 23 (depends on 20)

The method of claim 20, wherein the subject is human.

### Claim 24

A method comprising:
(a) obtaining a biological sample of cells from a subject diagnosed with T-ALL;
(b) assaying the T-ALL cells in the sample for the expression of TLR1 and TLR2;
(c) contacting the cells with a TLR-1 and TLR-2 agonist; and
(d) if TLR1 and TLR2 expression increases in response to administration of the TLR-1 and TLR2 agonist, then determining that T-ALL will respond to treatment with an IRAK-1,-4 inhibitor.

### Claim 25

A method comprising identifying a patient having T-ALL and administering a therapeutically effective amount of an IRAK-1,-4 inhibitor to the patient.

### Claim 26

A method comprising identifying a patient having melanoma and administering a therapeutically effective amount of an IRAK-1,-4 inhibitor to the patient.

### Claim 27

A method comprising
a) providing a test biological sample from a subject and a control biological sample from a healthy subject,
b) determining a level of p-IRAK-1 or p-IRAK-4 in the tests and control samples,
c) and if the expression of p-IRAK-1 or p-IRAK-4 in the test sample is significantly higher than the level of p-IRAKs-1 or p-IRAK-4 expression in the control sample, then determining that the subject is at risk for developing T-ALL.

### Claim 28

A method comprising
a) providing a test biological sample from a subject; and a control biological sample from a healthy subject,
b) determining a level of p-IRAK-1 or p-IRAK-4 in the test sand control samples,
c) and if the expression of p-IRAK-1 or p-IRAK-4 in the test sample is significantly higher than the level of p-IRAKs-1 or p-IRAK-4 expression in the control sample, then determining that the subject is at risk for developing melanoma.

### Claim 29

A method of increasing the efficacy of a chemotherapeutic drug comprising administering an IRAK-1,-4 inhibitor in combination with the chemotherapeutic drug.