Pharmacogenetic and bioengineering approaches to the treatment of glial tumors of the brain

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


The article analyzes the existing ideas about the specific mechanisms of therapeutic resistance of glial tumors of the brain, systematized the main trends in modern chemotherapy glial tumors, an attempt to justify the new bioengineering approaches to the creation of personalized cell preparations for therapy of glial tumors based on molecular - biological characteristics of tumor stem cells. It is shown that the main tool of the therapeutic effects can be own stem cells of cancer patients and tumor stem cell proteome can be considered as the primary target cell therapy.

Full Text

Restricted Access

About the authors

I. S Bryukhovetskiy

Far Eastern Federal University

AБ. S Bryukhovetskiy

Far Eastern Federal University

Y. S Khotimchenko

Far Eastern Federal University


  1. Omuro A., DeAngelis L.M. Glioblastoma and other malignant gliomas: a clinical review. JAMA 2013; 310(17): 1842-50.
  2. Perez-Barcena J., Llompart-Pou J.A., O'Phelan K.H. Intracranial Pressure Monitoring and Management of Intracranial Hypertension. Crit. Care Clin. 2014; 30(4): 735-50.
  3. Rispoli R., Conti C., Celli P. et al. Neural stem cells and glioblastoma Neuroradiol. J. 2014; 27(2): 169-74.
  4. Rutka J.T., Kim B., Etame A. et al. Nanosurgical resection of malignant brain tumors: beyond the cutting edge. ACS Nano 2014; 8(10): 9716-22.
  5. Louis D.N., Ohgaki H., Wiestler O.D. et al. The 2007 WHO classification of tambours of the central nervous system. Acta Neuropathol. 2007; 114(2): 97-109.
  6. Переводчикова Н.И. Руководство по химиотерапии опухолевых заболеваний. Москва; 2005.
  7. Louis D.N., Perry A., Burger P. et al. International Society of Neuropathology-Haarlem Consensus Guidelines, for Nervous System Tumor Classification and Grading. Brain Phatol. 2014; 24(6): 671-2.
  8. Kim S.S., Rait A., Kim E. et al. A nanoparticle carrying the p53 gene targets tumors including cancer stem cells, sensitizes
  9. Sasaki A., Udaka Y., Tsunoda Y. et al. Analysis of p53 and miRNA expression after irradiation of glioblastoma cell lines. Anticancer Res. 2012; 32(11): 4709-13.
  10. Rathod S.S., Rani S.B., Khan M. et al. Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways. FEBS Open Bio. 2014; 4: 485-95.
  11. Choi J.W., Schroeder M.A., Sarkaria J.N. et al. Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells. Cancer Res. 2014; 74(2): 484-96.
  12. Alentorn A. Labussiere M. Sanson M. et al. Genetics and brain gliomas. Presse Med. 2013; 42(5): 806-13.
  13. Labussiere M., Boisselier B., Mokhtari K. et al. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology 2014; 83(13): 1200-6.
  14. Liu X.J., Wu W.T., Wu W.H. et al. A minority subpopulation of CD133( + ) /EGFRvIII( + ) /EGFR(-) cells acquires stemness and contributes to gefitinib resistance. CNS Neurosci. Ther. 2013; 19(7): 494-502.
  15. Parker J.J., Dionne K.R., Massarwa R. et al. Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma. Neuro Oncol. 2013; 15(8): 1048-57.
  16. Wang F., Xiao W., Sun J. et al. MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol. 2014; 35(9): 8653-8.
  17. Addeo R., Zappavigna S., Parlato C. et al. Erlotinib: early clinical development in brain cancer. Expert Opin. Investig. Drugs 2014; 23(7): 1027-37.
  18. Zhang L., Wang H., Xu J. et al. Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. Tox. Lett. 2014; 228(3): 248-59.
  19. Inoue R., Moghaddam K.A., Ranasinghe M. et al. Infectious delivery of the 132 kb CDKN2A/CDKN2B genomic DNA region results in correctly spliced gene expression and growth suppression in glioma cells. Gene Ther. 2004; 11 (15): 1195-204.
  20. Liu X.Y., Gerges N., Korshunov A. et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and Tp53 mutations. Acta Neuropathol. 2012; 124(5): 615-25.
  21. Chen L., Han L., Zhang K. et al. VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1a/VEGF and p-catenin/Tcf-4 signaling. Neuro Oncol. 2012; 14(8): 1026-36.
  22. McGillicuddy L.T., Fromm J.A., Hollstein P.E. et al. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 2009; 16(1): 44-54.
  23. Nakuseva-Martic T., Berros V., Pecina - Slaus N. et al. Genetic changes of CDH1, APC, and CTNNB1 found in human brain tumors. Pathol. Res. Pract. 2007; 203(11): 779 - 87.
  24. Santoni M., Burattini L., Nabissi M. et al. Essential role of Gli proteins in glioblastoma multiforme. Curr. Protein. Pept. Sci. 2013; 14(2): 133-40.
  25. Gini B., Mischel P.S. Greater than the sum of its parts: singlenucleus sequencing identifies convergent evolution of independent EGFR mutants in GBM. Cancer Discov. 2014; 4(8): 876-8.
  26. Hewson C.A., Edbrooke M.R., Johnston S.L. PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J. Mol. Biol. 2004; 344(3) :683-95.
  27. Ducassou A., Uro-Coste E., Verrelle P. et al. avp3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I-II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma. Eur. J. Cancer. 2013; 49(9): 2161-9.
  28. Lustig R., Mikkelsen T., Lesser G. et al. Phase II preradiation R115777 (tipifarnib) in newly diagnosed GBM with residual enhancing disease. Neuro Oncol. 2008; 10(6): 1004-9.
  29. Del Vecchio C.A., Li G., Wong AJ. Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev. Vaccines. 2012; 11(2): 133-44.
  30. Del Vecchio C.A., Wong A.J. Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme. Curr. Opin. Mol. Ther. 2010; 12(6): 741-54.
  31. Cobbs C., Khan S., Matlaf L. et al. HCMV glycoprotein B is expressed in primary glioblastomas and enhances growth and invasiveness via PDGFR-alpha activation. Oncotarget 2014; 5(4): 1091-100.
  32. Dong Y., Jia L., Wang X. et al. Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells. Int. J. Oncol. 2011; 38(2): 555-69.
  33. Velghe A.I., Van Cauwenberghe S., Polyansky A.A. et al. PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations. Oncogene 2014; 33(20): 2568-76.
  34. Mathew P., Tannir N., Tu S.M. et al. Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: observations with tandutinib. Cancer Chemother. Pharmacol. 2011; 68(4): 889-96.
  35. Li J.T., Yan Q., Yu H.L. Expression of VEGF and NGF in gliomas of human. Sichuan Da Xue Xue Bao Yi Xue Ban. 2009; 40(3): 408-11.
  36. Veeravalli K.K., Ponnala S., Chetty C. et al. Integrin a9p1-mediated cell migration in glioblastoma via SSAT and Kir4.2 potassium channel pathway. Cell Signal 2012; 24(1): 272-81.
  37. Clara C.A., Marie S.K., de Almeida J.R. et al. Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1a in human glioblastoma. Neuropathol. 2014; 34(4): 343-52.
  38. Fan Y., Potdar A.A., Gong Y. et al. Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1a accumulation. Nat. Cell Biol. 2014; 16(5): 445-56.
  39. Marampon F., Gravina G.L., Zani B.M. et al. Hypoxia sustains glioblastoma radioresistance through ERKs/DNA-PKcs/HIF-1a functional interplay. Int. J. Oncol. 2014; 44(6): 2121-31.
  40. Murray D.W., Didier S., Chan A. et al. Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation. Br. J. Cancer. 2014; 110(5): 1307-15.
  41. Piha-Paul S.A., Shin S.J., Vats T. et al. Pediatric patients with refractory central nervous system tumors: experiences of a clinical trial combining bevacizumab and temsirolimus. Anticancer Res. 2014; 34(4): 1939-45.
  42. Krueger D.A., Care M.M., Agricola K. et al. Everolimus longterm safety and efficacy in subependymal giant cell astrocytoma. Neurology 2013; 80(6): 574-80.
  43. McGee M.C., Hamner J.B., Williams R.F. et al. Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation. Int. J. Radiat. Oncol. Biol. Phys. 2010; 6(5): 1537-45.
  44. Wick W., Steinbach J.P., Platten M. et. al. Enzastaurin before and concomitant with radiation therapy, followed by enzastaurin maintenance therapy, in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation. Neuro Oncol. 2013; 15(10): 1405-12.
  45. Martinez R., Rohde V., Schackert G. Different molecular patterns in glioblastoma multiforme subtypes upon recurrence. J. Neurooncol. 2010; 96(3): 321-9.
  46. Wick W., Weller M., van den Bent M. et al. MGMT testing--the challenges for biomarker-based glioma treatment. Nat. Rev. Neurol. 2014; 10(7): 372-85.
  47. Cadieux B., Ching T.T., VandenBerg S.R. et al. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res. 2006; 66(17): 8469-76.
  48. De la Rocha A.M., Sampron N., Alonso M.M. et al. Role of SOX family of transcription factors in central nervous system tumors. Am. J. Cancer Res. 2014; 4(4): 312-24.
  49. Kreth S., Thon N., Kreth FW. Epigenetics in human gliomas. Cancer Lett. 2014; 342(2): 185-92.
  50. Zhang L., Wang M., Wang W. et al. Incidence and prognostic value of multiple gene promoter methylations in gliomas. J. Neurooncol. 2014; 116(2): 349-56.
  51. Shinawi T., Hill V.K., Krex D. et al. DNA methylation profiles of long- and short-term glioblastoma survivors. Epigenetics 2013; 8(2): 149-56.
  52. Reifenberger G., Weber R.G., Riehmer V. Molecular characterization of long-term survivors of glioblastoma using genome-and transcriptome-wide profiling. Int. J. Cancer 2014; 135(8): 1822-31.
  53. Martinez R., Setien F., Voelter C. et al. CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. Carcinogenesis 2007; 28(6): 1264-8.
  54. Kondo Y., Katsushima K., Ohka F. et al. Epigenetic dysregulation in glioma. Cancer Sci. 2014; 105(4): 363-9.
  55. Nagarajan R.P., Costello J.F. Epigenetic mechanisms in glioblastoma multiforme. Semin. Cancer Biol. 2009; 19(3): 188-97.
  56. Kim Y.Z. Altered histone modifications in gliomas. Brain. Tumor. Res. Treat. 2014; 2(1): 7-21.
  57. Wei L., Hong S., Yoon Y. Early prediction of response to Vorinostat in an orthotopic rat glioma model. NMR Biomed. 2012; 25(9): 1104-11.
  58. Iwamoto F.M., Lamborn K.R., Kuhn J.G. et al. A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03. Neuro Oncol. 2011; 13 (5): 509-16.
  59. Borodovsky A., Salmasi V., Turcan S. et al. 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. Oncotarget 2013; 4(10): 1737-47.
  60. Turcan S., Fabius A.W., Borodovsky A. et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine. Oncotarget 2013; 4(10): 1729-36.
  61. Floyd D., Purow B. Micro-masters of glioblastoma biology and therapy: increasingly recognized roles for microRNAs. Neuro Oncol. 2014; 16(5): 622-7.
  62. Брюховецкий И.С., Брюховецкий А.С., Кумейко и др. Стволовые клетки в канцерогенезе мультиформной глиобластомы. Клеточная трансплантология и тканевая инженерия 2013; VIII (2): 13-19.
  63. Meacham C.E., Morrison S.J. Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501(7467): 328-37.
  64. Брюховецкий И.С., Брюховецкий А.С., Мищенко П.В. и др. Роль системных механизмов миграции и хоуминга стволовых клеток в развитии злокачественных опухолей центральной нервной системы и разработке новых методов противоопухолевой терапии. Российский биотерапевтический журнал 2013; 12(4): 3-12.
  65. He J., Liu Y., Lubman D.M. Targeting glioblastoma stem cells: cell surface markers. Curr. Med. Chem. 2012; 19(35): 6050-5.
  66. Li Z., Lee J.W., Mukherjee D. et al. Immunotherapy targeting glioma stem cells--insights and perspectives. Expert Opin. Biol. Ther. 2012; 12 (2): 165-78.
  67. Hamed H.A., Tavallai S., Grant S. et al. Sorafenib/Regorafenib and Lapatinib Interact to kill CNS Tumor Cells. J. Cell. Physiol. 2015; 230(1): 131-9.
  68. Procaccia V., Nakayama H., Shimizu A. et al. Gleevec/imatinib, an ABL2 kinase inhibitor, protects tumor and endothelial cells from semaphorin-induced cytoskeleton collapse and loss of cell motility. Biochem. Biophys. Res. Commun. 2014; 448(2): 134-8.
  69. Huang M., Ke Y., Sun X. et al. Mammalian target of rapamycin signaling is involved in the vasculogenic mimicry of glioma via hypoxia-inducible factor-1a. Oncol Rep. 2014; 32(5): 1973-80.
  70. Eimer S., Dugay F., Airiau K. et al. Cyclopamine cooperates with EGFR inhibition to deplete stem-like cancer cells in glioblastoma-derived spheroid cultures. Neuro Oncol. 2012; 14(12): 1441-51.
  71. Mohme M., Neidert M.C., Regli L. et al. Immunological challenges for peptide-based immunotherapy in glioblastoma. Cancer Treat. Rev. 2014; 40 (2): 248-58.
  72. Брюховецкий А.С., Шевченко В.Е., Чехонин В.П. и др. Сравнительное протеомное картирование опухолевых стволовых клеток, выделенных из глиобластомы линии U87, нейрональных стволовых и мультипотентных мезенхимальных стромальных клеток человека: от каталогизации клеточных белков к инновационной парадигме протеом-основанной клеточной терапии опухолей. Клеточная трансплантология и тканевая инженерия 2013; 8(2): 85-92.
  73. Bryukhovetskiy A., Bryukhovetskiy I., Shevchenko V. et al. Proteom-modifed anticancer cell systems in neurology: from postgenom technologies of proteome maping and protein profiling to model of gene expression transcriptome profiles and peptide engineering of stem and progenitor cells. Proceedings of the IANR VI and 10th GCNN conference; 2013 April 4 - 7. Bucharest. Romania. Bucharest; IANR; 2013.
  74. Брюховецкий А.С., Брюховецкий И.С. Концепция циторегу-ляторной терапии злокачественных глиальных опухолей головного мозга: новая теоретическая и методологическая платформа применения клеточных технологий в нейроонкологии. Клеточная трансплантология и тканевая инженерия 2011; VI(2): 93-101.
  75. Zhang L., Xu Q. Stem/Progenitor cells in vascular regeneration. Arterioscler. Thromb. Vasc. Biol. 2014; 34(6): 1114-9.
  76. Nagasawa T. CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4. J. Mol. Med. (Berl). 2014; 92(5): 433-9.
  77. Lin M.L., Lu Y.C., Chen H.Y. et al. Suppressing the formation of lipid raft-associated Rac1/PI3K/Akt signaling complexes by curcumin inhibits SDF-1a-induced invasion of human esophageal carcinoma cells. Mol. Carcinog. 2014; 53(5): 360-79.
  78. Li Z., Bao S., Wu Q. et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009; 15(6): 501-13.
  79. Imtiyaz H.Z., Simon M.C. Hypoxia-inducible factors as essential regulators of inflammation. Curr. Top Microbiol. Immunol. 2010; 345: 105-20.
  80. Брюховецкий И.С., Мищенко П.В., Хотимченко Ю.С. и др. Обоснование в эксперименте in vitro феномена направленной миграции гемопоэтических стволовых и прогениторных клеток взрослых млекопитающих к клеткам крысиной глиомы линии С6. Вестник РОНЦ им. Н.Н. Блохина РАМН 2014; 25(1-2): 31-7.
  81. Wang L.H., Ni C.W., Lin Y.Z. et al. Targeted induction of apoptosis in glioblastoma multiforme cells by an MRP3-specific TRAIL fusion protein in vitro. Tumour Biol. 2014; 35(2): 1157-68.
  82. Peng C.H., Huang C.N., Hsu S.P. et al. Penta-acetyl geniposide-induced apoptosis involving transcription of NGF/p75 via MAPK-mediated AP-1 activation in C6 glioma cells. Toxicology 2007; 238(2-3): 130-9.
  83. Park H.J. CARI III inhibits tumor growth in a melanoma-bearing mouse model through induction of G0/G1 cell cycle arrest. Molecules 2014; 19(9): 14383-95.
  84. Tang X.J., Lu J.T., Tu H.J. et al. TRAIL-engineered bone marrow-derived mesenchymal stem cells: TRAIL expression and cytotoxic effects on C6 glioma cells. Anticancer Res. 2014; 34(2): 729-34.
  85. Eisele G., Wolpert F., Decrey G. et al. AP0010, a synthetic hexameric CD95 ligand, induces death of human glioblastoma stem-like cells. Anticancer Res. 2013; 33(9): 3563-71.
  86. Брюховецкий И.С., Мищенко П.В., Толок Е.В. и др. Взаимодействие гемопоэтических стволовых и опухолевых клеток in vivo. Тихоокеанский медицинский журнал 2014; 4(58): 31-37.
  87. Schichor C., Aibrecht V., Korte B. et al. Mesenchymal stem cells and glioma cells form a structural as well as a functional syncytium in vitro. Exp. Neurol. 2012; 234(1): 208-19.
  88. Wurmser A.E., Gage F.H. Stem cells: cell fusion causes confusion. Nature 2002; 416(6880): 485-7.
  89. Ambrosi D.J, Rasmussen T.P. Reprogramming mediated by stem cell fusion. J. Cell Mol. Med. 2005; 9(2): 320-30.
  90. Lucas D., Frenette P.S. Stem cells: Reprogramming finds its niche. Nature 2014; 511(7509): 301-2.
  91. Lee J.H., Maalouf W.E. Nuclear transfer in ruminants. Methods Mol. Biol. 2015; 1222: 25-36.
  92. Брюховецкий А.С. Клиническая онкопротеомика: протеом-основанная персонализированная противоопухолевая клеточная терапия. Москва, 2013.
  93. Брюховецкий А.С., Брюховецкий И.С., Шевченко В.Е. Противоопухолевый индивидуальный протеом-основанный таргетный клеточный препарат, способ его получения и применения этого препарата для терапии рака и других злокачественных новообразований. Патентная заявка №2012156017; 24 декабря 2012.
  94. Bryukhovetskiy A., Shevchenko V., Kovalev S. et al. To the novel paradigm of proteome-based cell therapy of tumors: through comparative proteome mapping of tumor stem cells and tissue-specific stem cells of humans. Cell Transplant. 2014; 23, Suppl. 1: S151-70.
  95. Kannan N., Nguyen L.V., Eaves C.J. Integrin p3 links therapy resistance and cancer stem cell properties. Nat. Cell Biol. 2014; 16(5): 397-9.
  96. Oliveira-Ferrer L., Wellbrock J., Bartsch U. et al. Combination therapy targeting integrins reduces glioblastoma tumor growth through antiangiogenic and direct antitumor activity and leads to activation of the pro-proliferative prolactin pathway. Mol. Cancer. 2013; 12(1): 144.

Copyright (c) 2014 Eco-Vector

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 85657 от 21.07.2023 от 11.03.2014.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies