Advanced search
Publication Cover
Expert Review of Anticancer Therapy Volume 4, 2004 - Issue 1
Submit an article Journal homepage
172
Views
122
CrossRef citations to date
0
Altmetric
Review

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2: PI3K/Akt/PTEN, mTOR, SHH/PTCH and angiogenesis

Herbert B Newton Dardinger Neuro-Oncology Center, Department of Neurology, Ohio State University Hospitals, 465 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA. [email protected]
Pages 105-128 | Published online: 10 Jan 2014

References

  • Newton HB. Primary brain tumors: review of etiology, diagnosis and treatment. Aim Fain. Physician 49, 787–797 (1994).
  • •Detailed clinical review.
  • Davis FG, McCarthy BJ. Current epidemiological trends andsurveillance issues in brain tumors. and pharmacotherapy of patients with primary brain tumors. Expert Rev. Anticancer Ther 1, 395–401 (2001).
  • Newton HB. Neurological complications of
  • Wen PY, Loeffler JS. Management of brain metastases. Oncology13, 941–961 (1999).
  • ••Thorough review.
  • Newton HB, Turowski RC, Stroup TJ, McCoy LK. Clinical presentation, and diagnosis and pharmacotherapy of patients with primary brain tumors.Ann. Phatmacother. 33,816–832 (1999).
  • ••Thorough review of primary brain tumor pharmacotherapy.
  • Fine HA, Dear KBG, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer71, 2585–2597 (1993).
  • ••Meta-analysis demonstrates survival advantage for chemotherapy.
  • Newton HB. Chemotherapy for the treatment of metastatic brain tumors. Expert Rev Anticancer Ther. 2,495–506 (2002).
  • •Thorough review.
  • Chung RY, Seizinger BR. Tumor suppressor genes and cancer of the human nervous system. Cancer Investig 9,429–438 (1991).
  • von Deimling A, Louis DN, Wiestler OD. Molecular pathways in the formation of gliomas. Glia 15,328–338 (1995).
  • Shapiro JR, Coons SW Genetics of adult malignant gliomas. BNI Quart. 14,27–42 (1998).
  • •Thorough review
  • Maher EA, Furnari FB, Bachoo RM et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15,1311–1333 (2001).
  • ••Thorough review of molecular biology andsignal transduction.
  • Newton HB. Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: growth factor and Ras signaling pathways. Expert Rev Anticancer Ther 3(5), 89–108 (2003).
  • •• Thorough review
  • Aaronson SA. Growth factors and cancer. Science 254,1146–1153 (1991).
  • Claesson-Welsh L. Platelet-derived growth factor receptor signals. J. Biol. Chem. 269, 32023–32026 (1994).
  • Hackel PO, Zwick E, Prenzel N, Ullrich A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Cun: Opin. Cell Biol. 11,184–189 (1999).
  • Klagsbrun M. The fibroblast growth factor family: structural and biological properties. Frog. Growth Factor Res. 1,207–235 (1989).
  • •Detailed review of fibroblast growth factor biology.
  • Lowy DR, Willumsen BM. Function and regulation of Ras. Ann. Rev Biochem. 62, 851–891 (1993).
  • ••Detailed review.
  • Martin IKA, Blenis J. Co-ordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv. Cancer Res. 86, 1–39 (2002).
  • ••Detailed review.
  • Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Cun: Opin. Cell Biol. 10,262–267 (1998).
  • Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim. Biophys. Acta 1436,127–150 (1998).
  • •• Thorough review.
  • Rameh LE, Cantley LC. The role of phosphoinositide 3-kinase lipid products in cell function. J. Biol. Chem. 274, 8347–8350 (1999).
  • Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase—Akt pathway in human cancer. Nature Rev Cancer2, 489–501 (2002).
  • ••Detailed review of biology with clinicalcorrelation.
  • Gomperts BD, Kramer IM, Tatham PER. Phosphoinositide 3-kinases, protein kinase B and signaling through the insulin receptor. In: Signal 71ansduction. Academic Press, CA, USA 13,299–314 (2002).
  • Fruman DA, Cantley LC. PI3-kinases. Role in signal transduction. In: Signaling Networks, and Cell Cycle Control The Molecular Basis of Cancer and Other Diseases. Gutkind JS (Ed.), Humana Press, NJ, USA 14,247–266 (2000).
  • ••Thorough review.
  • Sekulic A, Hudson CC, Homme JL et al. A direct linkage between the phosphoinositide 3-kinase—Akt signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504–3513 (2000).
  • Tibbetts RS, Abraham RT. PI3K-related kinases. Roles in cell-cycle regulation and DNA damage responses. In: Signaling Networks, and Cell Cycle Control The Molecular Basis of Cancer and Other Diseases. Gutkind JS (Ed.), Humana Press, NJ, USA 15,267–301 (2000).
  • ••Thorough review.
  • Dennis PB, Fumagalli S, Thomas G. Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. Curl: Opin. Genet. Dev. 9, 49–54 (1999).
  • Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 103, 253–262 (2000).
  • ••Thorough review.
  • Chen J, Fang Y. A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling. Biochem. Pharmacol 64,1071–1077 (2002).
  • Burgering BMT, Coffer PJ. Protein kinase B (c-akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599–602 (1995).
  • Klippel A, Kavanaugh WM, Pot D, Williams LT A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mal Cell. Bid 17,338–344 (1997).
  • Andjelkovic M, Alessi DR, Meier R et al Role of translocation in the activation and function of protein kinase B. J. Biol. Chem. 272,31515–31524 (1997).
  • Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 13,2905–2927 (1999).
  • ••Excellent overview of Akt biology
  • Scheid MP, Woodgett JR. PKB/Akt: functional insights from genetic models. Nature Rev Mal Cell Biol. 2,760–768 (2001).
  • Kennedy SG, Wagner AJ, Conzen SD et al The PI 3-kinase signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11, 701–713 (1997).
  • Datta SR, Dudek H, Tao X et al Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Ce1191, 231–241 (1997).
  • Brunet A, Bonni A, Zigmond MJ et al Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96,857–868 (1999).
  • Cardone MET, Roy N, Stennicke HR et al Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318–1321 (1998).
  • Romashkova JA, Makarov SS. NF-KB is a target of Akt in anti-apoptotic PDGF signaling. Nature 401, 86–90 (1999).
  • Gesbert E, Sellers WR, Signoretti S, Loda M, Griffin JD. BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p271(1P1 through the phosphatidylinositol 3-kinase/Akt pathway. Biol. Chem. 273,39223-39230 (2000).
  • Zhou BP, Liao Y, Xia W, Spohn B, Lee MET, Hung MC. Cmlasmic localization of p21C1P1by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature Cell Biol. 3, 245–252 (2001).
  • Mayo LD. Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. 98,11598-11603 (2001).
  • Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2E Immunity7, 679–689 (1997).
  • Diehl JA, Cheng M, Roussel ME, Sherr CJ. Glycogen synthase-3I3 regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12,3499–3511 (1998).
  • Sakata K, Kato S, Fox JC, Shigemori M, Morimatsu M. Autocrine signaling through ras regulates cell survival activity in human glioma cells: potential cross-talk between ras and the phosphoinositide 3-kinase—Akt pathway. I Neuropathol Exp. Neural. 61, 975–983 (2002).
  • Choe G, Horvath S, Cloughesy TF et al Analysis of the phosphotidylinositol 3--kinase signaling pathway in glioblastoma patients in viva Cancer Res. 63, 2742–2746 (2003).
  • Sonoda Y, Ozawa T, Aldape KD, Deen DF, Berger MS, Pieper RO. Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res. 61, 6674–6678 (2001).
  • Kubiatowski T, Jang T, Lachyankar MB et al Association of increased phosphoinositide 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. I Neumsurg. 95, 480–488 (2001).
  • Li J, Yen C, Liaw D et al PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science 175, 1943–1947 (1997).
  • •Seminal article of PTEN discovery.
  • Steck PA, Pershouse MA, Jasser SA et al Identification of a candidate tumour suppressor gene, A421//4C/, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356–362 (1997).
  • •Seminal article of PTEN discovery.
  • Maehama T, Dixon JE. The tumor suppressor, P7EN/MIVIAC1, dephosphorylates the lipid messenger, phosphatidylinositol 3,4,5-triphosphate. Biol. Chem. 273, 13375–1378 (1998).
  • Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/Akt pathway. Proc. Natl Acad. Sc,. 96, 4240–4245 (1999).
  • Lee JO, Yang H, Georgescu MM et al Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Ce1199, 232–334 (1999).
  • Tamura M, Gu J, Tran H, Yamada KM. PTEN gene and integrin signaling in cancer. I Natl Cancer Inst. 91, 1820–1828 (1999).
  • Vazquez F, Sellers WR. The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim. Biophys. Acta 1470, M21—M35 (2000).
  • ••Detailed review of the phosphoinositide 3-kinase (PI3K)/Akt/PTEN pathway.
  • Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail regulates protein stability and function. Mal Cell Biol. 20, 5010–5018 (2000).
  • Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J. Biol. Chem. 276, 48627–4830 (2001).
  • Li IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. Natl Cancer Inst. 91, 1922–1932 (1999). •• Thorough review.
  • Rasheed BKA, Stenzel TT, McLendon RE et al PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res. 57, 4187–4190 (1997).
  • Wang SI, Puc J, Li J et al Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57, 4183–4186 (1997).
  • Duerr EM, Rollbrocker B, Hayashi Y et al PTEN mutations in gliomas and glioneuronal tumors. Oncogene 16, 2259–2264 (1998).
  • Zhou XP, Li YJ, Hoang-Xuan K et al Mutational analysis of the PTEN gene in gliomas: molecular and pathological correlations. [nt.j Cancer 84, 150–154 (1999).
  • Sano T, Lin H, Chen X et al Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res. 59, 1820–1824 (1999).
  • Davies MPA, Gibbs FEM, Halliwell N et al Mutation in the PTEN/MMAC1 gene in archival low grade and high grade gliomas. Br. Cancer79, 1542–1548 (1999).
  • Fults D, Pedone C. Immunocytochemical mapping of the phosphatase and tensin homolog (PTEN/MMAC1) tumor suppressor protein in human gliomas. Neuro-oncology2, 71–79 (2000).
  • Knobbe CB, Merlo A, Reifenberger G. PTEN signaling in gliomas. Neuro -oncology 4, 196–211 (2002).
  • ••Detailed review of PTEN biology ingliomas.
  • Sasaki H, Zlatescu MC, Betensky RA, Ino Y, Caimcross JG, Louis DN. PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Am. Pathol 159, 359–367 (2001).
  • Smith JS, Tachibana I, Passe SM et al PTEN mutation, EGFR amplification and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. Natl Cancer Inst. 93, 1246–1256 (2001).
  • Ermoian RP, Furniss CS, Lamborn KR et al Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin. Cancer Res. 8, 1100–1106 (2002).
  • Stein RC. Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. Endocr: Relat. Cancer8, 237–248 (2001).
  • ••Excellent review.
  • Powis G, Bonjouldian R, Berggren MM et al Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 54, 2419–2423 (1994).
  • Vlahos CJ, Matter WF, Hui KY, Brown RE A specific inhibitor of phosphatidylinositol 3-kinase, 2- (4-morpholiny0-8-pheny1-4H-1-benzopyran-4-one (LY-294002). I Biol. Chem. 269, 5241–5248 (1994).
  • Woscholski R, Kodaki T, McKinnona M, Waterfield MD, Parker PJ. A comparison of demethoxyviridin and wortmannin as inhibitors of phosphatidylinositol 3-kinase. FEBS Lett. 342, 109–114 (1994).
  • Norman BH, Shih C, Toth JE et al. Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs. I Med. Chem. 39, 1106–1111 (1996).
  • Wymann MP, Bulgarelli LG, Zvelebil MJ et al Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mal Cell. Biol. 16, 1722–1733 (1996).
  • Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. 351, 95–105 (2000).
  • Walker EH, Pacold MR, Perisic 0 et al Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY-294002, quercetin, myricetin and staurosporine. Mal Cell 6, 909–919 (2000).
  • Gescher A. Analogs of staurosporine: potential anticancer drugs? Gen. Pharmacol 31, 721–728 (1998).
  • Hill MM, Andjelkovic M, Brazil DP, Ferrari S, Fabbro D, Hemmings BA. Insulin-stimulated protein kinase B phosphorylation on ser-473 is independent of its activity and occurs through a staurosporine-insensitive kinase. I Biol. Chem. 276, 25643–25646 (2001).
  • Kubota N, Okada S, Inada T, Ohnishi K, Ohnishi T Wortmannin sensitizes human glioblastoma cell lines carrying mutant wild type TP3 gene to radiation. Cancer Lett. 161,141–147 (2000).
  • Klingler-Hoffman M, Bukczynska P, Tiganis T Inhibition of phosphatidylinositol 3-kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells. Int. J. Cancer 105,331–339 (2003).
  • Shingu T, Yamada K, Hara N et a/. Growth inhibition of human malignant glioma cells induced by the P13-K-specific inhibitor. .1. Neurosurg. 98,154-161 (2003).
  • Su JD, Mayo LD, Donner DB, Durden DL. PTEN and phosphatidylinositol 3 --kinase inhibitors upregulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. Cancer Res. 63,3858–3592 (2003).
  • Price BD, Youmell MB. The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks the induction of p53 following DNA damage. Cancer Res. 56,246–250 (1996).
  • Chernikova SB, Well RL, Elkind MM. Wortmannin sensitizes mammalian cells to radiation by inhibiting the DNA-dependent protein kinase mediated rejoining of double-strand breaks. Racliat. Res. 151,159–166 (1999).
  • Cheney IW, Johnson DE, Vaillancourt MT et al Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res. 58,2331–2334 (1998).
  • Davies MA, Lu Y, Sano T et a/. Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res. 58,5285–5290 (1998).
  • Cheney IW, Neuteboom STC, Vaillancourt MT, Ramachandra M, Bookstein R. Adenovirus-mediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S phase entry by the recruitment of p27K111 into cyclin E/CDK2 complexes. Cancer Res. 59,2318-2323 (1999).
  • Adachi JI, Ohbayashi K, Suzuki T, Sasaki T Cell cycle arrest and astrocytic differentiation resulting from PTEN expression in glioma cells. J. Neurosurg. 91, 822–830 (1999).
  • Wick W, Fumari FB, Naumann U, Cavanee WK, Weller M. PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Oncogene 18, 3936–3943 (1999).
  • Gomez-Manzano C, Fueyo J, Glass T et al MMAC/PTEN downregulates VEGF in gliomas. Neuro-oncology2, 265 (2000) (Abstract).
  • Abe T, Terada K, Wakimoto H et al PTEN decreases in vivo vascularization of experimental gliomas in spite of proangiogenic stimuli. Cancer Res. 63, 2300–2305 (2003).
  • Nave BT, Ouwens DM, Withers DJ, Alessi DR, Shepherd PR. Mammalian target or rapamycin is a direct target for Protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. j 344, 427–431 (1999).
  • Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl Acad. Sci. USA 99,13571–13576 (2002).
  • Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nature Cell Biol. 4,648-657 (2002).
  • Manning BD, Cantley LC. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem. Soc. Bans. 31,573-578 (2003).
  • Kwiatkowski DJ. Tuberous sclerosis complex: from tubers to mTOR. Ann. Hum. Genet. 67,1–10 (2003).
  • •Detailed review.
  • Kim KH, Sarbassov DD, Ali SM et al mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Ce//110, 163–175 (2002).
  • •Seminal description of raptor.
  • Hara K, Maruki Y, Long X et a/. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Genii( 177–189 (2002).
  • Mills GB, Lu Y, Kohn EC. Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc. Natl Acad. Li. 98,10031-10033 (2001).
  • Hu X, Dai C, Rajasekhar VK, Holland EC. The astrogenic effect of Akt signaling on glia is mediated through mTOR. Neum-oncology3, 276 (2001) (Abstract).
  • Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19,6680–6686 (2000).
  • •• Thorough review.
  • Neuhaus P, Klupp J, Langrehr JM. mTOR inhibitors: an overview. Liver 7iampl. 7,473-484 (2001).
  • Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin. Investig Drugs 3,295–304 (2002).
  • Dancey JE. Clinical development of mammalian target of rapamycin inhibitors. Hematol. Oncol. Clin. North Am. 16, 1101–1114 (2002).
  • Gibbons JJ, Discafani C, Peterson R, Hernandez R, Skotnicki J, Frost P The effect of CCI-779, a novel macrolide antitumor agent, on the growth of human tumor cells in vitro and in nude mouse xenografts in vivo. Proc. Am. Assoc. Cancer Res. 40,301 (1999) (Abstract).
  • Georger B, Kerr K, Tang CB et al Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumorimedulloblastoma models as single agent and in combination chemotherapy. Cancer Res. 61,1527–1532 (2001).
  • Raymond E, Alexandre J, Depenbrock H et al CCI-779, a rapamycin analog with antitumor activity: a Phase I study utilizing a weekly schedule. Proc. Am. Soc. Clin. Oncol. 19,187a (2000) (Abstract).
  • Hidalgo M, Rowinski E, Erlichman C et al CCI-779, a rapamycin analog and multifaceted inhibitor of signal transduction: a Phase I study. Proc. Am. Soc. Clin. Oncol. 19,187a (2000) (Abstract).
  • Punt CJA, Boni J, Bruntsh U, Peters M, Thielert C. Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann. Oncol. 14,931-937 (2003).
  • Chang S, Wen P, Greenberg H et al Phase I study of CCI-779 in patients with recurrent malignant glioma (MG) on enzyme inducing anti-epileptic drugs (EIAEDS). Neuro-oncology 4, 367 (2002) (Abstract).
  • Buckner J, Prados M, Rowinsky E et al A Phase I study of the safety, tolerability and pharmacokinetics of iv. CCI-779 given once daily for 5 days every 2 weeks to patients with CNS tumors. Neuro-oncology 4,365 (2002) (Abstract).
  • Chang S, Kuhn J, Wen P et al. Phase II/pharmacokinetic study of CCI-779 in recurrent glioblastoma multiforme (GM). Neum-oncology5, 349 (2003) (Abstract).
  • Ming JE, Roesseler E, Muenke M. Human developmental disorders and the sonic hedgehog pathway. Mal Med. Today Aug, 343–349 (1998).
  • ••Thorough analysis of sonic hedgehog(SHH) pathway in development.
  • Ingham PW. The patched gene in development and cancer. Cum Opin. Genet. Dev. 8,88–94 (1998).
  • •Role of PTCH gene in development and cancer.
  • Wicking C, Smyth I, Bale A. The hedgehog signaling pathway in tumorigenesis and development. Oncogene 18,7844–7851 (1999).
  • •Role of PTCH gene in development and cancer.
  • Motoyama J, Takabatake T, Takeshima T, Hui CC. PTCH2, a second mouse patched gene, is co-expressed with sonic hedgehog. Nature Genet. 18,104–106 (1998).
  • Smyth I, Narang MA, Evans T et al. Isolation and characterization of human patched 2 (P7-CH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum. Mal Genet. 8,291-297 (1999).
  • van den Heuvel M, Ingham PW. Smoothened encodes a receptor-like serpentine protein required for hedgehog signaling. Nature 382,547–551 (1996).
  • Kinzler KW, Bigner SH, Bigner DD et al Identification of an amplified, highly expressed gene in a human glioma. Science 236,70–73 (1987).
  • Saldanha G. The hedgehog signaling pathway and cancer. J. Pathol 193, 427–432 (2001).
  • Vortmeyer AO, Stavrou T, Selby D et al Deletion analysis of the adenomatous polyposis coli and PTCH gene loci in patients with sporadic and nevoid basal cell carcinoma syndrome-associated medulloblastoma. Cancer85, 2662–2667 (1999).
  • Wetmore C, Eberhart DE, Curran T The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res. 60,2239–2246 (2000).
  • •Analysis of PTCH in a transgenic mouse model.
  • Zurawel RII, Allen C, Wechsler-Reya R, Scott MP, Raffel C. Evidence that haploinsufficiency of PTCH leads to medulloblastoma in mice. Genes Chromosomes Cancer28, 77–81 (2000).
  • Corcoran RB, Scott MR A mouse model for medulloblastoma and basal cell nevus syndrome. I Neuro-oncol 53,307–318 (2001).
  • Hasselager G, Holland EC. Using mice to decipher the molecular genetics of brain tumors. Neurosurgery53, 685–695 (2003).
  • Wetmore C, Eberhart DE, Curran T Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 61,513–516 (2001).
  • Wechsler-Reya RJ, Oliver TG, Grasfeder LL et al. Sonic hedgehog-induced proliferation of neuronal precursors is mediated by N-myc and cyclin Dl. 13119C. A117. Assoc. Cancer Res. 44,1193 (2003) (Abstract).
  • Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 57, 2581–2585 (1997).
  • Pietsch T, Waha A, Koch A et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of drosophila patched. Cancer Res. 57,2085–2088 (1997).
  • Raffel C, Jenkins RB, Frederick L et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57,842–845 (1997).
  • Zurawel RII, Allen C, Chiappa S et al Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosomes Cancer27, 44–51 (2000).
  • ••Analysis of PTCH, SHH and Smomutations in sporadic medulloblastoma.
  • Dong J, Gailani MR, Pomeroy SL, Reardon D, Bale AE. Identification of patched mutations in medulloblastomas by direct sequencing. Hum. Mutat. 339,1–7 (2000).
  • Newton HB. Review of the molecular genetics and chemotherapeutic treatment of adult and pediatric medulloblastoma. Expert Opin. Investig. Drugs10,2089–2104 (2002).
  • Reifenberger J, Wolter M, Weber RG et al Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and Primitive neuroectodermal tumors of the central nervous system. Cancer Res. 58, 1798–1803 (1998).
  • Erez A, Ilan T, Amariglio N et al. G1i3 is not mutated commonly in sporadic medulloblastomas. Cancer 95,28–31 (2002).
  • Taylor MD, Liu L, Raffel C et al. Mutations in SUFU predispose to medulloblastoma. Nature Genet. 31, 306–310 (2002).
  • Katayama M, Yoshida K, Ishimori H et al. Patched and smoothened mRNA expression in human astrocytic tumors inversely correlates with histological malignancy. I Neuro-oncol 59,107–115 (2002).
  • Bergstein I, Leopold PL, Sato N, Panteleyev AA, Christiano AM, Crystal RG. hi vivo enhanced expression of patched dampens the sonic hedgehog pathway. Mal Ther. 6,258–264 (2002).
  • Incardona JP, Gaffield W, Kapur RP, Roelink H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125,3553–3562 (1998).
  • Taipale J, Chen JK, Cooper MK et al Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature 406,1005–1009 (2000).
  • Chen JK, Taipale J, Cooper MK et al Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev. 16,2743–2748 (2002).
  • Berman DM, Karhadkar SS, Hallahan AR et al Medulloblastoma growth inhibition by hedgehog pathway blockage. Science 297,1559–1561 (2002).
  • Chen JK, Taipale J, Young KE, Maiti T, Beachy PA. Small molecule modulation of smoothened activity. Proc. Natl Acad. ScL 99,14071–14076 (2002).
  • Dome JS, Look AT Three molecular determinants of malignant conversion and their potential as therapeutic targets. CUI7: Opin. Oncol 11,58–67 (1999).
  • Folkmard. Clinical applications of research on angiogenesis. N Engl. I Med. 333, 1757–1763 (1995).
  • ••Seminal review of angiogenesis andapplications to oncology
  • Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Ce1186, 353–364 (1996).
  • Beckner ME. Factors promoting tumor angiogenesis. Cancer Investig. 17,594–623 (1999).
  • Cavallaro U, Christofori G. Molecular mechanisms of tumor angiogenesis and tumor progression. Neuro-oncol 50,63–70 (2000).
  • Webb CP, Vande Woude GE Genes that regulate metastasis and angiogenesis. j Neuro-oncol 50,71–87 (2000).
  • Plate KH. Mechanisms of angiogenesis in the brain. .1. Neuropathol Exp. Neural. 58, 313–320 (1999).
  • ••Thorough review of normal and neoplasticangiogenesis in the brain.
  • Rutka JT, Apodaca G, Stern R, Rosenblum M. The extracellular matrix of the central and peripheral nervous systems: structure and function. J. Neumsurg. 69, 155–170 (1988).
  • ••Thorough review of the extracellularmatrix.
  • Giese A, Westphal M. Glioma invasion in the central nervous system. Neurosurgery 39,235–252 (1996).
  • Couldwell WT, De Tribolet N, Antel JP, Gauthier T, Kuppner MC. Adhesion molecules and malignant gliomas: implications for tumorigenesis. Neurosurg. 76,782–791 (1992).
  • ••Detailed review of adhesion molecules andtheir role in glioma invasion.
  • Uhm JH, Dooley NP, Villemure JG, Yong VW Mechanisms of glioma invasion: role of matrix-metalloproteinases. Can. J. Neural. Sc]. 24,3–15 (1997).
  • ••Extensive review of the role of matrixmetalloproteinases in glioma invasion.
  • Jensen RL. Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review. Sur& Neural. 49, 189–196 (1998).
  • Dunn IF, Heese 0, Black PM. Growth factors in glioma angiogenesis: FGFs, PDGF, EGF and TGFs. Neuro-oncol 50,121–137 (2000).
  • ••Excellent review of growth factors andangiogenesis.
  • Takahashi JA, Fukumoto M, Igarashi K, Oda Y, Kikuchi H, Hatanaka M. Correlation of basic fibroblast growth factor expression levels with the degree of malignancy and vascularity in human gliomas.j Neurosurg. 76,792–798 (1992).
  • Platten M, Wick W, Weller M. Malignant glioma biology: role for TGF-I3 in growth, motility, angiogenesis and immune escape. Nlicrosc. Res. Tech. 52, 401–410 (2001).
  • Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL. Expression of hypoxia-inducible factor la in brain tumors. Association with angiogenesis, invasion and progression. Cancer 88,2606–2618 (2000).
  • Gomez-Manzano C, Fueyo J, Glass T et al. MMAC/PTEN downregulates VEGF in gliomas. Neuro-oncology2, 265 (2000) (Abstract).
  • Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Dlikr. 12,363–369 (2001).
  • Wen S, Stolarov J, Myers MP et al. PTEN controls tumor-induced angiogenesis. Proc. Natl Acad. Sc]. 98, 4622–4627 (2001).
  • Blancher C, Moore JW, Robertson N, Harris AL. Effects of ras and von Hippel—Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF) -1a, HIF-2a and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3--kinase/Akt signaling pathway. Cancer Res. 61, 7349–7355 (2001).
  • Wesseling P, Ruiter DJ, Burger PC. Angiogenesis in brain tumors; pathobiological and clinical aspects. Neum-oncol 32,253–265 (1997).
  • •Detailed review.
  • Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77,362–372 (1996).
  • Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 60,203–212 (2000).
  • Plate KH, Breier G, Weich HA, Mennel HD, Risau W Vascular endothelial growth factor and glioma angiogenesis: co-ordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int. J. Cancer59, 520–529 (1994).
  • Pietsch T, Valter MM, Wolf HK et al. Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropathol 93, 109–117 (1997).
  • Machein MR, Plate KH. VEGF in brain tumors. .1. Neum-oncol 50,109–120 (2000).
  • ••Thorough review.
  • Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol 20,4368–4380 (2002).
  • •Detailed review of vascular endothelial growth factor biology
  • Davis S, Aldrich TH, Jones PP et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Ce1187, 1161–1169 (1996).
  • Maisonpierre PC, Sun i C, Jones PP et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277,55–60 (1997).
  • Stratmann A, Risau W Plate KH. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am. Pathol 153,1459–1466 (1998).
  • Ding H, Roncari L, Wu X et al. Expression and hypoxic regulation of angiopoietins in human astrocytomas. Neum-oncology2, 1–10 (2001).
  • Bernsen HJJA, van der Kogel AJ. Anti-angiogenic therapy in brain tumor models. J. Neuro-oncol 45,247–255 (1999).
  • Deplanque G, Harris AL. Anti-angiogenic agents: clinical trial design and therapies in development. Eur. Cancer36, 1713–1724 (2000).
  • Puduvalli VK, Sawaya R. Anti-angiogenesis — therapeutic strategies and clinical implications for brain tumors. Neuro-oncol 50,189–200 (2000).
  • •Detailed review.
  • Kirsch M, Schackert G, Black PM. Anti-angiogenic treatment strategies for malignant brain tumors. J. Neum-oncol 50, 149–163 (2000).
  • Scappaticci FA. Mechanisms and future directions for angiogenesis-based cancer therapies. J. Clin. Oncol 20,3906–3927 (2002).
  • •• Thorough review.
  • Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nature Rev Cancer 2,727–739 (2002).
  • •Detailed review.
  • O'Reilly MS, Holmgren L, Shing Y et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).
  • •Seminal description of the characterization of angiostatin.
  • Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM. Angiostatin suppresses malignant glioma growth in vivo. Cancer Res: 58,4654–4659 (1998).
  • Tanaka T, Cao Y, Folkman J, Fine HA. Viral vector-targeted anti-angiogenic gene therapy utilizing an angiostatin complementary DNA. Cancer Res. 58, 3362–3369 (1998).
  • Kong HL, Crystal RG. Gene therapy strategies for tumor anti-angiogenesis. .1. Natl Cancer Inst. 90,273-286 (1998).
  • •Detailed review.
  • Bernsen HJJA, Rijken PFJW, Peters H, Bakker H, van der Kogel AJ. The effect of the anti-angiogenic agent TNP-470 on tumor growth and vascularity in low passaged xenografts of human gliomas in nude mice. J. Neuro-oncol 38,51–57 (1998).
  • Gagliardi A, Hadd H, Collins DC. Inhibition of angiogenesis by suramin. Cancer Res. 52,5073–5075 (1992).
  • Stein CA. Suramin: a novel antineoplastic agent with multiple mechanisms of action. Cancer Res. 53,2239–2248 (1993).
  • Takano S, Gately S, Engelhard H, Tsanaclis AMC, Brem S. Suramin inhibits glioma cell proliferation in vitro and in the brain. J. Neuro-oncol 21,189–201 (1994).
  • Bernsen HJJA, Rijken PFJW, Peters JPW et al Suramin treatment of human glioma xenografts; effects on tumor vasculature and oxygenation status. J. Neuro-oncol 44, 129–136 (1999).
  • Laird AD, Vajkoczy P, Shawver LK et al. 5U6668 is a potent anti-angiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 60, 4152–4160 (2000).
  • O'Reilly MS, Boehm T, Shing Y et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. C1188, 277–285 (1997).
  • Read TA, Sorensen DR, Mahesparan R et al Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nature Biotechnol 19, 29–34 (2001).
  • Joki T, Machluf M, Atala A et al Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nature Biotechnol 19, 35–39 (2001).
  • Potapova 0, Laird AD, Li G et al. Combining a selective VEGF receptor inhibitor and a selective PDGF receptor inhibitor recapitulates the antitumor efficacy of SU11248, a selective oral multi-targeted tyrosine kinase inhibitor with antitumor and anti-angiogenic activity through targeting PDGFR, VEGFR, KIT and FLT3. Proc. Am. Assoc. Cancer Res. 44, 1118 (2003) (Abstract).
  • Laird AD, Li G, Potapova 0 etal. Mechanism of action and biomarker studies of SU11248, a selective oral multi-targeted tyrosine kinase inhibitor with antitumor and anti-angiogenic activity through targeting PDGFR, VEGFR, KIT and FLT3. Proc. Am. Assoc Cancer Res. 44,1081 (2003).
  • Rosen L. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer ContmI9, 36–44 (2002).
  • Tandle A, Libutti SK. Anti-angiogenic therapy: targeting vascular endothelial growth factor and its receptors. Clin. Adv. Hematol Oncol 1,41–48 (2003).
  • Kunkel P, Ulbricht U, Bohlen P, Westphal M, Lamszus K. Inhibition of intracranial glioma angiogenesis and growth by an antibody against VEGFR-2. Neuro-oncology3, 269 (2001).
  • Stefanik DF, Fellows WK, Rizkalla LR et al Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. Neuro-oncol 55,91–100 (2001).
  • Drevs J, Droll A, Mross K, Unger C. Angiogenesis inhibitors: drugs in clinical trials. Onkologie 22,282–290 (1999).
  • ••Thorough review of angiogenesisinhibitors in clinical trials.
  • Drummond AH, Beckett P, Brown PD et al Preclinical and clinical studies of MMP inhibitors in cancer. Ann. NY Acad. Sci. 878,228–235 (1999).
  • Steward WP. Marimastat (BB2516): current status of development. Cancer Chemother. Phatmacol 43, S56-560 (1999).
  • ••Thorough review of clinical studies withmarimastat.
  • Fine HA, Figg WD, Jaeckle K et al A Phase II trial of the anti-angiogenic agent thalidomide in patients with recurrent high-grade gliomas. j Clin. Oncol 18, 708–715 (2000).
  • •Thalidomide demonstrated modest activity against recurrent gliomas.
  • Short S, Traish D, Dowe A, Hines F, Brada M. Thalidomide as an anti-angiogenic agent in relapsed gliomas. Neuro-oncology2, S53 (2000) (Abstract).
  • Gruber ML, Glass J. Phase I/II study of carboplatin and thalidomide in recurrent glioblastoma multiforme. Cancerinvestig. 18,41-42 (2000) (Abstract).
  • Fine HA, Wen PY, Maher EA et al Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. j Clin. 0=1 21, 2299–2304 (2003).
  • Grossman SA, Phuphanich S, 1i=sser G et al. Toxicity, efficacy and pharmacology of suramin in adults with recurrent high-grade gliomas. Clin. Oncol 19,3260–3266 (2001).
  • Fine HA, Kim L, Royce C et al A Phase I trial of CC-5103, a potent thalidomide analog, in patients with recurrent high-grade gliomas and other refractory CNS malignancies. Proc. Am Soc. Clin. Oncol 2,105 (2003) (Abstract).
  • Yung WKA, Friedman H, Conrad C et al A Phase I trial of single-agent PTK 787/ZK 222584 (PTIK/ZK), an oral VEGFR tyrosine kinase inhibitor, in patients with recurrent glioblastoma multiforme. Proc. Am. Soc. Clin. Oncol 22,99 (2003) (Abstract).
  • Reardon D, Friedman HS, Yung WKA et al A Phase I trial of PTK787/ZK 222584 (PTK/ZK), an oral VEGF tyrosine kinase inhibitor, in combination with either temozolomide or lomustine for patients with recurrent glioblastoma multiforme (GBM). Proc. Am. Soc. Clin. Oncol 22,103 (2003).
  • Garrett MD, Workman P Discovering novel chemotherapeutic drugs for the third millennium. Eur.j Cancer 35,2010–2030 (1999).
  • •Detailed review of molecular drug discovery
  • Gelman KA, Eisenhauer EA, Harris AL, Ratain MJ, Workman P Anticancer agents targeting signaling molecules and cancer cell environments: challenges for drug development? J. Natl Cancer Inst. 91, 1281–1287 (1999).
  • Clarke PA, te Poele R, Wooster R, Workman P. Gene expression microarray analysis in cancer biology, pharmacology and drug development: progress and potential. Biochem. Pharmacol 62, 1311–1336 (2001).
  • ••Thorough review.
  • Workman P. The impact of genomic and proteomic technologies on the development of new cancer drugs. Ann. Oncol 13,115–124 (2002).
  • Groothuis DR. The blood—brain and blood—tumor barriers: a review of strategies for increasing drug delivery. Neuro-oncology 1,45–59 (2000).
  • Scheck AC. Molecular biology of chemotherapy and resistance. BNI Quart. 14,43–54 (1998).
  • Ramaswamy S, Golub TR. DNA microarrays in clinical oncology. Clin. Oncol 20, 1932–1941 (2001).
  • Mohr S, Leikauf GD, Keith G, Rihn BH. Microarrays as cancer keys: an array of possibilities. j Gun. Oncol 20,3165–3175 (2002).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.