METHODS AND COMPOSITIONS FOR CELL-PROLIFERATION-RELATED DISORDERS
Methods of treating and evaluating subjects having neoactive mutants are described herein.
1 - 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.