Novel methods of cancer therapy targeted against a cancer stem line

Abstract

Improved methods for treatment of cancer which involve the targeting of slow-growing, relatively mutationally-spared cancer stem line are provided. These methods are an improvement over previous cancer therapeutic methods because they provide for very early cancer treatment and reduce the likelihood of clinical relapse after treatment.

What is claimed is: 
     
         1 . An improved method of treating cancer which involves the administration of a therapeutic agent which selectively kills, inhibits or modulates the growth of cancer cells wherein the improvement comprises administering a therapeutic agent which provides for the selective killing, inhibition or modulation of the growth of a cancer stem line (defined as symmetrically dividing stem cell) present within a cancerous tumor. 
     
     
         2 . The method of  claim 1 , wherein the therapeutic agent comprises a ligand which selectively binds to a cancer stem line. 
     
     
         3 . The method of  claim 2 , wherein the ligand is molecule that specifically binds to a cancer stem Line-specific cell surface antigen stem cell markers and wherein said antigen is selected from the group consisting of CD34, Scl/Tal-1, Flk-1/KDR, Tie-1, Tie-2, c-Kit, AC133, PU.I, ikaros, beta-1 alpha (2,3,5) integrin, cytokeratin 19, basonuclin, skin 1a-i/Epoc-1/Oct11, cytokeratin 14, LEF-1, SP-1, SP-2, EGF-R, MUC-1, c-Kit, SCF, Ag/'s270.38,374.3, 18.11, AFP, IGF-2, TGP-alpha/beta, GGT, Isl-1, FA-1, TRA-1-60, SSEA (1,3,4), BCL-2, Muc-1, ESA, HMWCk (5,14), pp32, CD44, notch, numb, nestin, and p75. 
     
     
         4 . The method of  claim 2 , wherein said ligand is an antibody. 
     
     
         5 . The method of  claim 2 , wherein said ligand is specific to a cancer stem line receptor. 
     
     
         6 . The method of  claim 3 , wherein the ligand is administered alone or in conjunction with a therapeutic moiety. 
     
     
         7 . The method of  claim 6 , wherein the therapeutic moiety is selected from the group consisting of radionuclides, therapeutic enzymes, chemotherapeutic agents, cytokines, cytotoxins, growth modulators, and derivatives thereof. 
     
     
         8 . The method of  claim 7 , wherein such method does not substantially cause toxicity to normal stem cells. 
     
     
         9 . A method of treating cancer which involves the administration of a therapeutic agent which selectively causes a cancer stem line to switch from symmetric mitosis to asymmetric mitosis. 
     
     
         10 . The method of  claim 9 , wherein the therapeutic agent is selected from the group consisting of protein, antibody, and nucleic acid capable of either (i) activating factors which normally are capable of inducing a cancer stem line to switch from symmetric to asymmetric mitosis, or (ii) blocking factors which can normally inhibit a cancer stem line from switching from symmetric to asymmetric mitosis. 
     
     
         11 . The method of  claim 10 , wherein said nucleic acid is a naturally-occurring or synthetic DNA, RNA or riboprotein. 
     
     
         12 . The method of  claim 10 , wherein said therapeutic agent or factor which either activate asymmetric mitosis or block the inhibition of asymmetric mitosis is selected from the group consisting of Notch 1-4, notchless, GSK3beta, Pit-1, p78, Isl-1, mPAR, MARK, TFIIA, Y-box proteins, piwi/hiwi/elF2C/prg-1/rde-1 homolog, mut-7-homolog, X-linked modifiers of HD/PWS, glycipan-3, m-Numb, HASH-1/2, dHAND, BCl, Tan-1, SCL, Oct-2, spectrosome, hnRNP/'s (hnRNP1,A2), snRNP/'s (U1-snRNP), POMp75, POMp100, Myo-D, Myf-1, H19, SNRPN, IPW, PAR (1,5,SN), ASR (1,2), BD, ZNF127, aminoacyl tRNA's, endogenous antisense molecules specific to a gene selected from the group consisting of H19, IGF2, IGF2R, KvLQT1, ZNP127AS, and UBE3A; Ins2, U2af, an X-linked modifier of X transmission, loci selected from the group consisting of 3q21, 3q26, 4qter, 16p13, 16q22, and 15p, 1; an HPP-1 polypeptide having, a molecular weight of 75 of 100 kDa, BS, WS, ATM, topoisomerase-2, mos, SIR4, RAD50, zeste, polycombgenes, p57KIP2, M31/HSM1, M32, Sxl, dsx, a human homolog of a yeast gene selected from the group consisting of Ash1-p, HO, cdc 42, cdc 24, and Swi, a human homolog of a gene from  C. elegans  selected from the group consisting of Gip-1, LAG-2, Par-1/2/3, HAM-1, Unc-73/86, lin-11/12/17/18/26/44, Mom (1-5), Apr-1, Wrm-1, PIE-1, Skn-1, and Mec-3, a human homolog of a gene from  Drosophila  selected from the group consisting, of bicoid, oskar, gurken, caudal, nanos, hunchback, GCL, cyclin B, prospero, inscutable, miranda, staufen, numb, notch, delta, serrate, tramtrack, pumillo, wingless, frizzled, disheveled, hedgehog, En, patched, DPP, and achaete-acute; a human homolog of a  Xenopus  gene selected from the group consisting of Xwnt-11, Xcat-2/3, Xlsirt, Vg1, beta-Trcp, Elf4A, Xdazl, and PKC-alpha; and cytoskeletal inhibitors selected from the group consisting of colcemid, colchicine, cytochalasin D, latrunculin A, heavy metals, and taxanes. 
     
     
         13 . The method of  claim 12 , wherein the heavy metal is arsenic or platinum. 
     
     
         14 . The method of  claim 10 , wherein said therapeutic agent or factor which either activates asymmetric mitosis or blocks the inhibition of asymmetric mitosis is selected from the group consisting of enzymes involved in nucleic acid (DNA or RNA) synthesis, protein synthesis, the removal of essential growth factors and drugs, or chalones that induce a cellular starvation response. 
     
     
         15 . The method of  claim 14 , wherein said agent or factor is selected from the group consisting of retinoic acid or histone deacetylase inhibitors, sodium phenylbutyrate, sodium phenylacetate, DMSO, HMBA, PMA, tetramethyl urea, amino acid analogs, inosine monophosphate dehydrogenase inhibitor, rRNA inhibitors, inhibitor of charging tRNA or protein translation, and guanine nucleotide inhibitors. 
     
     
         16 . The method of  claim 15 , wherein said therapeutic agent or factor is selected from the group consisting of trichostatin, AzC, 6MMPR, L-alanosine, PALA, mycophenolic acid, methotrexate, heaprin, a synthetic peptide substrate of casein kinase II, actinomycin D, puromycin aminonucleoside, DRB, H10 histine, histidinol, a compound that effects EIF46 cleavage, virazole, and 6-chloropurin. 
     
     
         17 . The method of  claim 9 , wherein such a method does not substantially cause toxicity to stem cells undergoing asymmetric mitosis (normal stem cells). 
     
     
         18 . A method of treating cancer which comprises the administration of at least one therapeutic agent which selectively cause a cancer stem line to switch from symmetric mitosis to symmetric differentiation thereby resulting in irreversible eradication or said cancer stem line. 
     
     
         19 . The method of  claim 18 , wherein the administered therapeutic agent is selected from the group consisting of proteins, antibodies, nucleic acids, riboproteins, heavy metals, and other naturally-occurring or synthetic molecular species and wherein said method 1) causes a cancer stem line to remain in symmetric mitotic phase by either i) blocking factors which can normally cause a cancer stem line to switch from symmetric to asymmetric mitosis, or ii) activating factors which can normally inhibit a cancer stem line from switching from symmetric to asymmetric mitosis, and subsequently 2) inducing cell differentiation or starvation thereby causing the cancer stem line to undergo differentiation, resulting in symmetric differentiation and irreversible eradication of said cancer stem line. 
     
     
         20 . The method of  claim 19 , wherein said therapeutic agent or factor is selected from the group consisting of factors involved in structural asymmetry, downstream transcription factors, and unequally interacting and/or segregated factors ultimately responsible for inhibiting (or enacting) asymmetric mitosis. 
     
     
         21 . The method of  claim 19 , wherein said therapeutic agent or said factor selected from the group consisting of Notch 1-4, notchless, GSK3beta, Pit-1, p78, Isl-1, mPAR, MARK, TFIIA, Y-box proteins, piwi/hiwi/elF2C/prg-1/rde-1 homolog, mut-7-homolog, X-linked modifiers of HD/PWS, glycipan-3, m-Numb, HASH-1/2, dHAND, BCl, Tan-1, SCL, Oct-2, spectrosome, hnRNP/'s (hnRNP1,A2), snRNP/'s (U1-snRNP), POMp75, POMp100, Myo-D, Myf-1, H19, SNRPN, IPW, PAR (1,5,SN), ASR (1,2), BD, ZNF127, aminoacyl tRNA's, an endogenous antisense molecules specific to a gene selected from the group consisting of H19, IGF2, IGF2R, KvLQT1, ZNF127AS, and UBE3A; Ins2, U2af, an X-linked modifier of X transmission, loci selected from the group consisting of 3q21, 3q26, 4qter, 16p13, 16q22, and 15p, 1; HPP-1 polypeptides having a molecular weight of about 100 or 75 kDa, BS, WS, ATM, topoisomerase-2, moo, SIR4, RAD50, zeste, polycombgenes, p57KIP2, M31/HSM1, M32, Sxl, dsx, a human homolog of a gene selected from the group consisting of a yeast gene selected from the group consisting of Ash1-p, HO, cdc 42, cdc 24, and Swi; a  C. elegans  selected from the group consisting of Gip-1, LAG-2, Par-1/2/3, HAM-1, Unc-73/86, lin-11/12/17/18/26/44, Mom (1-5), Apr-1, Wrm-1, PIE-1, Skn-1, and Mec-3, a  Drosophila  gene selected from the group consisting of bicoid, oskar, gurken, caudal, nanos, hunchback, GCL, cyclin B, prospero, inscutable, miranda, staufen, numb, notch, delta, serrate, tramtrack, pumillo, wingless, frizzled, disheveled, hedgehog, En, patched, DPP, and achaete-acute; a  Xenopus  gene selected from the group consisting of Xwnt-11, Xcat-2/3, Xlsirt, Vg1, beta-Trep, 2/3, Xlsirt, Vg1, beta-Trcp, Elf4A, Xdazl, and PKC-alpha; and a cytoskeletal inhibitor selected from the group consisting of colcemid, colchicine, cytochalasin D, latrunculin A, a heavy metal, and a taxane. 
     
     
         22 . The method of  claim 19 , wherein said therapeutic agent or factor that can either block the switch from symmetric to asymmetric mitosis, or activate the inhibition of asymmetric mitosis is selected from the group consisting of an enzyme involved in nucleic acid (DNA or RNA) synthesis, protein synthesis, or the removal of essential growth factors, drugs, or chalones that induce a cellular starvation response. 
     
     
         23 . The method of  claim 19 , wherein said therapeutic agent or factor is selected from the group consisting of retinoic acid, and histone deacetylase inhibitors, sodium phenylbutyrate, sodium phenylacetate, DMSO, HMBA, PMA, tetramethyl urea, an amino acid analog, inosine monophosphate dehydrogenase inhibitor, methotrexate, rRNA inhibitors, an Inhibitor of charging tRNA or protein translation, and guanine nucleotide inhibitors. 
     
     
         24 . The method of  claim 22 , wherein said therapeutic agent or factor is selected from the group consisting of trichostatin, AzC, 6MMPR, L-alanosine, PALA, mycophenolic acid, heparin, a peptide substrate of casein kinase II, actinomycin D, puromycin aminonucleoside, DRB, H10 histone, histidinol, a compound that effects EIF46 cleavage, virazole, and 6-chloropurine. 
     
     
         25 . The method of  claim 19 , wherein said therapeutic agent or factor capable of inducing differentiation or starvation thereby causing a cancer stem line to undergo symmetric differentiation is selected from the group consisting of Notch 1-4, notchless, GSK3beta, Pit-1, p78, Isl-1, mPAR, MARK, TFIIA, a Y-box protein, piwi/hiwi/eIF2C/prg-1/rde-1 homolog, mut-7-homolog, an X-linked modifier of HD/PWS, glycipan-3, m-Numb, HASH-1/2, dHAND, BCl, Tan-1, SCL, Oct-2, spectrosome, hnRNP/'s (hnRNP1,A2), snRNP/'s (U1-snRNP), POMp75, POMp100, Myo-D, Myf-1, H19, SNRPN, IPW, PAR (1,5,SN), ASR(1,2), BD, ZNF127, aminoacyl tRNA's, an antisense molecule specific to a target selected from H19, IGF2, IGF2R, KvLQT1, ZNF127AS, and UBE3A, Ins2, U2af an X-finked modifier of X transmission, a loco selected from the group consisting of 3q21, 3q26, 4qter, 16p13, 16q22, and 15p 1; a HPP-1, polypeptide having a molecular weight of 100 or 75 kDa; BS, WS, ATM, topoisomerase-2, mos, SIR4, RAD50, zeste, polycombgenes, p57KIP2, M31/HSM1, M32, Sxl, dsx; a human homolog of a yeast gene selected from the group consisting of Ash1-p, HO, cdc 42, cdc 24, and Swi; a  C. elegans  gene selected from the group consisting of Gip-1, LAG-2, Par-1/2/3 HAM-1, Unc-73/86, tin-11/12/17/18/26/44, Mom (1-5), Apr-1, Wrm-1, PIE-1, Skn-1, and Mec-3; a  Drosophila  gene selected from the group consisting of bicoid, oskar, gurken, caudal, nanos, hunchback, GCL, cyclin B, prospero, inscutable, miranda, staufen, numb, notch, delta, serrate, tramtrack, pumillo, wingless, frizzled, disheveled, hedgehog, En, patched, DPP, and achaete-acute; a  Xenopus  gene selected from the group consisting of Xwnt-11, Xcat-2/3, Xlsirt, Vg1, beta-Trep, Elf4A, Xdazl, and PKC-alpha; and a cytoskeletal inhibitor. 
     
     
         26 . The method of  claim 25 , wherein said cytoskeletal inhibitor is selected from the group consisting of colcemid, colchicine, cytochalasin D, latrumculin A, arsenic, and taxane. 
     
     
         27 . The method of  claim 19 , wherein said therapeutic agent or factor capable of inducing a differentiation or starvation thereby causing a cancer stem line to undergo symmetric differentiation is selected from the group consisting of an enzyme involved in nucleic acid (DNA or RNA) synthesis, protein synthesis, or the removal of essential growth factors; or a drug chalone that induces a cellular starvation response. 
     
     
         28 . The method of  claim 27 , wherein said therapeutic agent or factor is selected from the group consisting of a retinoic acid or histone deacetylase inhibitor, sodium phenylbutyrate, sodium phenylacetate, DMSO, HMBA, PMA, tetramethyl urea, an amino acid analog, an inosine monophosphate dehydrogenase inhibitor, methotrexate, rRNA inhibitor, an inhibitor of charging tRNA or protein translation, and a guanine nucleotide inhibitor. 
     
     
         29 . The method of  claim 27 , wherein said agent or factor is selected from the group consisting of AzC, 6MMPR, L-alanosine, PALA, mycophenolic acid, heparin, a peptide substrate of casein kinase II, actinomycin D, puromycin aminonucleoside, DRB, H10 histine, histidinol, a compound that effects EIF46 cleavage, virazole, and 6-chloropurine. 
     
     
         30 . The method of  claim 19 , wherein such method does not canse significant toxicity to normal stem cells because said therapeutic agent upon internalization into a normal stem cell is selectively segregated out of normal stem cells.