METHODS AND COMPOSITIONS FOR CELL-PROLIFERATION-RELATED DISORDERS

• US 20140187435A1
• Filed: 07/11/2013
• Published: 07/03/2014
• Est. Priority Date: 03/13/2009
• Status: Abandoned Application

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Fantin, Valeria, Gross, Stefan, Jang, Hyun Gyung, Jin, Shengfang, Salituro, Francesco Gerald, Su, Shin-San Michael, Yen, Katharine, Dang, Leonard Luan C., Saunders, Jeffrey Owen
• Application Number:
  US13/939,519
• Publication Number:
  US 20140187435A1
• Time in Patent Office: Days
• US Class Current: 506/9
• CPC Class Codes: A61B 5/055 involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
• 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 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• 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 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C12Q 1/32 involving dehydrogenase
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Y 101/01042 Isocitrate dehydrogenase (NADP+) (1.1.1.42)
• CPC Class Codes: G01N 33/574 for cancer
• CPC Class Codes: G16H 20/10 relating to drugs or medications, e.g. for ensuring correct administration to patients
• CPC Class Codes: G16H 40/63 for local operation
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Methods of treating and evaluating subjects having neoactive mutants are described herein.

Claims

1-40. -40. (canceled)

41. A method of evaluating a subject comprising,

analyzing a parameter related to the IDH1 or IDH2 neoactivity phenotype of said subject, wherein analyzing comprises performing a test, on said subject, or on a sample from said subject, and responsive to said analysis, selecting said subject as having an IDH1 or IDH2 allele having 2HG neoactivity,

thereby evaluating the subject.

42. The method of claim 41, wherein analyzing comprises analyzing one or more of:

a) the presence of 2HG;

b) the presence of 2HG neoactivity from an IDH1 or IDH2 mutant protein;

or

c) the presence of RNA corresponding to an IDH1 or IDH2 mutant protein having 2HG neoactivity.

43. The method of claim 41, wherein analyzing comprises analyzing the presence 2HG.

44. The method of claim 41, wherein a sample, from said subject, is analyzed.

45. The method of claim 41, wherein said sample is a tumor sample, cancer cell sample, or precancerous cell sample.

46. The method of claim 45, wherein said sample is analyzed for the presence or level of 2HG.

47. The method of claim 45, wherein said analysis comprises a chromatographic method.

48. The method of claim 45, wherein said analysis comprises LC-MS analysis.

49. The method of claim 41, comprising subjecting said subject to imaging and/or spectroscopic analysis to provide a determination of the presence, distribution, or level of 2HG.

50. The method of claim 49, wherein said presence is associated with a tumor in said subject.

51. The method of claim 50, wherein said tumor is a glioma.

52. The method of claim 49, wherein said imaging and/or spectroscopic analysis comprises magnetic resonance-based analysis.

53. The method of claim 49, wherein said imaging and/or spectroscopic analysis comprises MRI and/or MRS imaging analysis.

54. The method of claim 41, wherein said subject has an increased level of 2HG as compared with a reference.

55. The method of claim 54, wherein said reference is the level seen in an otherwise similar cell, tissue or product lacking an IDH1 and IDH2 neoactive mutation.

56. The method of claim 54, wherein said reference is the level seen in an otherwise similar cell lacking said IDH1 or IDH2 mutation, or in a tissue or product, from said subject not having said IDH1 or IDH2 mutation.

57. The method of claim 41, further comprising determining that the subject has a cancer characterized by an IDH1 or IDH2 allele having 2HG neoactivity by DNA sequencing.

58. The method of claim 41, further comprising confirming or determining that the subject has a cancer characterized by an IDH1 allele having His, Ser, Cys, Gly, Val, Pro or Leu at residue 132 (SEQ ID NO:

8).

59. The method of claim 58, further comprising confirming or determining that the subject has a cancer characterized by an IDH1 allele having His at residue 132 (SEQ ID NO:

8).

60. The method of claim 58, further comprising confirming or determining that the subject has a cancer characterized by an IDH1 allele having Cys at residue 132 (SEQ ID NO:

8).

61. The method of claim 41, further comprising determining the identity of amino acid residue 132 (SEQ ID NO:

8) in the IDH1 gene.

62. The method of claim 57, further comprising confirming or determining that the subject has a cancer characterized an IDH2 allele having Lys, Gly, Met, Trp, Thr, or Ser at residue 172 (SEQ ID NO:

10).

63. The method of claim 41, further comprising diagnosing said subject as having cancer.

64. The method of claim 41, further comprising diagnosing said subject as having a precancerous disorder.

65. The method of claim 41, wherein said subject does not have 2-hydroxyglutaric aciduria.

66. The method of claim 41, wherein said subject has an IDH1 neoactive mutant.

67. The method of claim 66, wherein said neoactive mutant arises from a mutation at residue 132.

68. The method of claim 67, wherein said IDH1 mutant has His, Ser, Cys, Gly, Val, Pro or Leu, at residue 132.

69. The method of claim 67, wherein said IDH1 mutant has His at residue 132.

70. The method of claim 67, wherein said IDH1 mutant has Ser at residue 132.

71. The method of claim 67, wherein said IDH1 mutant has Cys at residue 132.

72. The method of claim 67, wherein said IDH1 mutant has Gly at residue 132.

73. The method of claim 67, wherein said IDH1 mutant has Val at residue 132.

74. The method of claim 67, wherein said IDH1 mutant has Pro at residue 132.

75. The method of claim 67, wherein said IDH1 mutant has Leu at residue 132.

76. The method of claim 41, wherein said subject has an IDH2 neoactive mutant.

77. The method of claim 76, wherein said neoactive mutant arises from a mutation at residue 172.

78. The method of claim 76, wherein said IDH2 mutant has a Lys, Gly, Met, Trp, Thr, or Ser at residue 172.

79. The method of claim 78, wherein said IDH2 mutant has a Lys at residue 172.

80. The method of claim 41, wherein said subject has a leukemia.

81. The method of claim 41, wherein said subject has AML.

82. The method of claim 41, wherein said subject has myelodisplasia.

83. The method of claim 41, wherein said subject has myelodisplastic syndrome.

84. The method of claim 41, further comprising providing a recommendation for treatment of said subject.

85. The method of claim 41, further comprising memorializing a result of, or output from, the method.

86. The method of claim 84, further comprising transmitting the memorialization to a party.

87. The method of claim 86, wherein said party is a healthcare provider.

88. The method of claim 86, wherein said party is an entity that pays for the subject'"'"'s treatment.

89. The method of claim 86, wherein said party is a government or insurance company.

90. The method of claim 41, further comprising, selecting a payment class for treatment with a therapeutic agent, comprising, responsive to said analysis,

performing at least one of (1) if the subject is positive for increased levels of 2HG selecting a first payment class, and (2) if the subject is a not positive for increased levels of 2HG selecting a second payment class.

91. The method of claim 90, wherein said selection is memorialized.

92. The method of claim 91, further comprising communicating said selection to another party.

93. A method of evaluating a subject for the presence or susceptibility to a cancer comprising analyzing the subject or a sample from the subject for one or more of:

a) the presence, distribution, or level of 2HG, wherein the subject is not having or not diagnosed as having 2-hydroxyglutaric aciduria;

b) the presence, distribution, or level of a mutant IDH1 enzyme or mutant IDH2 enzyme, either of which has 2HG neoactivity;

c) the presence, distribution, or level of a RNA encoding a mutant IDH1 enzyme or mutant IDH2 enzyme, either of which has 2HG neoactivity;

or

d) the presence of DNA encoding a mutant IDH1 enzyme or mutant IDH2 enzyme, either of which has 2HG neoactivity;

thereby evaluating the subject for such cancer.

94. The method of claim 93, wherein the cancer is an astrocytic tumor, an oligodendroglial tumor, an oligoastrocytic tumor, an anaplastic astrocytoma, fibrosarcoma, paraganglioma, prostate cancer, acute lymphoblastic leukemia, or acute myelogenous leukemia.

95. The method of claim 93, wherein the cancer is a glioblastoma.

96. The method of claim 93, the method comprising analyzing the presence, distribution, or level of 2HG.

97. The method of claim 96, wherein the presence, distribution or level of 2HG is determined non-invasively by imaging or spectroscopic analysis.

98. The method of claim 97, wherein the imaging or spectroscopic analysis comprises magnetic resonance imaging or magnetic resonance spectroscopy.

99. The method of claim 96, wherein the presence, distribution or level of 2HG is determined by evaluating a tissue, product or bodily fluid of the subject.