Methods and compositions for cell-proliferation-related disorders

Abstract

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.