WO2011041582A2 - Methods for modulation of autophagy through the modulation of autophagy-inhibiting gene products - Google Patents

Methods for modulation of autophagy through the modulation of autophagy-inhibiting gene products Download PDF

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WO2011041582A2
WO2011041582A2 PCT/US2010/050960 US2010050960W WO2011041582A2 WO 2011041582 A2 WO2011041582 A2 WO 2011041582A2 US 2010050960 W US2010050960 W US 2010050960W WO 2011041582 A2 WO2011041582 A2 WO 2011041582A2
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autophagy
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disease
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WO2011041582A3 (en
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Junying Yuan
Marta M. Lipinski
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President And Fellows Of Harvard College
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Priority to JP2012532325A priority Critical patent/JP2013506686A/ja
Priority to CA2774998A priority patent/CA2774998A1/en
Priority to BR112012007137A priority patent/BR112012007137A2/pt
Priority to EP10762835A priority patent/EP2483406A2/en
Priority to US13/499,313 priority patent/US20120315244A1/en
Priority to AU2010300531A priority patent/AU2010300531A1/en
Priority to CN2010800543027A priority patent/CN102869775A/zh
Publication of WO2011041582A2 publication Critical patent/WO2011041582A2/en
Publication of WO2011041582A3 publication Critical patent/WO2011041582A3/en
Priority to US14/820,270 priority patent/US20160194631A1/en

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Definitions

  • Autophagy is a catabolic process that mediates the turnover of intracellular constituents in a lysosome-dependent manner (Levine and Klionsky, (2004) Dev Cell 6, 463-377). Autophagy is initiated by the formation of an isolation membrane, which expands to engulf a portion of the cytoplasm to form a double membrane vesicle called the autophagosome. The autophagosome then fuses with a lysosome to form an autolysosome, where the captured material and the inner membrane are degraded by lysosomal hydrolases. Autophagy is therefore critical for the clearance of large protein complexes and defective organelles, and plays an important role in cellular growth, survival and homeostasis.
  • Autophagy inhibitors therefore can act as anti-cancer therapeutic agents either alone or in combination with other cancer treatments (Maiuri et al, (2007) Nat. Rev. Cell Biol. 8, 741-752; Amaravadi et al, (2007) J. Clin. Invest. 117, 326-336).
  • Autophagy has also been implicated as playing a role in axonal degeneration.
  • traumatic spinal cord injury results in a rapid increase of itraaxonal calcium levels, which results in an increase in neuronal autophagy and cell death (Knoferle et al, (2009), PNAS, 107, 6064-6069).
  • autophagy In addition to its role in responding to cellular stress, autophagy is an important intracellular mechanism for the maintenance of cellular homeostasis through the turnover of malfunctioning, aged or damaged proteins and organelles (Levine and Kroemer, (2008), Cell 132, 27-42). As a result, reduced levels of autophagy contribute to neurodegeneration by increasing the accumulation of misfolded proteins (Hara et al., (2006), Nature, 441, 885- 889; Komatsu et al, (2006), Nature, 441, 880-884). Upregulation of autophagy has been demonstrated to reduce both the levels of aggregated proteins and the symptoms of neurodegenerative diseases (Rubinsztein et al, (2007), Nat. Rev. Drug Discov. 6, 304-312). Agents that enhance cellular autophagy therefore can act as therapeutic agents for the prevention or treatment of neurodegenerative diseases.
  • modulation of autophagy is a therapeutic strategy in a wide variety of additional diseases and disorders.
  • liver diseases, cardiac diseases and muscle diseases are correlated with the accumulation of misfolded protein aggregates.
  • agents that increase cellular autophagy may enhance the clearance of disease-causing aggregates and thereby contribute to treatment and reduce disease severity (Levine and Kroemer, (2008), Cell, 132, 27-42).
  • elevated levels of autophagy have also been observed in pancreatic diseases, and have been demonstrated to be an early event in the progression of acute pancreatitis (Fortunato and Kroemer, (2009), Autophagy, 5(6)).
  • Inhibitors of autophagy may, therefore, function as therapeutic agents in the treatment of pancreatitis.
  • the present invention provides novel methods for the modulation of autophagy and the treatment of autophagy-related diseases, including cancer, neurodegenerative diseases, liver diseases, muscle diseases and pancreatitis.
  • autophagy-related diseases including cancer, neurodegenerative diseases, liver diseases, muscle diseases and pancreatitis.
  • a high-throughput image-based genome-wide screen of a human siRNA library was used to identify 236 autophagy-related genes. These genes were extensively characterized using a combination of high-throughput assays, low-throughput assays and bioinformatics analysis. Based on the results of these studies, biological and
  • the invention relates to methods of inducing autophagy in a cell comprising contacting the cell with an agent that inhibits the activity of a product of an autophagy-inhibiting gene of the invention.
  • the autophagy- inhibiting gene is selected from the genes listed in Table 1, Table 3, Table 5, Table 7, Figure 14, Figure 15, Figure 39, Figure 44, and/or Figure 55.
  • the autophagy-inhibiting gene is TRPM3, TMPRSS5, IRAK3, ADMR, FGFR1, UNC13B, PTGER2, AGER, BGN, GABBR2, PPARD, GHSR, BAIAIP2, SORCS2, PAQR6, EPHA6, TRHR, C5AR1, BAI3, TLR3, PTPRH, ADRA1A, UTS2R, RORC, CHRND, TACR2, P2RX1, PLXNA2, PTPRU, FCER1A, CD300C, TNFRSF19L CLCF1, LIF, FGF2, SDF1 or IGF.
  • the agent is an antibody, a siRNA molecule, a shRNA molecule, and/or an antisense RNA molecule. In other aspects, the agent is
  • Certain embodiments of the invention relate to methods of inhibiting autophagy in a cell comprising contacting the cell with an agent that inhibits the activity of a product of an autophagy-enhancing gene of the invention.
  • the autophagy- enhancing gene is selected from the genes listed in Table 2, Table 4 and/or Table 6.
  • the autophagy enhancing gene is TPR, GPR18, RelA or NFKB.
  • the agent is an antibody, a siRNA molecule, a shRNA molecule, and/or an antisense RNA molecule.
  • the invention relates to methods of inhibiting autophagy in a cell comprising contacting the cell with an agent that enhances the activity of a product of an autophagy-inhibiting gene of the invention.
  • the autophagy- inhibiting gene is selected from the genes listed in Table 1, Table 3, Table 5, Table 7, Figure 14, Figure 15, Figure 39, Figure 44, and/or Figure 55.
  • the autophagy-inhibiting gene is TRPM3, TMPRSS5, IRAK3, ADMR, FGFR1, UNC13B, PTGER2, AGER, BGN, GABBR2, PPARD, GHSR, BAIAIP2, SORCS2, PAQR6, EPHA6, TRHR, C5AR1, BAI3, TLR3, PTPRH, ADRA1A, UTS2R, RORC, CHRND, TACR2, P2RX1, PLXNA2, PTPRU, FCERIA, CD300C, TNFRSF19L CLCFl, LIF, FGF2, SDF1 or IGF.
  • the agent is an antibody.
  • the agent is FGF-1, acidic FGF-1, XRP0038, RhaFGF, GW501516, Ibutamoren Mesylate, KP- 102LN, EP1572, TRH, S-0373, Poly-ICR, CQ-07001 or cryptotanshinone.
  • the agent is a growth factor.
  • the growth factor is CLCFl, LIF, FGF2, SDF1 or IGF 1.
  • Some embodiments of the invention relate to methods of inducing autophagy in a cell comprising contacting the cell with an agent that enhances the activity of a product of an autophagy-enhancing gene of the invention.
  • the autophagy- enhancing gene is selected from the genes listed in Table 2, Table 4 and/or Table 6.
  • the autophagy enhancing gene is TPR, GPR18, RelA or NFKB.
  • the agent is an antibody.
  • the invention relates to methods of treating a
  • the autophagy-inhibiting gene is selected from the genes listed in Table 1, Table 3, Table 5, Table 7, Figure 14, Figure 15, Figure 39, Figure 44, and/or Figure 55.
  • the autophagy-inhibiting gene is TRPM3, TMPRSS5, IRAK3, ADMR, FGFR1, UNC13B, PTGER2, AGER, BGN, GABBR2, PPARD, GHSR, BAIAIP2, SORCS2, PAQR6, EPHA6, TRHR, C5AR1, BAI3, TLR3, PTPRH, ADRA1A, UTS2R, RORC, CHRND, TACR2, P2RX1, PLXNA2, PTPRU, FCERIA, CD300C, TNFRSF19L CLCFl, SDF1, LIF, FGF2 or IGF.
  • the agent is an antibody, a siRNA molecule, a shRNA molecule, and/or an antisense RNA molecule.
  • the agent is TK1258, PF 04494700, PMX53, Tamsulosin, Doxazosin, Prazosin hydrochloride, alfuzosin hydrochloride, Urotensin II, Mecamylamine hydrochloride, ISIS 3521, Gemcitabine, LY900003, MK- 5108, U73122 or D609.
  • the autophagy-enhancing gene is selected from the genes listed in Table 2, Table 4 and/or Table 6.
  • the autophagy enhancing gene is TPR, GPR18, RelA or NFKB.
  • the agent is an antibody.
  • the neurodegenerative disease is Adrenal Leukodystrophy, alcoholism, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral palsy, cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, familial fatal insomnia, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy body dementia, neuroborreliosis, Machado-Joseph disease, multiple system atrophy, multiple sclerosis, narcolepsy, Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy,
  • Refsum's disease Sandhoff disease, Schilder's disease, subacute combined degeneration of spinal cord secondary to pernicious anaemia, Spielmeyer-Vogt-Sjogren-Batten disease, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, toxic encephalopathy and combinations of these diseases.
  • the proteinopathy is a 1 -antitrypsin deficiency, sporadic inclusion body myositis, limb girdle muscular dystrophy type 2B and Miyoshi myopathy Alzheimer's disease, Parkinson's disease, Lewy Body Dementia, ALS, Huntington's disease, spinocerebellar ataxias, spinobulbar musclular atrophy and combinations of these diseases.
  • Certain embodiments of the invention relate to methods of treating cancer or pancreatitis in a subject comprising administering to the subject an agent that inhibits the activity of a product of an autophagy-enhancing gene of the invention.
  • the autophagy-enhancing gene is selected from the genes listed in Table 2, Table 4 and/or Table 6. In other embodiments, the autophagy enhancing gene is TPR, GPR18, RelA or NFKB. In certain embodiments the agent is an antibody, a siRNA molecule, a shRNA molecule, and/or an antisense RNA molecule.
  • the invention relates to methods of treating cancer or pancreatitis in a subject comprising administering to the subject an agent that enhances the activity of a product of an autophagy-inhibiting gene of the invention.
  • the autophagy-inhibiting gene is selected from the genes listed in Table 1, Table 3, Table 5, Table 7, Figure 14, Figure 15, Figure 39, Figure 44, and/or Figure 55.
  • the autophagy-inhibiting gene is TRPM3, TMPRSS5, IRAK3, ADMR, FGFR1, UNC13B, PTGER2, AGER, BGN, GABBR2, PPARD, GHSR, BAIAIP2, SORCS2, PAQR6, EPHA6, TRHR, C5AR1, BAI3, TLR3, PTPRH, ADRA1A, UTS2R, RORC, CHRND, TACR2, P2RX1, PLXNA2, PTPRU, FCERIA, CD300C, TNFRSF19L CLCF1, SDF1, LIF, FGF2 or IGF.
  • the agent is an antibody.
  • the agent is FGF-1, acidic FGF-1, XRP0038, RhaFGF, GW501516, Ibutamoren Mesylate, KP-102LN, EP1572, TRH, S-0373, Poly-ICR, CQ-07001 or cryptotanshinone.
  • the agent is a growth factor.
  • the growth factor is CLCF1, LIF, FGF2, SDF1 or IGF1.
  • the methods of treating cancer further comprise known cancer treatment therapies such as the administration of a chemotherapeutic agent and/or radiation therapy.
  • the chemotherapeutic agent is altretamine, asparaginase, BCG, bleomycin sulfate, busulfan, camptothecin, carboplatin, carmusine, chlorambucil, cisplatin, claladribine, 2-chlorodeoxyadenosine, cyclophosphamide, cytarabine, dacarbazine imidazole carboxamide, dactinomycin, daunorubicin - dunomycin, dexamethosone, doxurubicin, etoposide, floxuridine, fluorouracil, fluoxymesterone, flutamide, fludarabine, goserelin, hydroxyurea, idarubicin HCL, ifosfamide, interferon a, interferon a 2
  • inventions relate to methods of determining whether an agent is an autophagy inhibitor comprising the step of contacting a cell with the agent, wherein the cell expresses a heterologous autophagy-enhancing gene of the invention, whereby a reduction in autophagy in the cell indicates that the agent is an autophagy inhibitor.
  • the agent is a small molecule, an antibody, or an inhibitory R A molecule.
  • Certain embodiments of the invention relate to methods of determining whether an agent is an autophagy inhibitor, the method comprising the step of contacting a cell with the agent, wherein the expression of an autophagy-inhibiting gene of the invention is inhibited in the cell, whereby a reduction in autophagy in the cell indicates that the agent is an autophagy inhibitor.
  • the agent is a small molecule, an antibody, or an inhibitory RNA molecule.
  • the cell contains a mutation to the autophagy-related gene.
  • the autophagy-related gene is inhibited by an inhibitory RNA or small molecule.
  • Figure 1A shows fluorescent microscope images depicting the localization of GFP expressed in H4 cells that stably express LC3-GFP and that were transfected with non- targeting, control siRNA (ntRNA) or siRNA against mTOR or Atg5.
  • Figure IB shows the results of a western blot performed using antibodies specific for either LC3 or tubulin and lysates of H4 cells that were transfected with non-targeting, control siRNA (ntRNA) or siRNA against mTOR or Atg5.
  • Figure 2 shows the quantification of the level of autophagosome-associated GFP in H4 cells that stably express LC3-GFP and that were transfected with non-targeting, control siRNA (ntRNA) or siRNA against mTOR or Atg5.
  • ntRNA non-targeting, control siRNA
  • the asterisks indicate that the difference between the indicated level and that of the ntRNA transfected cells is statistically significant.
  • Figure 3 shows the gene symbols, Unigene ID numbers, Genbank accession numbers and names of the autophagy-modulating genes of the invention.
  • Figure 4 shows a schematic diagram depicting a selection of the screens and characterization assays used to identify and characterize the autophagy-modulating genes of the invention.
  • Figure 5 shows the quantification of a series of in-cell-western blot assays that measure mTORCl activity.
  • the asterisks indicate that the difference between the indicated samples and the ntRNA control samples is statistically significant.
  • Figure 6 shows the gene symbols, Unigene ID numbers, Genbank accession numbers and names of the genes for which the inhibition of their product results in reduced expression of mTORC.
  • Figure 7 shows the gene symbols, Unigene ID numbers, and names of the genes for which the inhibition of their product results in both reduced expression of mTORC and down-regulation of autophagy in the presence of rapamycin.
  • Figure 8A shows fluorescent microscope images depicting the localization of RFP expressed in H4 cells that stably express Lamp 1 -RFP and that were transfected with non- targeting, control siRNA (ntRNA) or siRNA against mTOR.
  • Figure 8B shows the quantification of the level of autophagosome-associated RFP in H4 cells that stably express LC3-GFP and that were transfected with non-targeting control siRNA (ntRNA) or siRNA against mTOR or Atg5.
  • ntRNA non-targeting control siRNA
  • Figure 9 shows the gene symbols, Unigene ID numbers, Genbank accession numbers and names of the genes for which the inhibition of their product result in a significant change in the levels of autophagosome-associated Lamp 1 -RFP in Lamp 1 -RFP expressing cells.
  • Figure 10A shows fluorescent microscope images depicting the localization of dsRed expressed in H4 cells that stably express FYVE-dsRed and that were transfected with siRNA against Vprs34 or mTOR.
  • Figure 10B shows the quantification of the level of autophagosome-associated dsRed in H4 cells that stably express FYVE-dsRed and that were transfected with siRNA against Vprs34 or mTOR. The asterisks indicate that the difference between the indicated level and that of the ntRNA transfected cells is statistically significant.
  • Figure IOC shows the quantification of the level of autophagosome-associated dsRed in H4 cells that stably express FYVE-dsRed and that were transfected with siRNA against Raptor or mTOR.
  • Figure 11 shows the gene symbols, Unigene ID numbers, Genbank accession numbers and names of the genes for which the inhibition of their product results in a significant change in the levels of PtdIns3P levels.
  • Figure 12 shows a Venn diagram depicting the subdivision of genes for which the inhibition of their products led to the induction of autophagy into functional categories based on their dependence on type III PI3 kinase activity, lysosomal function and mTORCl activity.
  • Figure 13 shows the relative average viability of wild-type H4 cells transfected with autophagy-related gene targeting siRNAs (H4) compared to Bcl-2 expressing H4 cells transfected with autophagy-related gene targeting siRNAs (H4 + Bcl-2).
  • H4 autophagy-related gene targeting siRNAs
  • Figure 14 shows the relative viability, gene symbols, Unigene ID numbers, and names of the genes for which the inhibition of their product results in enhancement of autophagy in Bcl-2 expressing cells.
  • Figure 15 shows the relative viability, gene symbols, Unigene ID numbers, and names of the genes for which the inhibition of their product results in enhancement of autophagy wild-type, but not in Bcl-2 expressing cells.
  • Figure 16 shows the quantification of in-cell western assays demonstrating an increase in the levels of GRP78 and GRP94 in H4 cells treated with tunicamycin. The asterisks indicate statistical significance.
  • Figure 17 shows the gene symbols, Unigene ID numbers, and names of the genes for which the inhibition of their product results in enhancement of autophagy and changes in Endoplasmic Reticulum (ER) stress levels.
  • Figure 18 shows a western blot depicting Bcl-2 expression in H4 LC3-GFP and H4
  • Figure 19A shows the quantification of the level of autophagosome-associated GFP in H4 cells that stably express LC3-GFP and Bcl-2 and that were transfected with non- targeting, control siRNA (ntRNA) or siRNA against mTOR. The asterisks indicate that the difference between the indicated level and that of the ntRNA transfected cells is statistically significant.
  • Figure 19B shows the quantification of the level of autophagosome-associated dsRed in H4 cells that stably express FYVE-dsRed and Bcl-2 and that were transfected with non-targeting, control siRNA (ntRNA) or siRNA against mTOR. The asterisks indicate that the difference between the indicated level and that of the ntRNA transfected cells is statistically significant.
  • Figure 19C shows the quantification of the level of
  • Figure 20 shows the subdivision of autophagy-related genes for which knock-down was able to induce autophagy under conditions of low PtdIns3P into functional categories based on their ability to up-regulate type III PI3 kinase activity or to alter lysosomal function.
  • Figure 21 A shows how selected autophagy-related gene products of the invention are associated with specific protein complexes.
  • Figure 21B shows how selected autophagy-related gene products of the invention are associated with a network of transcription factors and chromatin modifying enzymes.
  • Figure 22 shows how selected autophagy-related gene products of the invention interact with core autophagic machinery.
  • Figure 23 shows how selected autophagy-related gene products of the invention interact within axon-guidance regulatory pathways.
  • Figure 24 shows how selected autophagy-related gene products of the invention interact within actin-cytoskeleton regulatory pathways.
  • Figure 25A shows the subdivision of the autophagy-related genes of the invention into molecular function categories.
  • Figure 25B shows the further subdivision of the autophagy-related genes of the invention that are categorized as receptors in Figure 25 A into receptor categories.
  • Figure 26 shows the molecular function categories, gene symbols, Unigene ID numbers and gene names of autophagy-related genes of the invention.
  • Figure 27A shows the subdivision of the autophagy-related genes of the invention into biological process categories.
  • Figure 27B shows the further subdivision of the autophagy-related genes of the invention that are categorized as mediators of signal transduction in Figure 27A into signal transduction categories.
  • Figure 28 shows the quantification of autophagosome associated GFP in H4 LC3- GFP cells grown in the presence of the indicated growth factors (IGFl, FGF2, LIF, CLCFl and SDFl).
  • the asterisk indicates that the difference between the indicated level and that of the untreated cells is statistically significant.
  • Figure 29 shows fluorescent microscope images depicting the localization of GFP expressed in H4 cells that stably express LC3-GFP and that were either untreated under conditions of nutrient deprivation (untreated), untreated under normal growth conditions (serum), or treated with CLCFl, LIF, FGF2 or IGFl under conditions of nutrient deprivation (CLCFl, LIF, FGF2 and IGF, respectively).
  • Figure 30 shows that cytokines are able to suppress autophagy in the absence and presence of rapamycin.
  • H4 cells were grown in serum-free medium, followed by addition of lOOng/mL IGFl (A), 50ng/mL FGF2 (B), 50ng/mL LIF (C) or 50ng/mL CLCFl (D) and ⁇ / ⁇ E64d (E). Where indicated, cells were pre-treated with 50 nM rapamycin 1 hour prior to the addition of cytokines.
  • Figure 31 A shows the quantification of autophagosome associated GFP in H4 LC3- GFP cells grown in the presence of 5, 20, 100 or 200 ng ml of TNFa or the presence of rapamycin.
  • the asterisks indicate that the difference between the indicated level and that of the untreated cells is statistically significant.
  • Figure 31B shows western blots depicting the levels of p62 in H4 cells that were either untreated under conditions of nutrient deprivation (-), untreated under normal growth conditions (serum), treated with rapamycin (Rap), or treated with 5 ng/ml of TNFa under conditions of nutrient deprivation
  • Figure 32 shows fluorescent microscope images depicting the localization of GFP expressed in H4 cells that stably express LC3-GFP and that were transfected with non- targeting, control siRNA (ntRNA) or four distinct siRNAs specific for RelA.
  • Figure 33 shows the quantification of the level of autophagosome-associated GFP in H4 cells that stably express LC3-GFP and that were transfected with non-targeting, control siRNA (ntRNA) or four distinct siRNAs specific for RelA.
  • ntRNA non-targeting, control siRNA
  • the asterisks indicate that the difference between the indicated level and that of the ntRNA transfected cells is statistically significant.
  • Figure 34A shows the results of semi-quantitative RT-PCR detecting the level of RelA mRNA H4 cells that were transfected with non-targeting, control siRNA (ntRNA) or one of four distinct siRNAs specific for RelA.
  • Figure 34B shows the results a western blot detecting the level of p65 in H4 cells that were transfected with non-targeting, control siRNA (ntRNA), one of four distinct siRNAs specific for RelA, or a pool of the four RelA specific siRNAs.
  • Figure 35A shows western blots depicting the levels of RelA and LC3 in wild-type H4 cells (wt) and RelA " ' " and NFKB " ' " double knock-out (DKO) H4 cells.
  • Figure 35B shows western blots depicting the levels of RelA, p62 and LC3 in H4 cells that have been transfected with siRNAs specific for RelA, non-targeting siRNA (nt), mTor or Atg5.
  • Figure 36A shows FACS histograms depicting the levels of reactive oxygen species in wild-type H4 cells and RelA " ' " and NFKB " ' * double knock-out (DKO) H4 cells under normal growth conditions (mock) and conditions of nutrient deprivation (starvation).
  • Figure 36B shows the quantification of the data depicted in Figure 36A.
  • Figure 36C shows the quantification of the levels of reactive oxygen species in H4 cells transfected with non-targeting, control siRNA (ntRNA) or siRNAs specific for RelA grown under normal (+ serum) or starvation (HBSS) conditions.
  • ntRNA non-targeting, control siRNA
  • HBSS starvation
  • Figure 37 shows the quantification of the level of autophagosome-associated GFP in H4 cells that stably express LC3-GFP and that were transfected with non-targeting, control siRNA (ntRNA) or siRNAs specific for RelA grown under conditions of nutrient deprivation and either in the presence of antioxidant (NAC) or absence of antioxidant.
  • ntRNA non-targeting, control siRNA
  • NAC antioxidant
  • Figure 38 shows the gene symbols, Unigene ID numbers and prediction basis for the autophagy-related genes of the invention whose products are predicted to be localized to the mitochondria.
  • Figure 39 shows the gene symbols, Unigene ID numbers and names of autophagy- related genes of the invention with known connections to oxidative damage or the regulation of reactive oxygen species.
  • Figure 40A shows western blots depicting the levels of SODl, p62 and LC3 in H4 cells that were transfected with non-targeting, control siRNA (nt) or siRNA specific for SODl .
  • Figure 40B shows fluorescent microscope images depicting the levels of reactive oxygen species in cells transfected with non-targeting, control siRNA (nt) or siRNA specific for SODl or treated with 100 mM TBHP.
  • Figure 40C shows the quantification of the levels of reactive oxygen species in cells transfected with non-targeting, control siRNA (nt) or siRNA specific for SODl . The asterisks indicate that the difference between the indicated level and that of the ntRNA transfected cells is statistically significant.
  • Figure 41 shows the quantification of the level of autophagosome-associated GFP in H4 cells that stably express LC3-GFP and that were transfected with non-targeting, control siRNA (ntRNA) or siRNA specific for mTOR or SODl either in the presence of antioxidant (NAC) or absence of antioxidant (-).
  • ntRNA non-targeting, control siRNA
  • NAC antioxidant
  • - absence of antioxidant
  • Figure 42 shows the gene symbol, Unigene ID number and name of genes for which the inhibition of their product results in enhancement of autophagy in the absence but not in the presence of antioxidant.
  • Figure 43 shows the quantification of the average type III PI3 kinase activity following inhibition of the products of the autophagy-related genes of the invention able (yes) or unable (no) to induce autophagy in the presence of antioxidant (NAC).
  • Figure 44 shows the gene symbol, Unigene ID number and name of genes for which the inhibition of their product results in enhancement of autophagy in the presence of antioxidant.
  • Figure 45 shows an enrichment analysis of canonical pathways (MSigDB) among the hit genes relative to all genes examined in the screen. A p-value ⁇ 0.05 (hyper geometric distribution) is considered significant. Only categories with at least five genes are displayed.
  • Figure 46 shows that down-regulation of autophagy by 50ng/mL FGF2 is prevented by addition of ME inhibitor U0126.
  • H4 cells were grown in serum-free media, levels of autophagy were assessed in the presence of l( ⁇ g/mL E64d, with antibodies against LC3, inhibition MEK with phospho-ERK 1/2, phospho-RSK and phospho-S6 (Ser235/236). Quantification of LC3 II/tubulin ratio is shown.
  • Figure 47 shows, an enrichment analysis of cis-regulatory elements/transcription factor (TF)-binding sites in the promoters of the hit genes, using motif-based gene sets from MSigDB and TF -binding sites defined in the TRANSFAC database. SRF sites are highlighted.
  • TF cis-regulatory elements/transcription factor
  • Figure 48 shows a western-blot depicting the phosphorylation of Stat3 following treatment with 50ng/mL CLCF1.
  • Figure 49 shows that the down-regulation of autophagy by 50ng/mL LIF is prevented by siRNA mediated knock-down of Stat3.
  • H4 cells were transfected with indicated siRNAs for 72h, than cells were treated as described for Figure 46. Protein levels and phosphorylation of Stat3 are shown.
  • Figure 50 shows that suppression of autophagy by lOOng/mL IGF1 is prevented by Akt inhibitor VIII.
  • Cells were treated as described for Figure 46.
  • Akt activity was assessed with antibodies against phospho-Foxo3a and phospho-rpS6.
  • Figure 52 shows a correlation matrix for the data presented in Figure 45.
  • Figure 53 shows a clustering analysis (dChip) of mRNA expression levels of select autophagy hit genes in young ( ⁇ 40 years-old) or old (> 70 years old) human brain samples.
  • Figure 54 shows a correlation matrix for autophagy-related genes of the invention with the most significant age-dependent regulation.
  • Figure 55 shows the gene symbol, Unigene ID number, fold change and p value of autophagy-related genes of the invention that are differentially regulated in human brains during aging.
  • Figure 56 shows the expression levels of autophagy-related genes of the invention during aging.
  • Figure 57 shows that differential gene expression leads to up regulation of autophagy in Alzheimer's disease. Forrest plots of Normalized Enrichment Score (NES) estimates with standard deviation for the screen hit gene sets are shown.
  • Figure 57A shows a GSEA analysis of overall screen hit gene expression in different regions of AD brain as compared to unaffected age-matched controls.
  • Figures 57B and 57C show GSEA analysis of hit genes determined to function as negative (B) or positive (C) regulators of autophagy flux. The size of a square is inversely proportional to the respective SD.
  • Figure 58 shows a comparison of the levels of LC3-II accumulation in the presence or absence of 10 ⁇ E64d following treatment of H4 cells with 5 ⁇ ⁇ .
  • FIG 59 shows that ⁇ induces accumulation of PtdIns3P.
  • FYVE-dsRed cells were prepared as described in Figure 58, fixed and imaged. Where indicated the type III PI3 kinase inhibitor 3MA (lOmM) was added for 8 hours prior to fixation.
  • Figure 60 shows that the induction of the type III PI3 kinase activity by ⁇ is suppressed in the presence of antioxidant.
  • Cells were prepared as described in Figure 59 and treated with or without antioxidant NAC.
  • Figure 61 shows that the induction of autophagy by ⁇ is dependent on the type III PI3 kinase activity.
  • H4 GFP-LC3 cells were treated and imaged as described for Figure 59.
  • Figure 62 shows that the induction of autophagy by ⁇ is dependent on the type III PI3 kinase activity.
  • H4 cells were transfected with siRNA against the type III PI3 kinase subunit Vps34 or non-targeting control siRNA and than treated as described in Figure 59.
  • Autophagy and lysosomal changes were determined using antibodies against LC3 and Lamp 2, respectively.
  • Figure 63 shows the chemical structures of select small molecule agents that modulate activity of autophagy-related genes of the invention.
  • Figure 64 shows the Genbank accession numbers, names, gene symbols and mRNA sequences of the autophagy-related genes of the invention.
  • Autophagy is a lysosome-dependent catabolic process that mediates turnover of cellular components and protects multicellular eukaryotes from a wide range of diseases.
  • a high-throughput image-based genome -wide screen of a human siR A library was performed to identify genes involved in autophagy modulation and regulation. This screen led to the identification of 236 autophagy-related genes that, when knocked-down, led to either an increase or a decrease in levels of autophagy under normal nutrient conditions.
  • the autophagy-related genes of the invention are listed in Figure 3.
  • an element means one element or more than one element.
  • administering means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering.
  • the term "agent” refers to an entity capable of having a desired biological effect on a subject or cell.
  • a variety of therapeutic agents is known in the art and may be identified by their effects.
  • therapeutic agents of biological origin include growth factors, hormones, and cytokines.
  • a variety of therapeutic agents is known in the art and may be identified by their effects. Examples include small molecules ⁇ e.g., drugs), antibodies, peptides, proteins ⁇ e.g., cytokines, hormones, soluble receptors and nonspecific-proteins), oligonucleotides (e.g., peptide-coding DNA and RNA, double- stranded RNA and antisense RNA) and peptidomimetics.
  • antibody includes full-length antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chain thereof.
  • antigen binding fragment i.e., "antigen-binding portion” or single chain thereof.
  • antibody includes, but is not limited to, a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Antibodies may be polyclonal or monoclonal; xenogeneic, allogeneic, or syngeneic; or modified forms thereof (e.g., humanized, chimeric).
  • antigen-binding portion of an antibody, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.
  • the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V H , V L , CL and CHI domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V H and CHI domains; (iv) a Fv fragment consisting of the V H and V L domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341 :544 546), which consists of a V H domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, V H and V L , are code
  • single chain Fv single chain Fv
  • scFv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
  • cancer includes, but is not limited to, solid tumors and blood borne tumors.
  • the term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood and vessels.
  • the term “cancer” further encompasses both primary and metastatic cancers.
  • gene product and “product of a gene” refers to a substance encoded by a gene and able to be produced, either directly or indirectly, through the transcription of the gene.
  • gene product and “product of a gene” include R A gene products ⁇ e.g. mRNA), DNA gene products ⁇ e.g. cDNA) and polypeptide gene products ⁇ e.g. proteins).
  • the phrase "enhancing the activity" of a gene product refers to an increase in a particular activity associated with the gene product.
  • Examples of enhanced activity include, but are not limited to, increased translation of mRNA, increased signal transduction by polypeptides or proteins and increased catalysis by enzymes. Enhancement of activity can occur, for example, through an increased amount of activity performed by individual gene products, through an increase number of gene products performing the activity, or a through any combination thereof. If a gene product enhances a biological process ⁇ e.g. autophagy), "enhancing the activity" of such a gene product will generally enhance the process. Conversely, if a gene product functions as an inhibitor of a biological process, "enhancing the activity" of such a gene product will generally inhibit the process.
  • inhibiting the activity of a gene product refers to a decrease in a particular activity associated with the gene product.
  • inhibited activity include, but are not limited to, decreased translation of mRNA, decreased signal transduction by polypeptides or proteins and decreased catalysis by enzymes. Inhibition of activity can occur, for example, through a reduced amount of activity performed by individual gene products, through a decreased number of gene products performing the activity, or a through any combination thereof. If a gene product enhances a biological process ⁇ e.g. autophagy), "inhibiting the activity" of such a gene product will generally inhibit the process. Conversely, if a gene product functions as an inhibitor of a biological process, "inhibiting the activity" of such a gene product will generally enhance the process.
  • the term “isolated” refers to the state in which substances ⁇ e.g., polypeptides or polynucleotides) are free or substantially free of material with which they are naturally associated such as other polypeptides or polynucleotides with which they are found in their natural environment or the environment in which they are prepared ⁇ e.g., cell culture). Polypeptides or polynucleotides can be formulated with diluents or adjuvants and still be considered “isolated” - for example, polypeptides or polynucleotides can be mixed with pharmaceutically acceptable carriers or diluents when used in diagnosis or therapy.
  • the term “modulation” refers to up regulation ⁇ i.e., activation or stimulation), down regulation ⁇ i.e., inhibition or suppression) of a biological activity, or the two in combination or apart.
  • neurodegenerative disorder and “neurodegenerative disease” refers to a wide range of diseases and/or disorders of the central and peripheral nervous system, such as neuropathologies, and includes but is not limited to, Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), denervation atrophy, otosclerosis, stroke, dementia, multiple sclerosis, Huntington's disease, encephalopathy associated with acquired immunodeficiency disease (AIDS), and other diseases associated with neuronal cell toxicity and cell death.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • denervation atrophy otosclerosis
  • stroke dementia
  • dementia dementia
  • multiple sclerosis Huntington's disease
  • AIDS acquired immunodeficiency disease
  • AIDS acquired immunodeficiency disease
  • the phrase "pharmaceutically acceptable” refers to those agents, compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the phrase "pharmaceutically-acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting an agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting an agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • subject means a human or non-human animal selected for treatment or therapy.
  • the phrase "subject suspected of having” means a subject exhibiting one or more clinical indicators of a disease or condition.
  • the disease or condition is cancer, a neurodegenerative disorder or pancreatitis.
  • the phrase "subject in need thereof means a subject identified as in need of a therapy or treatment of the invention.
  • therapeutic effect refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by an agent.
  • therapeutically-ejfective amount and “effective amount” mean the amount of an agent that produces some desired effect in at least a sub-population of cells.
  • therapeutically effective amount includes an amount of an agent that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • certain agents used in the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.
  • treating a disease in a subject or “treating" a subject having or suspected of having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g. , the administration of an agent, such that at least one symptom of the disease is decreased or prevented from worsening.
  • the autophagy-related genes of the present invention can be divided into genes whose products inhibit autophagy (or autophagy-inhibiting genes, listed in Table 1) and genes whose products enhance autophagy (or autophagy-enhancing genes, listed in Table 2) ⁇
  • Agents that modulate the activity of products of autophagy-inhibiting genes are useful in the treatment of autophagy-related diseases.
  • Agents that inhibit the activity of the products of autophagy-inhibiting genes result in elevated autophagy levels and are therefore useful in methods of enhancing autophagy and the treatment of autophagy-related diseases that are responsive to elevated levels of autophagy, such as neurodegenerative diseases and proteinopathies.
  • agents that enhance the activity of products of autophagy-inhibiting genes result in reduced autophagy levels, and are therefore useful in methods of inhibition of autophagy and the treatment of autophagy-related diseases that are responsive to autophagy inhibition, such as cancer and pancreatitis.
  • nudix (nucleoside diphosphate linked moiety X)-
  • TNFRSF nerve receptor
  • G protein guanine nucleotide binding protein
  • EPHA6 203806 XM_1 14973 EPH receptor A6 CDCA8 55143 NM_ .018101 cell division cycle associated 8
  • GABBR2 9568 NM_ .005458 gamma-aminobutyric acid (GABA) B receptor, 2
  • G protein guanine nucleotide binding protein
  • SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d
  • cytochrome P450 family 27, subfamily A
  • PCGF1 84759 NM_ .032673 polycomb group ring finger 1
  • GTPBP4 23560 NM. .012341
  • CASP1 834 NM_001223 (interleukin 1 , beta, convertase)
  • RAB7A 7879 NM_004637 RAB7A, member RAS oncogene family
  • NM_002124 major histocompatibility complex, class II, DR beta
  • HLA-DRB1 3123 NM_172672 1
  • TGFBI 7045 NM_000358 transforming growth factor, beta-induced, 68kDa protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin),
  • ARSE 415 NM. .000047 arylsulfatase E (chondrodysplasia punctata 1 )
  • G protein guanine nucleotide binding protein
  • RNA III DNA directed polypeptide G
  • solute carrier family 25 mitochondria thiamine
  • NFIL3 4783 NM. .005384 nuclear factor, interleukin 3 regulated
  • chemokine (C-X-C motif) ligand 12 (stromal cell-
  • HIST2H3C 126961 NM. .021059 histone cluster 2 H3c
  • TRPA1 8989 NM. .007332 subfamily A, member 1
  • fibroblast growth factor receptor 1 (fms-related
  • WFDC2 10406 NM. .006103 WAP four-disulfide core domain 2
  • Agents that modulate the activity of products of autophagy-enhancing genes are also useful in the treatment of autophagy-related diseases.
  • agents that inhibit the activity of products of autophagy-enhancing genes result in reduced autophagy levels and are therefore useful in methods of inhibition of autophagy and the treatment of autophagy- related diseases that are responsive to autophagy inhibition, such as cancer and pancreatitis.
  • autophagy levels are therefore useful in methods of enhancement of autophagy and the treatment of autophagy-related diseases that are responsive to elevated levels of autophagy, such as neurodegenerative diseases and proteinopathies.
  • translocated promoter region to activated MET
  • certain embodiments of the present invention relate to methods of enhancing autophagy and/or treating neurodegenerative diseases and/or proteinopathies through the inhibition of the activity of products of the autophagy-inhibiting genes listed in Table 1 or the enhancement of the activity of products of the autophagy-enhancing genes listed in
  • nudix (nucleoside diphosphate linked moiety X)-
  • PNKD 25953 NM_015488 paroxysmal nonkinesiogenic dyskinesia guanine nucleotide binding protein (G protein),
  • GABBR2 9568 NM_005458 gamma-aminobutyric acid (GABA) B receptor, 2
  • G protein guanine nucleotide binding protein
  • SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d
  • cytochrome P450 family 27, subfamily A
  • PCGF1 84759 NM. .032673 polycomb group ring finger 1
  • GJA4 2701 NM. .002060 gap junction protein, alpha 4, 37kDa SF3A2 8175 NM_ .007165 splicing factor 3a, subunit 2, 66kDa
  • CASP1 834 NM _001223 (interleukin 1 , beta, convertase)
  • NM..002124 major histocompatibility complex, class II, DR beta
  • HLA-DRB1 3123 NM. .172672 1
  • PA2G4 5036 NM. .006191 proliferation-associated 2G4, 38kDa
  • ARSE 415 NM. .000047 arylsulfatase E (chondrodysplasia punctata 1 )
  • G protein guanine nucleotide binding protein
  • RNA III DNA directed polypeptide G
  • solute carrier family 25 mitochondria thiamine
  • NFIL3 4783 NM. .005384 nuclear factor, interleukin 3 regulated
  • chemokine (C-X-C motif) ligand 12 (stromal cell-
  • HIST2H3C 126961 NM. .021059 histone cluster 2 H3c
  • fibroblast growth factor receptor 1 (fms-related
  • WFDC2 10406 NM. .006103 WAP four-disulfide core domain 2 CPNE6 9362 NM_006032 copine VI (neuronal)
  • P2RX1 5023 NM_002558 purinergic receptor P2X, ligand-gated ion channel, 1
  • v-rel reticuloendotheliosis viral oncogene homolog A nuclear factor of kappa light polypeptide gene enhancer in
  • translocated promoter region to activated MET
  • the products of the autophagy-related genes of the invention can be classified into a number of non-mutually exclusive categories.
  • certain gene products of the present invention can be classified as oxidoreductases, receptors, proteases, ligases, kinases, synthases, synthetases, chaperones, hydrolases, membrane traffic proteins, calcium binding proteins and/or regulatory molecules.
  • the classification of selected autophagy-inhibiting gene products is listed in Table 5, while the classification of selected autophagy-enhancing gene products is listed in Table 6. Since certain types of agents are better suited for the modulation of the activity of a specific class of gene product, in some embodiments the present invention is directed towards the modulation of one or more class of autophagy- related gene product.
  • CYP27A1 cytochrome P450 family 27, subfamily A, Oxidoreductase
  • subunit B iron sulfur (lp);SDHB
  • ADMR Also adrenomedullin receptor
  • FGFR1 fibroblast growth factor receptor 1 (fms- Receptor related tyrosine kinase 2, Pfeiffer
  • UNC13B unc-13 homolog B C. elegans
  • UNC13B Receptor PTGER2 prostaglandin E receptor 2 subtype EP2
  • AGER advanced glycosylation end product- Receptor specific receptor AGER
  • GABA gamma-aminobutyric acid
  • GHSR growth hormone secretagogue Receptor receptor GHSR
  • UBE1 L2 Also ubiquitin-activating enzyme E1 -like Ligase known as 2;UBE1 L2
  • IHPK3 Also inositol hexaphosphate kinase 3;IHPK3 Kinase known as
  • PRKAA2 protein kinase, AMP-activated, al Kinase catalytic subunit
  • PRKCZ protein kinase C zeta
  • PRKCA protein kinase C alpha
  • NLK nemo-like kinase NLK nemo-like kinase
  • NLK Kinase NLK nemo-like kinase
  • PFDN2 prefoldin subunit 2 PFDN2 Chaperone CHID1 chitinase domain containing 1 ;CHID1 Hydrolase ARSE arylsulfatase E (chondrodysplasia Hydrolase punctata 1 );ARSE
  • NUDT1 nudix (nucleoside diphosphate linked Hydrolase
  • COPE coatomer protein complex subunit Membrane traffic epsilon;COPE protein
  • HRC histidine rich calcium binding protein HRC Calcium binding protein
  • GTPBP4 GTP binding protein 4;GTPBP4 Regulatory molecule
  • GNAI 1 guanine nucleotide binding protein (G Regulatory protein), alpha inhibiting activity molecule polypeptide 1 ;GNAI 1
  • CDKN2D cyclin-dependent kinase inhibitor 2D (p19, Regulatory
  • GNG5 guanine nucleotide binding protein G Regulatory
  • GNG1 1 guanine nucleotide binding protein (G Regulatory
  • WFDC2 WAP four-disulfide core domain 2;WFDC2 Regulatory
  • Certain embodiments of the present invention relate to methods of modulating autophagy or treating autophagy-related diseases (e.g. neurodegenerative disease, liver disease, muscle disease, cancer, pancreatitis). These methods involve administering an agent that modulates the activity of one or more autophagy-related gene products of the invention.
  • methods of the invention include treatment of autophagy-related diseases by administering to a subject an agent which decreases the activity of one or more products of the genes listed in Tables 1-4.
  • methods of the invention include treatment of autophagy-related diseases by administering to a subject an agent which increases the activity of one or more products of the genes listed in Tables 1-4.
  • Agents which may be used to modulate the activity of a gene product listed in Tables 1-4, and to thereby treat or prevent an autophagy-related disease include antibodies (e.g., conjugated antibodies), proteins, peptides, small molecules, R A interfering agents, e.g., siR A molecules, ribozymes, and antisense oligonucleotides.
  • Any agent that modulates the activity of an autophagy-related gene product of the invention can be used to practice certain methods of the invention.
  • Such agents can be those described herein, those known in the art, or those identified through routine screening assays (e.g. the screening assays described herein).
  • assays used to identify agents useful in the methods of the present invention include a reaction between the autophagy-related gene product and one or more assay components.
  • the other components may be either a test compound (e.g. the potential agent), or a combination of test compounds and a natural binding partner of the autophagy-related gene product.
  • Agents identified via such assays, such as those described herein, may be useful, for example, for modulating autophagy and treating autophagy- related diseases.
  • Agents useful in the methods of the present invention may be obtained from any available source, including systematic libraries of natural and/or synthetic compounds. Agents may also be obtained by any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive; see, e.g., Zuckermann et al, 1994, J. Med. Chem. 37:2678-85); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the One-bead one-compound' library method; and synthetic library methods using affinity chromatography selection.
  • the biological library and peptoid library approaches are limited to peptide libraries, while the other four approaches are applicable to peptide, non- peptide oligomer or small molecule libraries of compounds (Lam, 1997, Anticancer Drug Des. 12: 145).
  • Biotechniques 13:412-421 or on beads (Lam, 1991, Nature 354:82-84), chips (Fodor, 1993, Nature 364:555-556), bacteria and/or spores, (Ladner, USP 5,223,409), plasmids (Cull et al, 1992, Proc Natl Acad Sci USA 89: 1865-1869) or on phage (Scott and Smith, 1990, Science 249:386-390; Devlin, 1990, Science 249:404-406; Cwirla et al, 1990, Proc. Natl. Acad. Sci. 87:6378-6382; Felici, 1991 , J. Mol. Biol. 222:301-310; Ladner, supra.).
  • Agents useful in the methods of the present invention may be identified, for example, using assays for screening candidate or test compounds which are substrates of an autophagy-related gene product of the invention or biologically active portion thereof.
  • agents useful in the methods of the invention may be identified using assays for screening candidate or test compounds which bind to an autophagy-related gene product of the invention or a biologically active portion thereof. Determining the ability of the test compound to directly bind to an autophagy-related gene product can be
  • compounds can be labeled with 125 1, 35 S, 14 C, or 3 H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting.
  • assay components can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product.
  • Agents useful in the methods of the invention may also be identified, for example, using assays that identify compounds which modulate (e.g., affect either positively or negatively) interactions between an autophagy-related gene product and its substrates and/or binding partners.
  • Such compounds can include, but are not limited to, molecules such as antibodies, peptides, hormones, oligonucleotides, nucleic acids, and analogs thereof.
  • Such compounds may also be obtained from any available source, including systematic libraries of natural and/or synthetic compounds.
  • the basic principle of the assay systems used to identify compounds that modulate the interaction between the autophagy-related gene product and its binding partner involves preparing a reaction mixture containing the autophagy-related gene product and its binding partner under conditions and for a time sufficient to allow the two products to interact and bind, thus forming a complex.
  • the reaction mixture is prepared in the presence and absence of the test compound.
  • the test compound can be initially included in the reaction mixture, or can be added at a time subsequent to the addition of the autophagy-related gene product and its binding partner. Control reaction mixtures are incubated without the test compound or with a placebo. The formation of any complexes between the autophagy-related gene product and its binding partner is then detected.
  • the assay for compounds that modulate the interaction of the autophagy-related gene product with its binding partner may be conducted in a heterogeneous or
  • Heterogeneous assays involve anchoring either the autophagy-related gene product or its binding partner onto a solid phase and detecting complexes anchored to the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the compounds being tested. For example, test compounds that interfere with the interaction between the autophagy-related gene products and the binding partners (e.g., by competition) can be identified by conducting the reaction in the presence of the test substance, i.e., by adding the test substance to the reaction mixture prior to or simultaneously with the autophagy-related gene product and its interactive binding partner.
  • test compounds that disrupt preformed complexes e.g., compounds with higher binding constants that displace one of the components from the complex
  • test compounds that disrupt preformed complexes e.g., compounds with higher binding constants that displace one of the components from the complex
  • either the autophagy-related gene product or its binding partner is anchored onto a solid surface or matrix, while the other corresponding non-anchored component may be labeled, either directly or indirectly.
  • microtitre plates are often utilized for this approach.
  • the anchored species can be immobilized by a number of methods, either non-covalent or covalent, that are typically well known to one who practices the art. Non-covalent attachment can often be
  • a fusion protein can be provided which adds a domain that allows one or both of the assay components to be anchored to a matrix.
  • glutathione- S-transferase/marker fusion proteins or glutathione-S-transferase/binding partner can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.
  • the test compound or the test compound and either the non-adsorbed autophagy-related gene product or its binding partner are then combined with the test compound or the test compound and either the non-adsorbed autophagy-related gene product or its binding partner, and the mixture incubated under conditions conducive to complex formation (e.g., physiological conditions).
  • the beads or microtiter plate wells are washed to remove any unbound assay components, the immobilized complex assessed either directly or indirectly, for example, as described above.
  • the complexes can be dissociated from the matrix, and the level of autophagy-related gene product binding or activity determined using standard techniques.
  • a homogeneous assay may also be used to identify modulators of autophagy-related gene products. This is typically a reaction, analogous to those mentioned above, which is conducted in a liquid phase in the presence or absence of the test compound. The formed complexes are then separated from unreacted components, and the amount of complex formed is determined. As mentioned for heterogeneous assay systems, the order of addition of reactants to the liquid phase can yield information about which test compounds modulate (inhibit or enhance) complex formation and which disrupt preformed complexes.
  • reaction products may be separated from unreacted assay components by any of a number of standard techniques, including but not limited to: differential centrifugation, chromatography, electrophoresis and
  • the relatively different charge properties of the complex as compared to the uncomplexed molecules may be exploited to differentially separate the complex from the remaining individual reactants, for example through the use of ion-exchange chromatography resins.
  • ion-exchange chromatography resins Such resins and chromatographic techniques are well known to one skilled in the art (see, e.g., Heegaard, 1998, J Mol.
  • Gel electrophoresis may also be employed to separate complexed molecules from unbound species (see, e.g., Ausubel et al (eds.), In: Current Protocols in Molecular Biology, J. Wiley & Sons, New York. 1999). In this technique, protein or nucleic acid complexes are separated based on size or charge, for example. In order to maintain the binding interaction during the electrophoretic process, nondenaturing gels in the absence of reducing agent are typically preferred, but conditions appropriate to the particular interactants will be well known to one skilled in the art.
  • Immunoprecipitation is another common technique utilized for the isolation of a protein-protein complex from solution (see, e.g., Ausubel et al (eds.), In: Current Protocols in Molecular Biology, J. Wiley & Sons, New York. 1999).
  • Ausubel et al eds.
  • all proteins binding to an antibody specific to one of the binding molecules are precipitated from solution by conjugating the antibody to a polymer bead that may be readily collected by centrifugation.
  • the bound assay is another common technique utilized for the isolation of a protein-protein complex from solution.
  • Modulators of autophagy-related gene product expression may also be identified, for example, using methods wherein a cell is contacted with a candidate compound and the expression of mRNA or protein, corresponding to an autophagy-related gene in the cell, is determined. The level of expression of mRNA or protein in the presence of the candidate compound is compared to the level of expression of mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of autophagy-related gene product expression based on this comparison. For example, when expression of autophagy-related gene product is greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of marker mRNA or protein expression.
  • the candidate compound when expression of autophagy-related gene product is less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of marker mRNA or protein expression.
  • the level of autophagy-related gene product expression in the cells can be determined by methods described herein for detecting marker mRNA or protein.
  • Agents that inhibit the activity of autophagy-inhibiting gene products are useful, for example, in enhancing autophagy and in the treatment of neurodegenerative diseases.
  • FGFR1 fibroblast growth factor receptor 1 (fms- TK1258 (CHIR258)
  • CASP1 caspase 1 apoptosis-related cysteine Pralnacasan (VX-740, HMR peptidase (interleukin 1 , beta, 3480) convertase);CASP 1
  • PR CA protein kinase C alpha
  • PRKCA ISIS 3521 carboplatin, paclitaxel
  • agents that enhance the activity of autophagy-inhibiting gene products are useful, for example, in inhibiting autophagy and in the treatment of cancer and pancreatitis.
  • enhancers of autophagy-inhibiting gene products are listed in Table 8 and Figure 63.
  • FGFR1 fibroblast growth factor receptor 1 (fms- Cardio Vascu-Grow (FGF-1, related tyrosine kinase 2, Pfeiffer CVBT-141) syndrome);FGFRl
  • FGFR1 fibroblast growth factor receptor 1 fms- Acidic FGF (aFGF);
  • FGFR1 fibroblast growth factor receptor 1 fms- XRP0038 (NV1FGF)
  • FGFR1 fibroblast growth factor receptor 1 fms- Rh-aFGF
  • GHSR growth hormone secretagogue Ibutamoren Mesylate Ibutamoren Mesylate (MK- receptor;GHSR 0677)
  • GHSR growth hormone secretagogue EP1572 (ghrelin agonist) receptor GHSR
  • agents that modulate the autophagy-related gene products listed in tables 1-4 can be found in, for example, U.S. Patent Numbers: 7,348,140; 6,982,265;
  • oligonucleotide inhibitors of autophagy-related RNA gene products are used to modulate autophagy and to treat autophagy-related diseases.
  • Oligonucleotide inhibitors include, but are not limited to, antisense molecules, siRNA molecules, shRNA molecules, ribozymes and triplex molecules. Such molecules are known in the art and the skilled artisan would be able to create oligonucleotide inhibitors for any of the autophagy-related genes of the invention using routine methods.
  • Antisense molecules, siRNA or shRNA molecules, ribozymes or triplex molecules may be contacted with a cell or administered to an organism. Alternatively, constructs encoding such molecules may be contacted with or introduced into a cell or organism. Antisense constructs, antisense oligonucleotides, RNA interference constructs or siRNA duplex RNA molecules can be used to interfere with expression of a protein of interest, e.g., an autophagy-related gene of the present invention. Typically at least 15, 17, 19, or 21 nucleotides of the complement of the mRNA sequence are sufficient for an antisense molecule. Typically at least 15, 19, 21, 22, or 23 nucleotides of a target sequence are sufficient for an RNA interference molecule.
  • an RNA interference molecule will have a 2 nucleotide 3' overhang. If the RNA interference molecule is expressed in a cell from a construct, for example from a hairpin molecule or from an inverted repeat of the desired autophagy-related gene sequence, then the endogenous cellular machinery may create the overhangs.
  • siRNA molecules can be prepared by chemical synthesis, in vitro transcription, or digestion of long dsR A by Rnase III or Dicer. These can be introduced into cells by transfection, electroporation, intracellular infection or other methods known in the art. See, for example: Hannon, GJ, 2002, R A Interference, Nature 418: 244-251; Bernstein E et al., 2002, The rest is silence.
  • Short hairpin RNAs induce sequence-specific silencing in mammalian cells. Genes & Dev. 16:948-958; Paul CP, Good PD, Winer I, and Engelke DR. (2002). Effective expression of small interfering RNA in human cells. Nature Biotechnol. 20:505-508; Sui G, Soohoo C, Affar E-B, Gay F, Shi Y, Forrester WC, and Shi Y. (2002). A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl. Acad. Sci. USA 99(6):5515-5520; Yu J-Y, DeRuiter SL, and Turner DL.
  • Antisense or RNA interference molecules can be delivered in vitro to cells or in vivo, e.g., to tumors or diseased tissues of a mammal. Typical delivery means known in the art can be used. For example, delivery to a tumor can be accomplished by intratumoral injections. Other modes of delivery can be used without limitation, including: intravenous, intramuscular, intraperitoneal, intraarterial, local delivery during surgery, endoscopic, subcutaneous, and per os. Vectors can be selected for desirable properties for any particular application. Vectors can be viral, bacterial or plasmid. Adenoviral vectors are useful in this regard.
  • Tissue-specific, cell-type specific, or otherwise regulatable promoters can be used to control the transcription of the inhibitory polynucleotide molecules.
  • Non- viral carriers such as liposomes or nanospheres can also be used.
  • a RNA interference molecule or an RNA interference encoding oligonucleotide can be administered to the subject, for example, as naked RNA, in combination with a delivery reagent, and/or as a nucleic acid comprising sequences that express the siRNA or shRNA molecules.
  • the nucleic acid comprising sequences that express the siRNA or shRNA molecules are delivered within vectors, e.g. plasmid, viral and bacterial vectors.
  • Suitable delivery reagents include, but are not limited to, e.g, the Minis Transit TKO lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations (e.g., polylysine), atelocollagen, nanoplexes and liposomes.
  • telocollagen as a delivery vehicle for nucleic acid molecules is described in Minakuchi et al. Nucleic Acids Res., 32(13):el09 (2004); Hanai et al. Ann NY Acad Sci., 1082:9-17 (2006); and Kawata et al. Mol Cancer Ther., 7(9):2904-12 (2008); each of which is incorporated herein in their entirety.
  • liposomes are used to deliver an inhibitory oligonucleotide to a subject.
  • Liposomes suitable for use in the invention can be formed from standard vesicle-forming lipids, which generally include neutral or negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of factors such as the desired liposome size and half-life of the liposomes in the blood stream. A variety of methods are known for preparing liposomes, for example, as described in Szoka et al. (1980), Ann. Rev. Biophys. Bioeng. 9:467; and U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, the entire disclosures of which are herein incorporated by reference.
  • the liposomes for use in the present methods can comprise a ligand molecule that targets the liposome to cancer cells, pancreatic cells or neurons.
  • Ligands which bind to receptors prevalent in cancer cells, pancreatic cells or neurons such as monoclonal antibodies that bind to cell-type specific antigens, are preferred.
  • the liposomes for use in the present methods can also be modified so as to avoid clearance by the mononuclear macrophage system ("MMS") and reticuloendothelial system ("RES").
  • MMS mononuclear macrophage system
  • RES reticuloendothelial system
  • modified liposomes have opsonization-inhibition moieties on the surface or incorporated into the liposome structure.
  • a liposome of the invention can comprise both opsonization-inhibition moieties and a ligand.
  • Opsonization-inhibiting moieties for use in preparing the liposomes of the invention are typically large hydrophilic polymers that are bound to the liposome membrane.
  • an opsonization inhibiting moiety is "bound" to a liposome membrane when it is chemically or physically attached to the membrane, e.g., by the intercalation of a lipid- soluble anchor into the membrane itself, or by binding directly to active groups of membrane lipids.
  • These opsonization-inhibiting hydrophilic polymers form a protective surface layer that significantly decreases the uptake of the liposomes by the MMS and RES; e.g., as described in U.S. Pat. No. 4,920,016, the entire disclosure of which is herein incorporated by reference.
  • Opsonization inhibiting moieties suitable for modifying liposomes are preferably water-soluble polymers with a number-average molecular weight from about 500 to about 40,000 daltons, and more preferably from about 2,000 to about 20,000 daltons.
  • Such polymers include polyethylene glycol (PEG) or polypropylene glycol (PPG) derivatives; e.g., methoxy PEG or PPG, and PEG or PPG stearate; synthetic polymers such as polyacrylamide or poly N-vinyl pyrrolidone; linear, branched, or dendrimeric
  • polyamidoamines polyacrylic acids; polyalcohols, e.g., polyvinylalcohol and polyxylitol to which carboxylic or amino groups are chemically linked, as well as gangliosides, such as ganglioside GM1.
  • Copolymers of PEG, methoxy PEG, or methoxy PPG, or derivatives thereof, are also suitable.
  • the opsonization inhibiting polymer can be a block copolymer of PEG and either a polyamino acid, polysaccharide, polyamidoamine, polyethyleneamine, or polynucleotide.
  • the opsonization inhibiting polymers can also be natural polysaccharides containing amino acids or carboxylic acids, e.g., galacturonic acid, glucuronic acid, mannuronic acid, hyaluronic acid, pectic acid, neuraminic acid, alginic acid, carrageenan; aminated polysaccharides or oligosaccharides (linear or branched); or carboxylated polysaccharides or oligosaccharides, e.g., reacted with derivatives of carbonic acids with resultant linking of carboxylic groups.
  • the opsonization-inhibiting moiety is a PEG, PPG, or derivatives thereof. Liposomes modified with PEG or PEG- derivatives are sometimes called "PEGylated liposomes.”
  • the opsonization inhibiting moiety can be bound to the liposome membrane by any one of numerous well-known techniques.
  • an N-hydroxysuccinimide ester of PEG can be bound to a phosphatidyl-ethanolamine lipid-soluble anchor, and then bound to a membrane.
  • a dextran polymer can be derivatized with a stearylamine lipid- soluble anchor via reductive amination using Na(CN)BH 3 and a solvent mixture, such as tetrahydrofuran and water in a 30: 12 ratio at 60°C. Liposomes modified with opsonization-inhibition moieties remain in the circulation much longer than unmodified liposomes.
  • Stealth liposomes are sometimes called “stealth” liposomes.
  • Stealth liposomes are known to accumulate in tissues fed by porous or "leaky” micro vasculature.
  • tissue characterized by such microvasculature defects for example solid tumors, will efficiently accumulate these liposomes; see Gabizon, et al. (1988), Proc. Natl. Acad. Sci., USA, 18:6949-53.
  • the reduced uptake by the RES lowers the toxicity of stealth liposomes by preventing significant accumulation of the liposomes in the liver and spleen.
  • antibodies specific for polypeptide autophagy-related gene products are able to either inhibit or enhance the activities of such gene products and thereby inhibit or enhance autophagy.
  • an antibody specific for a receptor can inhibit the activity of the receptor by blocking its interaction with an activating ligand.
  • antibodies specific for a soluble ligand ⁇ e.g. a cytokine or growth factor) or a membrane -bound ligand can inhibit the activity of a receptor that is capable of binding to the ligand by inhibiting the binding of the ligand to the receptor.
  • antibodies specific for a receptor can be used to cross-link and thereby activate the receptor.
  • antibodies specific for peptide products of autophagy-related genes are useful as biological agents for the methods of the present invention.
  • Antibodies that specifically bind to a peptide product of an autophagy-related gene can be produced using a variety of known techniques, such as the standard somatic cell hybridization technique described by Kohler and Milstein, Nature 256: 495 (1975).
  • Polyclonal antibodies can be prepared by immunizing a suitable subject with a polypeptide immunogen.
  • the polypeptide antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide.
  • ELISA enzyme linked immunosorbent assay
  • the antibody directed against the antigen can be isolated from the mammal ⁇ e.g. , from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction.
  • antibody- producing cells can be obtained from the subject and used to prepare monoclonal antibodies.
  • an immortalized cell line can be applied for the purpose of generating monoclonal antibodies specific against the products of autophagy-related genes (see, e.g., Galfre, G. et al. (1977) Nature 266:55052; Gefter et al. (1977) supra; Lerner (1981) supra; Kenneth (1980) supra). Moreover, the ordinary skilled worker will appreciate that there are many variations of such methods which also would be useful.
  • an immortal cell line ⁇ e.g., a myeloma cell line
  • murine hybridomas can be made by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the present invention with an immortalized mouse cell line.
  • An example of an appropriate mouse cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium").
  • HAT medium culture medium containing hypoxanthine, aminopterin and thymidine
  • Any of a number of myeloma cell lines can be used as a fusion partner according to standard techniques, e.g., the P3-NSl/l-Ag4-l, P3-x63-Ag8.653 or Sp2/0- Agl4 myeloma lines.
  • HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG"). Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and
  • Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind a given polypeptide, e.g., using a standard ELISA assay.
  • a monoclonal antibody specific for one of the above described autophagy-related gene products can be identified and isolated by screening a recombinant combinatorial immunoglobulin library ⁇ e.g., an antibody phage or yeast display library) with the appropriate autophagy-related gene product to thereby isolate immunoglobulin library members that bind the autophagy-related gene product.
  • Kits for generating and screening phage display libraries are commercially available ⁇ e.g., the Pharmacia Recombinant Phage
  • chimeric and humanized antibodies against autophagy-related gene products can be made according to standard protocols such as those disclosed in US patent 5,565,332.
  • antibody chains or specific binding pair members can be produced by recombination between vectors comprising nucleic acid molecules encoding a fusion of a polypeptide chain of a specific binding pair member and a component of a replicable generic display package and vectors containing nucleic acid molecules encoding a second polypeptide chain of a single binding pair member using techniques known in the art, e.g., as described in US patents 5,565,332, 5,871,907, or 5,733,743.
  • human monoclonal antibodies directed against autophagy- related gene product can be generated using transgenic or transchromosomal mice carrying parts of the human immune system rather than the mouse system.
  • transgenic mice referred to herein as "humanized mice,” which contain a human immunoglobulin gene miniloci that encodes unrearranged human heavy and light chain variable region immunoglobulin sequences, together with targeted mutations that inactivate or delete the endogenous ⁇ and ⁇ chain loci (Lonberg, N. et al. (1994) Nature 368(6474): 856 859).
  • the mice may also contain human heavy chain constant region immunoglobulin sequences.
  • mice express little or no mouse IgM or ⁇ , and in response to immunization, the introduced human heavy and light chain variable region transgenes undergo class switching and somatic mutation to generate high affinity human variable region antibodies (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N. (1994)
  • mice can be used to generate fully human monoclonal antibodies using the techniques described above or any other technique known in the art.
  • the preparation of humanized mice is described in Taylor, L. et al. (1992) Nucleic Acids Research 20:6287 6295; Chen, J. et al. (1993) International Immunology 5: 647 656;
  • compositions comprising modulators of autophagy-related gene products.
  • the present invention provides pharmaceutical compositions comprising modulators of autophagy-related gene products.
  • compositions which comprise a therapeutically-effective amount of one or more of the agents described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the agents of the invention can be administered as such, or administered in mixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with other agents.
  • Conjunctive therapy thus includes sequential, simultaneous and separate, or coadministration of one or more agent of the invention, wherein the therapeutic effects of the first administered has not entirely disappeared when the subsequent compound is administered.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets
  • agents of the invention may be compounds containing a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • a basic functional group such as amino or alkylamino
  • These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or through a separate reaction of a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the agents of the present invention may be compounds containing one or more acidic functional groups and, thus, are capable of forming pharmaceutically- acceptable salts with pharmaceutically-acceptable bases.
  • These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., supra).
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • the formulations of the agents of the invention may be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the agent which produces a therapeutic effect.
  • a formulation of the present invention comprises an excipient, including, but not limited to, cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and an agent of the present invention.
  • an aforementioned formulation renders orally bioavailable a agent of the present invention.
  • Methods of preparing these formulations or compositions may include the step of bringing into association an agent of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. Compositions of the invention may also be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • Exemplary formulations comprising agents of the invention are determined based on various properties including, but not limited to, chemical stability at body temperature, functional efficiency time of release, toxicity and optimal dose.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • the above-described pharmaceutical compositions comprise one or more of the agents of the invention, a chemotherapeutic agent, and optionally a pharmaceutically acceptable carrier.
  • chemotherapeutic agent includes, without limitation, platinum-based agents, such as carboplatin and cisplatin; nitrogen mustard alkylating agents; nitrosourea alkylating agents, such as carmustine (BCNU) and other alkylating agents; antimetabolites, such as methotrexate; purine analog antimetabolites; pyrimidine analog antimetabolites, such as fluorouracil (5-FU) and gemcitabine; hormonal antineoplastics, such as goserelin, leuprolide, and tamoxifen; natural antineoplastics, such as taxanes (e.g., docetaxel and paclitaxel), aldesleukin, interleukin-2, etoposide (VP- 16), interferon a, and tretinoin
  • platinum-based agents such as carboplatin and cisplatin
  • nitrogen mustard alkylating agents such as nitrosourea alkylating agents, such as carmustine (BCNU) and other al
  • ATRA antibiotic natural antineoplastics, such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin
  • vinca alkaloid natural antineoplastics such as vinblastine and vincristine.
  • the following drugs may also be used in combination with a
  • chemotherapeutic agents themselves: dactinomycin; daunorubicin HC1; docetaxel; doxorubicin HC1; epoetin a; etoposide (VP- 16); ganciclovir sodium; gentamicin sulfate; interferon a; leuprolide acetate; meperidine HC1; methadone HC1; ranitidine HC1; vinblastin sulfate; and zidovudine (AZT).
  • fluorouracil has recently been formulated in conjunction with epinephrine and bovine collagen to form a particularly effective combination.
  • SOD superoxide dismutase
  • Chemotherapeutic agents for use with the compositions and methods of treatment described herein include, but are not limited to alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan;
  • aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil
  • prednimustine, trofosfamide, uracil mustard nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine
  • antibiotics such as the enediyne antibiotics (e.g.
  • calicheamicin especially calicheamicin gammall and calicheamicin omegall ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin
  • doxorubicin including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxy doxorubicin
  • epirubicin including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxy doxorubicin
  • epirubicin including esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin
  • anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogues such as denopterin,
  • amsacrine bestrabucil
  • bisantrene edatraxate
  • defofamine demecolcine
  • diaziquone diaziquone
  • elformithine elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex);
  • razoxane rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol;
  • pipobroman gacytosine; arabinoside ("Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine;
  • methotrexate platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone;
  • DMFO difluoromethylomithine
  • retinoids such as retinoic acid
  • capecitabine and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • composition of the invention may comprise other biologically active substances, including therapeutic drugs or pro-drugs, for example, other chemotherapeutic agents, scavenger compounds, antibiotics, anti-virals, anti-fungals, antiinflammatories, vasoconstrictors and anticoagulants, antigens useful for cancer vaccine applications or corresponding pro-drugs.
  • therapeutic drugs or pro-drugs for example, other chemotherapeutic agents, scavenger compounds, antibiotics, anti-virals, anti-fungals, antiinflammatories, vasoconstrictors and anticoagulants, antigens useful for cancer vaccine applications or corresponding pro-drugs.
  • Exemplary scavenger compounds include, but are not limited to thiol-containing compounds such as glutathione, thiourea, and cysteine; alcohols such as mannitol, substituted phenols; quinones, substituted phenols, aryl amines and nitro compounds.
  • chemotherapeutic agents and/or other biologically active agents may be used. These include, without limitation, such forms as uncharged molecules, molecular complexes, salts, ethers, esters, amides, and the like, which are biologically active.
  • the present invention further provides novel therapeutic methods of treating autophagy-related diseases, including cancer, neurodegenerative diseases, spinal cord injury, peripheral nerve injury, liver diseases, muscle diseases and pancreatitis, comprising administering to a subject, ⁇ e.g., a subject in need thereof), an effective amount of a modulator of an autophagy-related gene product of the invention.
  • autophagy-related diseases including cancer, neurodegenerative diseases, spinal cord injury, peripheral nerve injury, liver diseases, muscle diseases and pancreatitis
  • a subject in need thereof may include, for example, a subject who has been diagnosed with a tumor, including a pre-cancerous tumor, a cancer, or a subject who has been treated, including subjects that have been refractory to previous treatment.
  • the invention relates to the treatment or prevention of axonal degeneration following neural trauma through the modulation of calcium-binding autophagy modulating gene products or through the modulation of other autophagy-related gene products.
  • the methods of the present invention may be used to treat any cancerous or precancerous tumor.
  • Cancers that may treated by methods and compositions of the invention include, but are not limited to, cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung,
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma;
  • lymphoepithelial carcinoma basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma;
  • adenocarcinoma in adenomatous polyp adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic
  • adenocarcinoma basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous
  • adenocarcinoma adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary
  • cystadenocarcinoma papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma;
  • fibrosarcoma fibrous histiocytoma, malignant; myxosarcoma; liposarcoma;
  • rhabdomyosarcoma stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant;
  • choriocarcinoma mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma;
  • osteosarcoma juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma;
  • astrocytoma protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma;
  • glioblastoma oligodendroglioma; oligodendroblastoma; primitive neuroectodermal;
  • cerebellar sarcoma cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia;
  • plasma cell leukemia erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia;
  • megakaryoblastic leukemia myeloid sarcoma
  • hairy cell leukemia myeloid sarcoma
  • the methods of the present invention include the treatment of cancer comprising the administration of an autophagy-inhibiting agent of the present invention in combination with a chemotherapeutic agent.
  • autophagy-inhibiting agents include agents that inhibit the activity of products of autophagy-enhancing genes (Table 2) and agents that enhance the activity of the products of autophagy-inhibiting genes (Table 1).
  • Any chemotherapeutic agent is suitable for use in the methods of the instant invention, particularly chemotherapeutic agents that that induce cellular stress in cancer cells.
  • Chemotherapeutic agents useful in the instant invention include, but are not limited to, to alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a
  • camptothecin including the synthetic analogue topotecan
  • bryostatin including its adozelesin, carzelesin and bizelesin synthetic analogues
  • cryptophycins particularly cryptophycin 1 and cryptophycin 8
  • dolastatin duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;
  • mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, if
  • nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin
  • antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin

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