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Application of advances in molecular biology to the treatment of brain tumors

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Abstract

Recent advances in molecular biology have substantially improved our understanding of the molecular genetics of primary brain neoplasms. Soon each histopathologic category of glioma will be further divided into subgroups according to similar genetic background, gene expression profile, and similarity of biologic responses to radiotherapy or chemotherapy. Identification of key molecules that are specifically altered in neoplastic cells will provide candidate molecular targets for tumor treatment. Novel therapeutic tools for targeting tumor cells, such as viral vectors for gene therapy, have been created. In the near future, the accumulation of new knowledge in brain tumor biology and genetics, combined with rational drug design, will revolutionize the treatment of malignant gliomas, which are among the most lethal human cancers.

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References

  1. Kleihues P, Burger PC, Scheithauer BW: Tumors of neuroepithelial tissues. In Histological Typing of Tumors of the Central Nervous System: World Health Organization International Histological Classification of Tumors, edn 2. Berlin: Springer Verlag; 1993:11–30.

    Google Scholar 

  2. Daumas DC, Scheithauer B, O’Fallon J, et al.: Grading of astrocytomas. A simple and reproducible method. Cancer 1988, 62:2152–2165.

    Article  Google Scholar 

  3. Watanabe K, Sata K, Biernat W, et al.: Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. Clin Cancer Res 1997, 3:523–530.

    PubMed  CAS  Google Scholar 

  4. Claesson Welsh L: Platelet-derived growth factor receptor signals. J Biol Chem 1994, 269:32023–32026.

    PubMed  CAS  Google Scholar 

  5. Jen J, Harper JW, Bigner SH, et al.: Deletion of p16 and p15 genes in brain tumors. Cancer Res 1994, 54:6353–6358.

    PubMed  CAS  Google Scholar 

  6. Zhang Y, Xiong Y, Yarbrough WG: ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998, 92:725–734.

    Article  PubMed  CAS  Google Scholar 

  7. Steck PA, Pershouse MA, Jasser SA, et al.: Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997, 15:356–362.

    Article  PubMed  CAS  Google Scholar 

  8. Reyes-Mugica M, Reiger-Christ K, Ohgaki H, et al.: Loss of DCC expression and glioma progression. Cancer Res 1997, 57:382–386.

    PubMed  CAS  Google Scholar 

  9. Scherer HJ: Cerebral astrocytomas and their derivatives. Am J Cancer 1940, 40:159–198.

    Google Scholar 

  10. Lang FF, Miller DC, Koslow M, et al.: Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors. J Neurosurg 1994, 81:427–436.

    PubMed  CAS  Google Scholar 

  11. Ding H, Macmaster S, Roncari L, et al.: Transgenic mouse model of malignant astrocytoma: astrocyte specific expression of activated ras. Abstracts from the Thirteenth International Conference on Brain Tumor Research and Therapy; 1999.

  12. Reifenberger J, Reifenberger G, Liu L, et al.: Molecular genetic analysis of oligodendroglial tumors shows prefential allelic deletions on 19q and 1p. Am J Pathol 1994, 145:1175–1190.

    PubMed  CAS  Google Scholar 

  13. Reifenberger J, Reifenberger G, Ichimura K, et al.: Epidermal growth factor receptor expression in oligodendroglial tumours. Am J Pathol 1996, 149:29–35.

    PubMed  CAS  Google Scholar 

  14. Ohgaki H, Eibl RH, Wiestler OD, et al.: p53 mutations in nonastrocytic human brain tumors. Cancer Res 1991, 51:6202–6205.

    PubMed  CAS  Google Scholar 

  15. Sato K, Schauble B, Kleihues P, et al.: Infrequent alterations of the p15, p16, CDK4 and cyclin D1 genes in non-astrocytic human brain tumors. Int J Cancer 1996, 66:305–308.

    Article  PubMed  CAS  Google Scholar 

  16. Bijlsma EK, Voesten AM, Bijleveld EH, et al.: Molecular analysis of genetic changes in ependymomas. Genes Chromosomes Cancer 1995, 13:272–277.

    Article  PubMed  CAS  Google Scholar 

  17. von Haken MS, White EC, Daneshvar Shyesther L, et al.:Molecular genetic analysis of chromosome arm 17p and chromosome arm 22q DNA sequences in sporadic pediatric ependymomas. Genes Chromosomes Cancer 1996, 17:37–44.

    Article  Google Scholar 

  18. Birch BD, Johnson JP, Parsa A, et al.: Frequent type 2 neurofibromatosis gene transcript mutations in sporadic intramedullary spinal cord ependymomas. Neurosurgery 1996, 39:135–140.

    Article  PubMed  CAS  Google Scholar 

  19. Ebert C, von Haken M, Meyer-Puttlitz B, et al.: Molecular genetic analysis of ependymal tumors: NF2 mutations and chromosome 22q loss occur preferentially in intramedullary spinal ependymomas. Am J Pathol 1999, 155:627–632.

    PubMed  CAS  Google Scholar 

  20. Griffin CA, Hawkins AL, Packer RJ, et al.: Chromosome abnormalities in pediatric brain tumors. Cancer Res 1988, 48:175–180.

    PubMed  CAS  Google Scholar 

  21. Adesina AM, Nalbantoglu J, Cavenee WK: p53 mutation and mdm2 gene amplification are uncommon in medulloblastoma. Cancer Res 1994, 54:5649–5651.

    PubMed  CAS  Google Scholar 

  22. Mollenhauer J, Wiemann S, Scheurlen W, et al.: DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3-26.1 is deleted in malignant brain tumours. Nat Genet 1997, 17:32–39.

    Article  PubMed  CAS  Google Scholar 

  23. Goodrich LV, Scott P: Hedgehog and patched in neuronal development and disease. Neuron 1998, 21:1243–1257.

    Article  PubMed  CAS  Google Scholar 

  24. Goodrich LV, Milenkovic L, Higgins KM, et al.: Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997, 277:1109–1113.

    Article  PubMed  CAS  Google Scholar 

  25. Zurawel RH, Chiappa SA, Allen C, et al.: Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 1998, 58:896–899.

    PubMed  CAS  Google Scholar 

  26. Huang H, Mahler-Araujo BM, Sankila A, et al.: APC mutations in sporadic medulloblastomas. Am J Pathol 2000, 156:433–437.

    PubMed  CAS  Google Scholar 

  27. Hurtt MR, Moossy J, Donovan Peluso M, et al.: Amplification of epidermal growth factor receptor gene in gliomas: histopathology and prognosis. J Neuropathol Exp Neurol 1992, 51:84–90.

    PubMed  CAS  Google Scholar 

  28. Bigner SH, Burger PC, Wong AJ, et al.: Gene amplification in malignant human gliomas: clinical and histopathologic aspects. J Neuropathol Exp Neurol 1988, 47:191–205.

    PubMed  CAS  Google Scholar 

  29. Cairncross JG, Ueki K, Zlatescu MC, et al.: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998, 90:1473–1479. This study demonstrated that genetic alteration of anaplastic oligodendrogliomas allows accurate prediction of their response to chemotherapy.

    Article  PubMed  CAS  Google Scholar 

  30. Miettinen H, Kononen J, Sallinen P, et al.: CDKN2/p16 predicts survival in oligodendrogliomas: comparison with astrocytomas. J Neuro-Oncol 1999, 41:205–211. Report on a study leading to the discovery that CDKN2/p16 immunohistochemistry could be used as a tool to identify a subset of oligodendrogliomas and low-grade astrocytomas that are likely to progress and have poor outcome.

    Article  CAS  Google Scholar 

  31. Tada M, Matsumoto R, Iggo RD, et al.: Selective sensitivity to radiation of cerebral glioblastomas harboring p53 mutations. Cancer Res 1998, 58:1793–1797. P53 mutation is a marker for better radiation response in glioblastomas, which results in significantly longer survival, according to this report.

    PubMed  CAS  Google Scholar 

  32. Fulci G, Ishii N, van Meir EG: p53 and brain tumors: from gene mutation to gene therapy. Brain Pathol 1998, 8:599–613.

    Article  PubMed  CAS  Google Scholar 

  33. Kastan MB, Canman CE, Leonard CJ: p53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev 1995, 14:3–15.

    Article  PubMed  CAS  Google Scholar 

  34. Velculescu VE, El-Deiry WS: Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem 1996, 42:853–868.

    Google Scholar 

  35. Flaman J, Frebourg T, Moreau V, et al.: A simple p53 functional assay for screening cell lines, blood, and tumors. Proc Natl Acad Sci U S A 1995, 92:3963–3967.

    Article  PubMed  CAS  Google Scholar 

  36. Lang FF, Yung WKA, Sawaya R, et al.: Adenovirus-mediated p53 gene therapy for human gliomas. Neurosurgery 1999, 45:1093–1104.

    Article  PubMed  CAS  Google Scholar 

  37. Kondo S, Ishizaka Y, Okada T, et al.: FADD gene therapy for malignant gliomas in vitro and in vivo. Hum Gene Ther 1998, 9:1599–1608.

    PubMed  CAS  Google Scholar 

  38. Shinoura N, Yoshida Y, Sadata A, et al.: Apoptosis by retrovirus-and adenovirus-mediated gene transfer of Fas ligand to glioma cells: implications for gene therapy. Hum Gene Ther 1998, 9:1983–1993.

    PubMed  CAS  Google Scholar 

  39. Nagane M, Pan G, Weddle JJ, et al.: Death receptor 5 (DR5) is induced by chemotherapeutic agents in p53-positive human glioma cells and causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in vitro and in vivo. Neuro-Oncology 1999, 1:S83.

    Google Scholar 

  40. Schwyer M, Fontana A: Partial purification and biochemical characterization of a T cell suppressor factor produced by human glioblastoma cells. J Immunol 1985, 134:1003–1009.

    Google Scholar 

  41. van Meir EG: Cytokine expression in brain tumors: its role in tumor biology and tumor-associated immune responses. In Inflammatory Cells and Mediators in CNS Disease. Edited by Ruffolo RR Jr, Feuerstein GZ, Hunter AJ, et al. London: Harwood Academic Publishers; 1999:169–244.

    Google Scholar 

  42. Freeman SM, Abboud CN, Whartenby KA, et al.: The ‘bystander effect’: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993, 53:5274–5283.

    PubMed  CAS  Google Scholar 

  43. Freeman SM, Ramesh R, Marrogi AJ: Immune system in suicide-gene therapy. Lancet 1997, 349:2–3.

    Article  PubMed  CAS  Google Scholar 

  44. Gagandeep S, Brew R, Green B, et al.: Prodrug-activated gene therapy: involvement of an immunological component in the ‘bystander effect’. Cancer Gene Ther 1996, 3:83–88.

    PubMed  CAS  Google Scholar 

  45. Eck SL, Alavi JB, Alavi A, et al.: Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: a phase I trial. Hum Gene Ther 1996, 7:1465–1482.

    PubMed  CAS  Google Scholar 

  46. Izquierdo M, Martin V, de Felipe P, et al.: Human malignant brain tumor response to herpes simplex thymidine kinase (HSVtk)/ganciclovir gene therapy. Gene Ther 1996, 3:491–495.

    PubMed  CAS  Google Scholar 

  47. Klatzmann D, Valery CA, Bensimon G, et al.: A phase I/II study of herpes simplex virus type 1 thymidine kinase ‘suicide’ gene therapy for recurrent glioblastoma: Study Group on Gene Therapy for Glioblastoma. Hum Gene Ther 1998, 9:2595–2604.

    Article  PubMed  CAS  Google Scholar 

  48. Ram Z, Culver KW, Oshiro EM, et al.: Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med. 1997, 3:1354–1361.

    Article  PubMed  CAS  Google Scholar 

  49. Dewey RA, Morrissey G, Cowsill CM, et al.: Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials. Nat Med 1999, 5:1256–1263. This report addresses the potential but significant risk of suicide-gene therapy. Careful safety studies in this area must be conducted prior to clinical testing.

    Article  PubMed  CAS  Google Scholar 

  50. Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182–1186.

    Article  PubMed  CAS  Google Scholar 

  51. Weidner N.: Intratumoral microvessel density as a prognostic factor in cancer. Am J Pathol 1995, 147:9–19.

    PubMed  CAS  Google Scholar 

  52. Stan AC, Nemati MN, Pietsch T, et al.: In vivo inhibition of angiogenesis and growth of the human U-87 malignant glial tumor by treatment with an antibody against basic fibroblast growth factor. J Neurosurg 1995, 82:1044–1052.

    Article  PubMed  CAS  Google Scholar 

  53. Takamiya Y, Brem H, Ojeifo J, et al.: AGM-1470 inhibits the growth of human glioblastoma cells in vitro and in vivo. Neurosurgery 1994, 34:869–875.

    Article  PubMed  CAS  Google Scholar 

  54. Joe YA, Hong YK, Chung DS, et al.: Inhibition of human malignant glioma growth in vivo by human recombinant plasminogen kringles 1–3. Int J Cancer 1999, 82:694–699. Results from this reported study indicate that anti-angiogenic therapy using angiostatin could be a potential antineoplastic therapy in malignant glioma.

    Article  PubMed  CAS  Google Scholar 

  55. Tanaka T, Cao Y, Folkman J, et al.: Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA. Cancer Res 1998, 58:3362–3369.

    PubMed  CAS  Google Scholar 

  56. Price A, Shi Q, Morris D, et al.: Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340. Clin Cancer Res 1999, 5:845–854.

    PubMed  CAS  Google Scholar 

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Takeshima, H., Sawamura, Y., Gilbert, M.R. et al. Application of advances in molecular biology to the treatment of brain tumors. Curr Oncol Rep 2, 425–433 (2000). https://doi.org/10.1007/s11912-000-0062-4

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