METHODS FOR OVERCOMING GLUCOCORTICOID RESISTANCE AND FOR DETERMINING GLUCOCORTICOID RESISTANCE POTENTIAL IN CANCER

• US 20160230173A1
• Filed: 09/16/2014
• Published: 08/11/2016
• Est. Priority Date: 09/16/2013
• Status: Active Grant

• Current Assignee: St Jude Children's Research Hospital Incorporated (Abbott Laboratories)
• Original Assignee: St Jude Children's Research Hospital Incorporated (Abbott Laboratories)
• Inventors: Paugh, Steven W., Evans, William E., Bonten, Erik
• Granted Patent: US 10,457,946 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/44 Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/531 Stem-loop; Hairpin
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/154 : Methylation markers
• CPC Class Codes: C12Q 2600/158 : Expression markers

Abstract

The invention provides methods for overcoming glucocorticoid resistance of cancers by inhibition of CASP1. Also disclosed are diagnostic methods for determining glucocorticoid resistance potential by measuring expression level or promoter methylation status of CASP1 gene and/or NLRP3 gene.

Claims

1. A method of sensitizing a cancer cell to glucocorticoid-induced apoptosis or cell death, wherein said cell is resistant to glucocorticoid-induced apoptosis or cell death, comprising contacting the cell with an effective amount of an inhibitor of CASP1.

4. The method of claim 1, wherein the cancer cell is in a patient.

5. The method of claim 1, wherein the inhibitor of CASP1 directly inhibits expression or function of CASP1.

6. The method of claim 1, wherein the inhibitor of CASP1 directly inhibits expression or function of NLRP3.

7. The method of claim 1, wherein the inhibitor of CASP1 inhibits NLRP3 inflammasome formation or NLRP3 inflammasome activity.

8. The method of claim 1, wherein the inhibitor of CASP1 is selected from the group consisting of z-VAD-DCB, Ac-YVAD-CHO, Ac-YVAD-chloromethylketone, cytokine response modifier A (crmA), Pralnacasan (VX-740), IDN-6556, VX-765, VRT-043198, ML132, and SNAP.

9. The method of claim 1, wherein the glucocorticoid is selected from the group consisting of prednisolone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, cortisol, budesonide, and combinations, enantiomers, optical isomers, diastereomers, N-oxides, crystalline forms, hydrates, metabolites or pharmaceutically acceptable salts thereof.

78. The method of claim 5, wherein the inhibitor of CASP1 is siRNA or shRNA.

79. The method of claim 8, wherein the inhibitor of CASP1 is cytokine response modifier A (crmA).

2. A method of killing a cancer cell, wherein said cell is resistant to glucocorticoid-induced apoptosis or cell death, comprising contacting the cell with an amount of an inhibitor of CASP1 that is effective to sensitize the cell to glucocorticoid-induced apoptosis or cell death and further comprising contacting the cell with an effective amount of a glucocorticoid.

3. The method of claim 2, further comprising contacting the cell with a second agent for inducing apoptosis or cell death.

10. A method of treating a glucocorticoid-resistant cancer in a subject in need thereof which method comprises administering to the subject (i) a therapeutically effective amount of an inhibitor of CASP 1 and (ii) a therapeutically effective amount of a glucocorticoid.

11. The method of claim 10, wherein the therapeutically effective amount of the inhibitor of CASP1 is an amount that is effective to sensitize cancer cells within the subject to glucocorticoid-induced apoptosis or cell death.

12-23. -23. (canceled)

24. A pharmaceutical composition comprising a CASP1 inhibitor, a glucocorticoid, and a pharmaceutically acceptable carrier or excipient.

25-26. -26. (canceled)

27. A method for determining whether a cancer in a subject is likely to be resistant to a glucocorticoid treatment, said method comprising the steps of:

(a) determining the expression level of CASP1 gene and/or NLRP3 gene in cancer cells from the subject;

(b) comparing the expression level of each gene determined in step (a) with a corresponding control expression level for that gene, and

(c) (i) identifying that the cancer in the subject is likely to be resistant to the glucocorticoid treatment when the expression level of CASP1 gene and/or NLRP3 gene in step (a) is increased by at least 1.5 fold as compared to the corresponding control expression level or (ii) identifying that the cancer in the subject is not likely to be resistant to the glucocorticoid treatment when the expression level of CASP1 gene and/or NLRP3 gene in step (a) is not increased or is increased by less than 1.5 fold as compared to the corresponding control expression level.

28-44. -44. (canceled)

45. A method for determining whether a cancer in a subject is likely to be resistant to a glucocorticoid treatment, said method comprising the steps of:

(a) determining the methylation level of CASP1 gene promoter and/or NLRP3 gene promoter in cancer cells from the subject;

(b) comparing the methylation level of each gene promoter determined in step (a) with a corresponding control methylation level for that gene promoter, and

(c) (i) identifying that the cancer in the subject is likely to be resistant to glucocorticoid treatment when the methylation level of CASP1 gene promoter and/or NLRP3 gene promoter in step (a) is decreased by at least 1.5 fold as compared to the corresponding control methylation level or (ii) identifying that the cancer in the subject is not likely to be resistant to glucocorticoid treatment when the methylation level of CASP1 gene promoter and/or NLRP3 gene promoter in step (a) is not increased or is increased by less than 1.5 fold as compared to the corresponding control methylation level.

46-64. -64. (canceled)

65. A kit for diagnosing likelihood of cancer resistance to glucocorticoid treatment, said kit comprising one or more pairs of oligonucleotides directed toward CASP1 and/or NLRP3 nucleic acid, wherein said pairs of oligonucleotides can be used to determine the expression level of CASP1 gene and/or NLRP3 gene.

66-69. -69. (canceled)

70. A kit for diagnosing likelihood of cancer resistance to glucocorticoid treatment, said kit comprising antibodies directed toward CASP1 protein and/or NLRP3 protein, wherein said antibodies can be used to determine the expression level of CASP1 and/or NLRP3 protein.

71-73. -73. (canceled)

74. A kit for diagnosing likelihood of cancer resistance to glucocorticoid treatment, said kit comprising means for detecting promoter methylation of CASP1 gene and/or NLRP3 gene.

75. (canceled)

76. A method of treating a glucocorticoid-resistant asthma in a subject in need thereof which method comprises administering to the subject (i) a therapeutically effective amount of an inhibitor of CASP1 and (ii) a therapeutically effective amount of a glucocorticoid.

77. (canceled)