Diagnosing idh1 related subgroups and treatment of cancer

Abstract

The invention relates to classification, diagnosis and treatment of cancers. In one embodiment, the present invention provides methods and kits that classify cancers into various subtypes based on expression patterns of AKT pathway components. In another embodiment, the present invention provides methods and kits that diagnose cancer subtypes by evaluating expression patterns of AKT pathway components. In still another embodiment, the present invention provides methods and kits that treat a cancer subtype by administering an alkylating agent or a PI3K/AKT/mTOR inhibitor to a patient. Cancers suitable with various embodiments of the invention include but are not limited to brain tumors, gliomas and GBM.

1 - 29 . (canceled) 
     
     
         30 . A method for treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a cancer in a subject, comprising:
 assaying a sample obtained from the subject to detect increases and/or decreases in expression levels of AKT pathway components relative to reference samples or values, wherein the AKT pathway components is selected from the group consisting of ATP citrate lyase (ACLY), V-akt murine thymoma viral oncogene homolog 1 (AKT1), Ataxin 1 (ATXN1), B-cell CLL/lymphoma 10 (BCL10), Cyclin D1 (CCND1), Cell division cycle 37 (CDC37), Cyclin-dependent kinase inhibitor 1A (CDKN1A), Cyclin-dependent kinase inhibitor 1B (CDKN1B), Complement factor D (CFD), Checkpoint kinase 1 (CHEK1), Epidermal growth factor receptor (EGFR), Eukaryotic translation initiation factor 3 subunit B (EIF3B), Eukaryotic translation initiation factor 3 subunit E (EIF3E), Eukaryotic translation initiation factor 3 subunit G (EIF3G), Eukaryotic translation initiation factor 3 subunit F (EIF3H), Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), Endothelial PAS domain protein 1 (EPAS1), Enhancer of zeste homolog 2 (EZH2), Fibroblast growth factor receptor 2 (FGFR2), Fibroblast growth factor receptor 3 (FGFR3), Forkhead box 03 (FOXO3), FYN oncogene related to SRC FGR YES (FYN), GRB2-associated binding protein 1 (GAB1), GRB2-associated binding protein 2 (GAB2), Growth factor receptor-bound protein 10 (GRB10), Glycogen synthase kinase 3 beta (GSK3B), Hypoxia inducible factor 1, alpha subunit (HIF1A), Heat shock protein 90 alpha (cytosolic) class B member 1 (HSP90AB1), Heat shock protein 90 beta (Grp94) member 1 (HSP90B1), Inositol polyphosphate-5-phosphatase (INPP5D), Insulin receptor substrate 1 (IRS1), Insulin receptor substrate 2 (IRS2), Kinase insert domain receptor (KDR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), Mitogen-activated protein kinase kinase kinase 5 (MAP3K5), Mitogen-activated protein kinase 8 interacting protein 1 (MAPK8IP1), Neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), Palladin, cytoskeletal associated protein (PALLD), Platelet-derived growth factor alpha (PDGFA), platelet derived growth factor C (PDGFC), Platelet derived growth factor D (PDGFD), Platelet-derived growth factor receptor beta (PDGFRB), 3-phosphoinositide dependent protein kinase-1 (PDK1), PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1), Phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 beta (PIK3C2B), Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1), Polycystic kidney disease 2 (PKD2), Protein kinase N2 (PKN2), Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A), Protein phosphatase 2 regulatory subunit A alpha (PPP2R1A), Protein phosphatase 2 regulatory subunit B beta (PPP2R2B), V-raf-1 murine leukemia viral oncogene homolog 1 (RAF1), Sorbin and SH3 domain containing 2 (SORBS2), Serine/arginine-rich splicing factor 1 (SRSF1), Sjogren syndrome antigen B (SSB), Spleen tyrosine kinase (SYK), Tumor protein p53 (TP53), Tribbles homolog 3 (TRIB3), Tuberous sclerosis 1 (TSC1), Tuberous sclerosis 2 (TSC2), Twist basic helix-loop-helix transcription factor 1 (TWIST1), Vimentin (VIM), WNK lysine deficient protein kinase 1 (WNK1), and combinations thereof;   detecting an expression pattern of AKT pathway components in the sample based on the detected increases and/or decreases, wherein the expression pattern of AKT pathway components is C1 ‘s expression pattern, PN's expression pattern, MES's expression pattern, CLAS's expression pattern of AKT pathway components, SL's expression pattern, or PROLIF’ s expression pattern, and wherein
 C1's expression pattern comprise increased expression levels in one or more of ATXN1, BCL10, CDKN1B, CFD, CHEK1, EIF3E, EIF3H, EPAS1, EZH2, FOXO3, HIF1A, HSP90B1, IRS1, IRS2, KRAS, MAP3K5, NRAS, PALLD, PDGFA, PDGFC, PDGFD, PDK1, PIK3CA, PIK3R1, PKD2, PKN2, PPARGC1A, PPP2R2B, SRSF1, SSB, SYK, TWIST1, and WNK1; and/or insignificantly changed expression levels in one or more of CCND1, CDKN1A, KDR, TRIB3, and VIM; and/or decreased expression levels in one or more of ACLY, AKT1, CDC37, EGFR, EIF3B, EIF3G, EIF4EBP1, FGFR2, FGFR3, FYN, GAB1, GAB2, GRB10, GSK3B, HSP90AB1, INPP5D, MAPK8IP1, PDGFRB, PHLPP1, PIK3C2B, PPP2R1A, RAF1, SORBS2, TP53, TSC1, and TSC2; 
 PN's expression pattern of AKT pathway components comprise increased expression levels in one or more of ATXN1, FGFR2, FGFR3, GAB2, GSK3B, HSP90AB1, IRS1, KRAS, MAP3K5, MAPK8IP1, PHLPP1, PIK3C2B, PIK3R1, PPARGC1A, PPP2R1A, PPP2R2B, SORBS2, TSC1, and TSC2; and/or insignificantly changed expression levels in one or more of CDKN1B, CFD, EPAS1, FOXO3, GAB1, KDR, and WNK1; and/or decreased expression levels in one or more of ACLY, AKT1, BCL10, CCND1, CDC37, CDKN1A, CHEK1, EGFR, EIF3B, EIF3E, EIF3G, EIF3H, EIF4EBP1, EZH2, FYN, GRB10, HIF1A, HSP90B1, INPP5D, IRS2, NRAS, PALLD, PDGFA, PDGFC, PDGFD, PDGFRB, PDK1, PIK3CA, PKD2, PKN2, RAF1, SRSF1, SSB, SYK, TP53, TRIB3, TWIST1, and VIM; 
 MES's expression pattern of AKT pathway components comprise increased expression levels in one or more of AKT1, BCL10, CCND1, CDC37, CDKN1A, CFD, EIF3B, EPAS1, GRB10, HIF1A, HSP90B1, INPP5D, IRS1, IRS2, KDR, PALLD, PDGFA, PDGFC, PDGFD, PDGFRB, PDK1, PKD2, SYK, TRIB3, TWIST1, and VIM; and/or insignificantly changed expression levels in one or more of CHEK1, EIF3G, EIF4EBP1, MAP3K5, PKN2, SORBS2, TP53, and WNK1; and/or decreased expression levels in one or more of ACLY, ATXN1, CDKN1B, EGFR, EIF3E, EIF3H, EZH2, FGFR2, FGFR3, FOXO3, FYN, GAB1, GAB2, GSK3B, HSP90AB1, KRAS, MAPK8IP1, NRAS, PHLPP1, PIK3C2B, PIK3CA, PIK3R1, PPARGC1A, PPP2R1A, PPP2R2B, RAF1, SRSF1, SSB, TSC1, and TSC2; 
 CLAS's expression pattern of AKT pathway components comprise increased expression levels in one or more of ACLY, AKT1, CDC37, CDKN1A, CHEK1, EGFR, EIF3B, EIF3E, EIF3G, EIF4EBP1, EPAS1, FGFR3, FYN, GAB1, GRB10, HIF1A, HSP90B1, IRS2, KDR, MAPK8IP1, NRAS, PALLD, PDGFA, PDGFC, PDGFD, PDGFRB, PDK1, PKD2, PKN2, PPARGC1A, PPP2R1A, PPP2R2B, RAF1, SRSF1, SSB, TP53, TRIB3, TWIST1, and VIM; and/or insignificantly changed expression levels in one or more of ATXN1, BCL10, EIF3H, EZH2, HSP90AB1, INPP5D, PIK3R1, and SYK; and/or decreased expression levels in one or more of CCND1, CDKN1B, CFD, FGFR2, FOXO3, GAB2, GSK3B, IRS1, KRAS, MAP3K5, PHLPP1, PIK3C2B, PIK3CA, SORBS2, TSC1, TSC2, and WNK1; 
 SL's expression pattern of AKT pathway components comprise increased expression levels in one or more of ACLY, CCND1, CDKN1B, EGFR, EIF3B, EIF3E, EIF3G, EIF3H, FOXO3, FYN, GAB1, GAB2, INPP5D, IRS1, MAP3K5, MAPK8IP1, PDGFC, PHLPP1, PIK3C2B, PIK3CA, PIK3R1, RAF1, SYK, TP53, TRIB3, TSC1, and TSC2; and/or insignificantly changed expression levels in one or more of ATXN1, CDC37, GSK3B, HSP90AB1, PKN2, PPP2R2B, and SRSF1; and/or decreased expression levels in one or more of AKT1, BCL10, CDKN1A, CFD, CHEK1, EIF4EBP1, EPAS1, EZH2, FGFR2, FGFR3, GRB10, HIF1A, HSP90B1, IRS2, KDR, KRAS, NRAS, PALLD, PDGFA, PDGFD, PDGFRB, PDK1, PKD2, PPARGC1A, PPP2R1A, SORBS2, SSB, TWIST1, VIM, and WNK1; and 
 PROLIF's expression pattern of AKT pathway components comprise increased expression levels in one or more of ACLY, AKT1, BCL10, CCND1, CDKN1B, CHEK1, EIF3B, EIF3E, EIF3G, EIF3H, EIF4EBP1, EZH2, FYN, GSK3B, HSP90AB1, HSP90B1, NRAS, PDK1, PIK3CA, PPP2R1A, RAF1, SRSF1, SSB, TP53, TRIB3, TSC2, and TWIST1; and/or insignificantly changed expression levels in one or more of CDC37, GAB1, GRB10, IRS1, KRAS, PHLPP1, PKN2, and VIM; and/or decreased expression levels in one or more of ATXN1, CDKN1A, CFD, EGFR, EPAS1, FGFR2, FGFR3, FOXO3, GAB2, HIF1A, INPP5D, IRS2, KDR, MAP3K5, MAPK8IP1, PALLD, PDGFA, PDGFC, PDGFD, PDGFRB, PIK3C2B, PIK3R1, PKD2, PPARGC1A, PPP2R2B, SORBS2, SYK, TSC1, and WNK1; and 
   administering a therapeutically effective amount of a therapeutic to the subject, thereby treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of the cancer.   
     
     
         31 . The method of  claim 30 , wherein the cancer is a brain tumor, glioma, high grade glioma (HGG), glioblastoma, or glioblastoma multiforme (GBM). 
     
     
         32 . The method of  claim 30 , wherein the subgroup is subgroup SL, and wherein the therapeutic is BCNU or CCNU, a functional equivalent, analog, derivative or salt of BCNU or CCNU, or a combination thereof. 
     
     
         33 . The method of  claim 32 , further comprising preventing the subject from receiving TMZ, or a functional equivalent, analog, derivative or salt of TMZ. 
     
     
         34 . The method of  claim 30 , wherein the subgroup is subgroup MES, and wherein the therapeutic is TMZ, a functional equivalent, analog, derivative or salt of TMZ, or a combination thereof. 
     
     
         35 . The method of  claim 30 , further comprising detecting a marker for the ATK expression pattern. 
     
     
         36 . The method of  claim 35 , wherein the marker is one or more mutations in IDH1, IDH2 or both. 
     
     
         37 . The method of  claim 35 , wherein the marker is an increased expression level in VIM, CD44, CD45, Fibronectin, or Nucleostemin, or a combination thereof. 
     
     
         38 . The method of  claim 35 , wherein the marker is one or more mutations in EGFR and/or CDKN2A, or copy number alterations (CNAs), or combinations thereof. 
     
     
         39 . A method for treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a cancer in a subject, comprising:
 administering a therapeutically effective amount of TMZ, a functional equivalent, analog, derivative or salt of TMZ to the subject, thereby treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of the cancer,   wherein the subject has been detected as having a MES subgroup/subtype cancer or a marker for the MES subgroup/subtype, wherein the therapeutic is TMZ, a functional equivalent, analog, derivative or salt of TMZ, or a combination thereof.