- Department of Neurosurgery, Division of Oncology, New York University School of Medicine, NY, USA
- Department of Pediatrics, Division of Oncology, New York University School of Medicine, NY, USA
Correspondence Address:
David H. Harter
Department of Neurosurgery, Division of Oncology, New York University School of Medicine, NY, USA
DOI:10.4103/2152-7806.132138
Copyright: © 2014 Wilson TA This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int 08-May-2014;5:64
How to cite this URL: Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int 08-May-2014;5:64. Available from: http://sni.wpengine.com/surgicalint_articles/glioblastoma-multiforme-state-of-the-art-and-future-therapeutics/
Abstract
Background:Glioblastoma multiforme (GBM) is the most common and lethal primary malignancy of the central nervous system (CNS). Despite the proven benefit of surgical resection and aggressive treatment with chemo- and radiotherapy, the prognosis remains very poor. Recent advances of our understanding of the biology and pathophysiology of GBM have allowed the development of a wide array of novel therapeutic approaches, which have been developed. These novel approaches include molecularly targeted therapies, immunotherapies, and gene therapy.
Methods:We offer a brief review of the current standard of care, and a survey of novel therapeutic approaches for treatment of GBM.
Results:Despite promising results in preclinical trials, many of these therapies have demonstrated limited therapeutic efficacy in human clinical trials. Thus, although survival of patients with GBM continues to slowly improve, treatment of GBM remains extremely challenging.
Conclusion:Continued research and development of targeted therapies, based on a detailed understanding of molecular pathogenesis can reasonably be expected to yield improved outcomes for patients with GBM.
Keywords: Glioblastoma multiforme, gene therapy, immunotherapy, molecularly targeted therapy
BIOLOGY OF GLIOBLASTOMA MULTIFORME
Glioblastoma multiforme (GBM), a World Health Organization (WHO) grade IV glioma, is the most common and lethal primary malignancy of the central nervous system (CNS). More than 10,000 new cases are reported annually in the United States.[
Experimental evidence supports the hypothesis that GBM contains a subpopulation of highly tumorigenic cells, glioblastoma stem cells (GSCs), from which recurrent GBM is thought to derive.[
Primary versus secondary GBM
GBM can be classified as primary or secondary. Primary GBM occurs de novo; without evidence of a less malignant precursor, whereas secondary GBM develops from an initially low-grade diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The majority of GBMs (~90%) are primary.[
Prior to the discovery of IDH1 mutation in secondary GBM, primary and secondary GBM were distinguished based upon clinical findings. The diagnosis of primary GBM was made in patients without radiologic or histologic evidence of a less malignant precursor, whereas a diagnosis of secondary GBM was made in patients with preexisting low-grade astrocytoma or evidence of a less malignant precursor either radiographically or histologically.[
GBM subtypes
Targeting the underlying genetic alterations leading to GBM is critical to develop effective treatment strategies. Although GBM is a highly heterogeneous tumor, high dimensional genomic profiling has allowed GBM to be categorized into four subtypes based upon characteristic genetic alterations and distinct molecular profiles. In order to better understand the pathogenesis of GBM, high dimensional genomic profiling has been used to identify genetic abnormalities driving GBM tumorigenesis. Using gene expression-based molecular classification of GBM that integrates multidimensional genomic data to establish patterns of aberrant gene expression and copy number alterations seen in GBM, four subtypes of GBM were identified. These GBM subtypes are classical, mesenchymal, proneural, and neural.[
Each subtype harbors distinct genetic alterations and expression profiles.[
GBM without IDH1 mutation has been identified as classical, mesenchymal, proneural, and neural. The majority of GBM with IDH1 mutation have the proneural gene expression pattern; however, only 30% of GBM with proneural gene expression patterns have the IDH1 mutation.[
Overall, the proneural subtype is diagnosed at a younger age than other subtypes.[
CURRENT STANDARD OF CARE AND TREATMENT
The current standard of care for patients with GBM includes maximal safe resection, followed by concurrent radiation therapy (RT) to the resection cavity and chemotherapy (with temozolomide (TMZ), followed by adjuvant TMZ).[
Surgical resection
Surgery remains an important component in the treatment of GBM. It allows for a histologic confirmation of the diagnosis as well as cytoreduction. Surgery may also serve a therapeutic role by reducing the intracranial pressure, and depending on the location of the tumor, occasionally leads to recovery of some neurological function. The principal contraindications to resective surgery are poor performance status (Karnofsky performance scale [KPS] <70), advanced age, eloquent location or extensive bihemispheric involvement.
The goal of surgery is to achieve gross total resection of the contrast enhancing component of the tumor, without compromising neurological function.[
Chemo-and radiotherapy
The combination of RT plus TMZ is the most efficacious adjuvant therapy to prolong survival after primary resection. Treatment following surgery usually consists of 6 weeks of RT to the surgical cavity and TMZ, followed by 6 adjuvant cycles of TMZ.[
The current standard of care for RT in GBM is focal, fractionated external beam radiation therapy (EBRT) to the surgical resection cavity and to a 2 cm margin of surrounding brain tissue.[
TMZ, an oral alkylating chemotherapeutic agent, causes DNA damage and triggers a cascade of events leading to tumor cell apoptosis.[
As mentioned earlier, TMZ derives its therapeutic benefit from adding a methyl group to purine bases of DNA, which leads to DNA damage and triggers a cascade of events that leads to tumor cell apoptosis.[
Implantation of carmustine wafers into the resection cavity is another Food and Drug Administration (FDA) approved treatment of GBM.[
THERAPIES UNDER INVESTIGATION MOLECULARLY TARGETED THERAPIES
Genetically, GBM is a highly heterogeneous tumor harboring multiple recurrent and nonrecurrent genetic alterations.[
Figure 1
Activation of RTKs triggers a cascade of downstream signaling events, and inappropriate activation of these pathways drives tumor growth, survival, invasion into normal brain, and secretion of angiogenic factors. The hexagons labeled with TK represent the intracellular component of the RTK, and the TKI is shown inhibiting the TK activity. MABs are too large to cross cell membranes, so they are used to target cell surface proteins and other extracellular peptides.[
Molecularly targeted therapies can broadly be divided into small molecule inhibitors and monoclonal antibodies. Small molecule inhibitors are nonpolymeric, organic compounds able to cross cell membranes and target specific intracellular constituents.[
Inhibition of growth factor pathways
Amplification of EGFR signaling is one of the most common genetic alterations seen in GBM.[
Gefitinib and erlotinib are oral small molecule EGFR TKIs that have been extensively studied in preclinical and clinical trials of GBM. Binding to intracellular kinase domain of EGFR, they inhibit the activation of its downstream signaling pathways. In preclinical models of GBM, gefitinib and erlotinib have demonstrated antiproliferative and antiinvasive effects, potent inhibition of EGFR, and prolonged survival. Unfortunately, in clinical trials, they have shown limited therapeutic efficacy.[
Cetuximab is a chimeric murine-human monoclonal antibody that blocks activation of EGFR by its ligands.[
Overexpression of PDGFR signaling is another frequent alteration found in GBM. PDGF stimulates tumor growth through autocrine signaling, promoting angiogenesis through paracrine effects on adjacent endothelial cells.[
Inhibition of angiogenic pathways
GBM is a highly vascularized tumor characterized by extensive angiogenesis.[
Bevacizumab (trade name Avastin) is a humanized monoclonal antibody that binds and neutralizes the VEGF ligand, preventing activation of its receptors.[
Cedarinib, sunitinib, and vatalanib are multikinase TKIs with predominant VEGF inhibition that have been used to block angiogenesis in GBM. Cedarinib and sunitinib are inhibitors of VEGF, PDGFR, and c-kit. Despite encouraging results in preclinical trials, clinical trials with these agents have demonstrated limited therapeutic benefit, and in some trials, were associated with high toxicity rates.[
Cilengitide is another novel antiangiogenic therapy being studied in GBM. It is a cyclized pentapeptide small molecule inhibitor that selectively blocks activation of the ανβ3 and ανβ5 integrins. The integrins are a family of cell adhesion molecule transmembrane glycoprotein receptors that mediate cell-matrix and cell-cell interactions. In GBM, the ανβ3 and ανβ5 integrins are widely overexpressed in GBM cells and tumor vasculature, and in addition to VEGF, they are key mediators of angiogenesis, tumor growth, and metastasis.[
Inhibition of intracellular signaling pathways
Downstream signaling of many RTKs, including EGFR and PDGFR, lead to activation of the PI3K/AKT/mTOR and RAS/RAF/MAPK secondary messenger systems. Dysregulation of these intracellular signaling pathways often occurs in GBM.[
PI3K signals through activation of AKT and subsequently mTOR. Perifosine is a small molecule inhibitor of AKT that has been shown in preclinical trials to reduce signaling through the PI3K pathway. Currently, clinical trials with perifosine are being conducted to evaluate its clinical efficacy.[
Multi-targeted kinase inhibitors and combination therapy
Clinical trials of small molecule TKIs have demonstrated limited efficacy in patients with GBM. This is likely the result, at least in part, of multiple mutations and pathways driving tumor growth. Due to the intratumor heterogeneity, lack of a dominant single oncogenic “driver” mutation and redundancy of signaling pathways in cancer cells has become increasingly clear that targeting a single receptor or signaling pathway is unlikely to succeed in GBM.[
IMMUNOTHERAPY
Immunotherapy attempts to harness the immune system to selectively destroy tumor cells. It includes both passive and active strategies.[
The immune system can be divided into the innate and the adaptive immune systems.[
Passive immunotherapy: Adoptive cell transfer
Adoptive cell transfer uses stimulated immune effector cells to generate cell-based cytotoxic responses to attack GBM cells.[
Some of the earliest attempts at immunotherapy for treatment of GBM involved LAK cells and/or CTLs.[
Active immunotherapy: Cancer vaccines
Active immunotherapy is similar in concept to vaccination. It boosts the patient's native immune response against the tumor cells by priming it with antigen exposure.[
Figure 2
In peptide-based therapies, GBM-related antigens are administered to the patient as a vaccine to stimulate an immune response. Once administered, DCs, which are professional APCs, internalize these GBM-related antigens and present them to the immune effector cells to stimulate an immune response. In cell-based therapies, APCs are activated with GBM-related antigens, rather than the antigen itself, to prime the immune system and then injected into the patients to generate an immune response
In cell-based therapies, APCs are activated with GBM-related antigens, rather than the antigen itself, to prime the immune system and then injected into the patients to generate an immune response.[
GENE THERAPY
Gene therapy for the treatment of cancer involves the delivery of genetic material, which includes transgenes, toxins, and viruses, into tumor cells for therapeutic purposes. The genetic material is typically packaged within a vector for delivery into cells. See
Vectors
Vectors are classified as viral or nonviral. Viral vectors were the first and most commonly used vectors in gene therapy for GBM. Viral vector-based delivery systems take advantage of the ability of viruses to deliver their genetic information into the host cell.[
Vectors ideally transduce tumor cells while sparing normal cells in order to avoid toxicity to the surrounding brain.[
Retroviruses are a large family of enveloped RNA viruses.[
Adenoviruses, large double-stranded DNA viruses, are unlike retroviruses and lentiviruses. They are unable to integrate their DNA into the host genome following transduction.[
In addition to viruses, stem cells have been explored as vectors for delivery of gene therapies in GBM. The three types of stem cells studied as vectors in GBM are neural, embryonic, and mesenchymal.[
Conditionally cytotoxic gene therapy
Conditionally cytotoxic gene therapy, also referred to as enzyme-prodrug activating therapy or suicide gene therapy, is the most commonly used gene therapy approach in GBM.[
Figure 3
This figure shows conditionally cytotoxic gene therapy, also referred to as enzyme-prodrug activating therapy or suicide gene therapy, which is the most commonly used gene therapy. In conditionally cytotoxic approaches, as described in the text, the transgene for a noncytotoxic enzyme is delivered into tumor cells using a vector, and this enzyme remains noncytotoxic until the administration of a noncytotoxic prodrug. Upon prodrug administration, the enzyme converts the noncytotoxic prodrug into a toxic metabolite that induces tumor cell death
In GBM, the most commonly studied enzyme/prodrug combination is the herpes simplex virus-1 thymidine kinase (HSV1-TK)/ganciclovir (GCV) system.[
Directly cytotoxic gene therapy
Directly cytotoxic gene therapy, otherwise known as targeted toxin therapy, utilizes surface molecules overexpressed in GBM to target toxins directly into tumor cells to cause tumor cell death. This can be accomplished through viral vector-mediated delivery of transgenes for highly toxic proteins or with recombinant molecules: Immunotoxins. Immunotoxins consist of a tumor-specific monoclonal antibody or ligand conjugated to a toxin.[
One of the most studied immunotoxons in GBM is IL-13-PE, a recombinant protein of the cytokine IL-13 fused with the PE toxin. In normal cells, IL-13 binds to a heterodimeric receptor complex composed of IL-13 and IL-4 receptors. The majority of GBM cells, however, overexpress a mutant form of the IL-13 receptor, IL-13Rα2.[
Monoclonal antibodies can be conjugated to radionuclides, small molecule inhibitors, enzymes that require prodrug administration for activation, and chemotherapeutic agents for antibody-mediated targeted delivery into tumor cells.[
Immunostimulatory gene therapy
Immunomodulatory gene therapy uses the genetic material of cytokines, lymphocytes, or other immune modulators to enhance the host immune response to the tumor. Immunomodulatory approaches are based on the expectation that antitumor immune responses, activated by tumor-specific antigen expression, would effectively eliminate tumor cells. Unfortunately, often tumors develop mechanisms to evade these immune responses, creating an immune suppressive tumor microenvironment.[
Cytokines are a group of immune effector molecules that play a critical role in initiating, supporting, and inhibiting specific immune pathways. Cytokine-mediated gene therapy aims to use these cytokines to facilitate immune surveillance and stimulate cell-mediated immune responses against tumor cells. It involves specific delivery of transgenes for various immunostimulatory agents into tumor cells.[
Immune cell recruitment strategies attempt to recruit DCs or other APCs into the tumor microenvironment in order to prime an immune response against GBM. One strategy to do this combines cytokine-mediated gene therapy with cytotoxic gene therapy. This approach involves delivery of fms-like tyrosine kinase-3 ligand (Flt3L), a cytokine that stimulates recruitment of DCs, as well as HSV1-TK into the surgical resection cavity.[
Oncolytic virotherapy
In oncolytic virotherapy, unlike in other approaches, viral toxicity is directly responsible for tumor cell death. Oncolytic viral vectors are engineered as conditionally replicating viruses that specifically infect and replicate within tumor cells, while sparing the surrounding normal brain.[
Figure 4
This figure shows conditionally cytotoxic gene therapy, also referred to as enzyme-prodrug activating therapy or suicide gene therapy, which is the most commonly used gene therapy. In conditionally cytotoxic approaches, as described in the text, the transgene for a noncytotoxic enzyme is delivered into tumor cells using a vector, and this enzyme remains noncytotoxic until the administration of a noncytotoxic prodrug. Upon prodrug administration, the enzyme converts the noncytotoxic prodrug into a toxic metabolite that induces tumor cell death
The first oncolytic virus tested in GBM was conditionally replicating HSV1.[
Conditionally replicating adenoviruses have also been studied.[
A major drawback of oncolytic viruses is the host immune response, which limits their ability to spread to surrounding cells and reduces their transduction efficiency. Currently, direct delivery of oncolytic virus to the tumor is the only method that has been used in clinical trials. Preclinical trials are investigating novel delivery of these viruses into the bloodstream, which include the use of neural and mesenchymal stem cells as vectors.[
OTHER NOVEL THERAPIES
A variety of other novel approaches for the treatment of GBM are currently being investigated. The NovoTTF-100A is a device that uses alternating electric fields to disrupt cell division, and it is currently being studied as a treatment option for GBM.[
CONCLUSION
GBM is the most common and lethal primary malignancy of the CNS. Even with surgical resection and aggressive treatment with chemo-and radiotherapy, the prognosis remains very poor. Due to continued advancements, the understanding of the complex biology of GBM and its pathogenesis, a wide variety of novel therapeutic approaches have been developed and are currently under study as potential treatments for GBM. Despite promising results in preclinical trials, many of these therapies have provided limited or no therapeutic efficacy in human clinical trials. Thus, although survival of patients with GBM continues to slowly improve, treatment of GBM remains extremely challenging. Continued research and development of new molecular targeted and immunotherapeutic approaches, based on a detailed understanding of molecular pathogenesis, can reasonably be expected to lead to increased survival and more favorable prognosis of patients with GBM.
References
1. Aguilar LK, Arvizu M, Aguilar-Cordova E, Chiocca EA. The spectrum of vaccine therapies for patients with glioblastoma multiforme. Curr Treat Options Oncol. 2012. 13: 437-50
2. Ahmed AU, Thaci B, Alexiades NG, Han Y, Qian S, Liu F. Neural stem cell-based cell carriers enhance therapeutic efficacy of an oncolytic adenovirus in an orthotopic mouse model of human glioblastoma. Mol Ther. 2011. 19: 1714-26
3. Ahmed AU, Tyler MA, Thaci B, Alexiades NG, Han Y, Ulasov IV. A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma. Mol Pharm. 2011. 8: 1559-72
4. Anton K, Baehring JM, Mayer T. Glioblastoma multiforme: Overview of current treatment and future perspectives. Hematol Oncol Clin North Am. 2012. 26: 825-53
5. Ardon H, De Vleeschouwer S, Van Calenbergh F, Claes L, Kramm CM, Rutkowski S. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr Blood Cancer. 2010. 54: 519-25
6. Ardon H, Van Gool S, Lopes IS, Maes W, Sciot R, Wilms G. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: A pilot study. J Neurooncol. 2010. 99: 261-72
7. Arjona D, Rey JA, Taylor SM. Early genetic changes involved in low-grade astrocytic tumor development. Curr Mol Med. 2006. 6: 645-50
8. Bai RY, Staedtke V, Riggins GJ. Molecular targeting of glioblastoma: Drug discovery and therapies. Trends Mol Med. 2011. 17: 301-12
9. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008. 116: 597-602
10. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006. 444: 756-60
11. Barba D, Saris SC, Holder C, Rosenberg SA, Oldfield EH. Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg. 1989. 70: 175-82
12. Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010. 28: 2817-23
13. Bello L, Francolini M, Marthyn P, Zhang J, Carroll RS, Nikas DC. Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery. 2001. 49: 380-9
14. Beltinger C, Fulda S, Kammertoens T, Meyer E, Uckert W, Debatin KM. Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc Natl Acad Sci U S A. 1999. 96: 8699-704
15. Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D. Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma. Proc Natl Acad Sci U S A. 2007. 104: 20007-12
16. Bigner DD, Brown M, Coleman RE, Friedman AH, Friedman HS, McLendon RE. Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab’) 2--a preliminary report. J Neurooncol. 1995. 24: 109-22
17. Blancher A, Roubinet F, Grancher AS, Tremoulet M, Bonate A, Delisle MB. Local immunotherapy of recurrent glioblastoma multiforme by intracerebral perfusion of interleukin-2 and LAK cells. Eur Cytokine Netw. 1993. 4: 331-41
18. Boiardi A, Silvani A, Ruffini PA, Rivoltini L, Parmiani G, Broggi G. Loco-regional immunotherapy with recombinant interleukin-2 and adherent lymphokine-activated killer cells (A-LAK) in recurrent glioblastoma patients. Cancer Immunol Immunother. 1994. 39: 193-7
19. Brady LW, Miyamoto C, Woo DV, Rackover M, Emrich J, Bender H. Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: A phase II trial. Int J Radiat Oncol Biol Phys. 1992. 22: 225-30
20. Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PloS One. 2009. 4: e7752-
21. Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol. 2008. 26: 5603-9
22. Buchschacher GL, Wong-Staal F. Development of lentiviral vectors for gene therapy for human diseases. Blood. 2000. 95: 2499-504
23. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS. A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function. J Neurosci. 2008. 28: 264-78
24. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007. 11: 69-82
25. . Cancer Genome Atlas Research N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008. 455: 1061-8
26. Candolfi M, Yagiz K, Foulad D, Alzadeh GE, Tesarfreund M, Muhammad AK. Release of HMGB1 in response to proapoptotic glioma killing strategies: Efficacy and neurotoxicity. Clin Cancer Res. 2009. 15: 4401-14
27. Caruso DA, Orme LM, Neale AM, Radcliff FJ, Amor GM, Maixner W. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro Oncol. 2004. 6: 236-46
28. Castro MG, Candolfi M, Kroeger K, King GD, Curtin JF, Yagiz K. Gene therapy and targeted toxins for glioma. Curr Gene Ther. 2011. 11: 155-80
29. Chambers R, Gillespie GY, Soroceanu L, Andreansky S, Chatterjee S, Chou J. Comparison of genetically engineered herpes simplex viruses for the treatment of brain tumors in a scid mouse model of human malignant glioma. Proc Natl Acad Sci U S A. 1995. 92: 1411-5
30. Chang CN, Huang YC, Yang DM, Kikuta K, Wei KJ, Kubota T. A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma. J Clin Neurosci. 2011. 18: 1048-54
31. Chaudhry IH, O’Donovan DG, Brenchley PE, Reid H, Roberts IS. Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology. 2001. 39: 409-15
32. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012. 488: 522-6
33. Chen J, McKay RM, Parada LF. Malignant glioma: Lessons from genomics, mouse models, and stem cells. Cell. 2012. 149: 36-47
34. Chinot OL, Barrie M, Fuentes S, Eudes N, Lancelot S, Metellus P. Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol. 2007. 25: 1470-5
35. Chinot OL, de La Motte Rouge T, Moore N, Zeaiter A, Das A, Phillips H. AVAglio: Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme. Adv Ther. 2011. 28: 334-40
36. Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther. 2004. 10: 958-66
37. Choi BD, Archer GE, Mitchell DA, Heimberger AB, McLendon RE, Bigner DD. EGFRvIII-targeted vaccination therapy of malignant glioma. Brain Pathol. 2009. 19: 713-23
38. Chow KH, Gottschalk S. Cellular immunotherapy for high-grade glioma. Immunotherapy. 2011. 3: 423-34
39. Clarke J, Butowski N, Chang S. Recent advances in therapy for glioblastoma. Arch Neurol. 2010. 67: 279-83
40. Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: A North American Brain Tumor Consortium Study. J Clin Oncol. 2006. 24: 3651-6
41. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008. 5: e8-
42. Combs SE, Heeger S, Haselmann R, Edler L, Debus J, Schulz-Ertner D. Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT)--phase I/II trial: Study protocol. BMC Cancer. 2006. 6: 133-
43. Corey L. Laboratory diagnosis of herpes simplex virus infections. Principles guiding the development of rapid diagnostic tests. Diagn Microbiol Infect Dis. 1986. 4: 111-9S
44. Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 2009. 6: e10-
45. Cutter JL, Kurozumi K, Chiocca EA, Kaur B. Gene therapeutics: The future of brain tumor therapy?. Expert Rev Anticancer Ther. 2006. 6: 1053-64
46. Day ED, Lassiter S, Woodhall B, Mahaley JL, Mahaley MS. The localization of radioantibodies in human brain tumors. I. Preliminary exploration. Cancer Res. 1965. 25: 773-8
47. Day SE, Waziri A. Clinical trials of small molecule inhibitors in high-grade glioma. Neurosurg Clin N Am. 2012. 23: 407-16
48. De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res. 2008. 14: 3098-104
49. Debinski W, Gibo DM. Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol Med. 2000. 6: 440-9
50. Debinski W, Gibo DM, Slagle B, Powers SK, Gillespie GY. Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. Int J Oncol. 1999. 15: 481-6
51. Debinski W, Miner R, Leland P, Obiri NI, Puri RK. Receptor for interleukin (IL) 13 does not interact with IL4 but receptor for IL4 interacts with IL13 on human glioma cells. J Biol Chem. 1996. 271: 22428-33
52. Debinski W, Obiri NI, Powers SK, Pastan I, Puri RK. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin Cancer Res. 1995. 1: 1253-8
53. Debinski W, Slagle B, Gibo DM, Powers SK, Gillespie GY. Expression of a restrictive receptor for interleukin 13 is associated with glial transformation. J Neurooncol. 2000. 48: 103-11
54. Del Vecchio CA, Wong AJ. Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme. Curr Opin Mol Ther. 2010. 12: 741-54
55. Dembinski JL, Spaeth EL, Fueyo J, Gomez-Manzano C, Studeny M, Andreeff M. Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells. Cancer Gene Ther. 2010. 17: 289-97
56. Dillman RO. Cancer immunotherapy. Cancer Biother Radiopharm. 2011. 26: 1-64
57. Dillman RO, Duma CM, Ellis RA, Cornforth AN, Schiltz PM, Sharp SL. Intralesional lymphokine-activated killer cells as adjuvant therapy for primary glioblastoma. J Immunother. 2009. 32: 914-9
58. Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K. Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother. 2004. 27: 398-404
59. Dirks PB. Brain tumor stem cells: Bringing order to the chaos of brain cancer. J Clin Oncol. 2008. 26: 2916-24
60. Drablos F, Feyzi E, Aas PA, Vaagbo CB, Kavli B, Bratlie MS. Alkylation damage in DNA and RNA--repair mechanisms and medical significance. DNA Repair (Amst). 2004. 3: 1389-407
61. Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: A patient series. Ann Oncol. 2005. 16: 1702-8
62. 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. 2002. 20: 4368-80
63. Ehtesham M, Black KL, Yu JS. Recent progress in immunotherapy for malignant glioma: Treatment strategies and results from clinical trials. Cancer Control. 2004. 11: 192-207
64. El-Aneed A. An overview of current delivery systems in cancer gene therapy. J Control Release. 2004. 94: 1-14
65. Eller JL, Longo SL, Kyle MM, Bassano D, Hicklin DJ, Canute GW. Anti-epidermal growth factor receptor monoclonal antibody cetuximab augments radiation effects in glioblastoma multiforme in vitro and in vivo. Neurosurgery. 2005. 56: 155-62
66. Ferguson SD, Ahmed AU, Thaci B, Mercer RW, Lesniak MS. Crossing the boundaries: Stem cells and gene therapy. Discov Med. 2010. 9: 192-6
67. Ferrara N. VEGF as a therapeutic target in cancer. Oncology. 2005. 69: 11-6
68. Ferrara N. VEGF-A: A critical regulator of blood vessel growth. Eur Cytokine Netw. 2009. 20: 158-63
69. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003. 9: 669-76
70. Floeth FW, Shand N, Bojar H, Prisack HB, Felsberg J, Neuen-Jacob E. Local inflammation and devascularization--in vivo mechanisms of the “bystander effect” in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma. Cancer Gene Ther. 2001. 8: 843-51
71. Forsyth P, Roldan G, George D, Wallace C, Palmer CA, Morris D. A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas. Mol Ther. 2008. 16: 627-32
72. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009. 27: 4733-40
73. Fueyo J, Alemany R, Gomez-Manzano C, Fuller GN, Khan A, Conrad CA. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J Natl Cancer Inst. 2003. 95: 652-60
74. Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene. 2000. 19: 2-12
75. Fujisawa H, Reis RM, Nakamura M, Colella S, Yonekawa Y, Kleihues P. Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab Invest. 2000. 80: 65-72
76. Fukai J, Nishio K, Itakura T, Koizumi F. Antitumor activity of cetuximab against malignant glioma cells overexpressing EGFR deletion mutant variant III. Cancer Sci. 2008. 99: 2062-9
77. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A. Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 2007. 21: 2683-710
78. Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group Study. J Clin Oncol. 2005. 23: 5294-304
79. Geoerger B, Grill J, Opolon P, Morizet J, Aubert G, Terrier-Lacombe MJ. Oncolytic activity of the E1B-55 kDa-deleted adenovirus ONYX-015 is independent of cellular p53 status in human malignant glioma xenografts. Cancer Res. 2002. 62: 764-72
80. Germano IM, Fable J, Gultekin SH, Silvers A. Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: Preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol. 2003. 65: 279-89
81. Gerson SL. MGMT: Its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004. 4: 296-307
82. Gilbert M.editors. RTOG 0825: Phase III double. blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). Chicago: 2013 ASCO Annual Meeting; 2013. p.
83. Gomez-Manzano C, Jiang H, Alonso M, Yung WK, Fueyo J. Gene therapy. Handb Clin Neurol. 2012. 104: 331-8
84. Grandi P, Peruzzi P, Reinhart B, Cohen JB, Chiocca EA, Glorioso JC. Design and application of oncolytic HSV vectors for glioblastoma therapy. Expert Rev Neurother. 2009. 9: 505-17
85. Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005. 97: 880-7
86. Han ZQ, Assenberg M, Liu BL, Wang YB, Simpson G, Thomas S. Development of a second-generation oncolytic Herpes simplex virus expressing TNFalpha for cancer therapy. J Gene Med. 2007. 9: 99-106
87. Harsh GR, Deisboeck TS, Louis DN, Hilton J, Colvin M, Silver JS. Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: A gene-marking and neuropathological study. J Neurosurg. 2000. 92: 804-11
88. Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K. Chemotherapeutic wafers for High Grade Glioma. Cochrane Database Syst Rev. 2008. 3: CD007294-
89. Hasselbalch B, Lassen U, Hansen S, Holmberg M, Sorensen M, Kosteljanetz M. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: A phase II trial. Neuro Oncol. 2010. 12: 508-16
90. Hasselbalch B, Lassen U, Poulsen HS, Stockhausen MT. Cetuximab insufficiently inhibits glioma cell growth due to persistent EGFR downstream signaling. Cancer Invest. 2010. 28: 775-87
91. Hawasli AH, Bagade S, Shimony JS, Miller-Thomas M, Leuthardt EC. Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: Single-institution series. Neurosurgery. 2013. 73: 1007-17
92. Hayes RL, Arbit E, Odaimi M, Pannullo S, Scheff R, Kravchinskiy D. Adoptive cellular immunotherapy for the treatment of malignant gliomas. Crit Rev Oncol Hematol. 2001. 39: 31-42
93. Hayes RL, Koslow M, Hiesiger EM, Hymes KB, Hochster HS, Moore EJ. Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer. 1995. 76: 840-52
94. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005. 352: 997-1003
95. Heimberger AB, Sampson JH. The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients. Expert Opin Biol Ther. 2009. 9: 1087-98
96. Holladay FP, Heitz-Turner T, Bayer WL, Wood GW. Autologous tumor cell vaccination combined with adoptive cellular immunotherapy in patients with grade III/IV astrocytoma. J Neurooncol. 1996. 27: 179-89
97. Hoover JM, Chang SM, Parney IF. Clinical trials in brain tumor surgery. Neuroimaging Clin N Am. 2010. 20: 409-24
98. Immonen A, Vapalahti M, Tyynela K, Hurskainen H, Sandmair A, Vanninen R. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: A randomised, controlled study. Mol Ther. 2004. 10: 967-72
99. Iwami K, Natsume A, Wakabayashi T. Gene therapy for high-grade glioma. Neurol Med Chir. 2010. 50: 727-36
100. Izquierdo M, Cortes ML, Martin V, de Felipe P, Izquierdo JM, Perez-Higueras A. Gene therapy in brain tumours: Implications of the size of glioblastoma on its curability. Acta Neurochir Suppl. 1997. 68: 111-7
101. Izquierdo M, Martin V, de Felipe P, Izquierdo JM, Perez-Higueras A, Cortes ML. Human malignant brain tumor response to herpes simplex thymidine kinase (HSVtk)/ganciclovir gene therapy. Gene Ther. 1996. 3: 491-5
102. Jacobs A, Breakefield XO, Fraefel C. HSV-1-based vectors for gene therapy of neurological diseases and brain tumors: Part I. HSV-1 structure, replication and pathogenesis. Neoplasia. 1999. 1: 387-401
103. Jacobs A, Breakefield XO, Fraefel C. HSV-1-based vectors for gene therapy of neurological diseases and brain tumors: Part II. Vector systems and applications. Neoplasia. 1999. 1: 402-16
104. Jacobs SK, Wilson DJ, Kornblith PL, Grimm EA. Interleukin-2 or autologous lymphokine-activated killer cell treatment of malignant glioma: Phase I trial. Cancer Res. 1986. 46: 2101-4
105. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007. 8: 610-22
106. Joshi BH, Leland P, Asher A, Prayson RA, Varricchio F, Puri RK. In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a recombinant IL-4 cytotoxin in primary glioblastoma cell cultures. Cancer Res. 2001. 61: 8058-61
107. Kahn T, Harth T, Kiwit JC, Schwarzmaier HJ, Wald C, Modder U. In vivo MRI thermometry using a phase-sensitive sequence: Preliminary experience during MRI-guided laser-induced interstitial thermotherapy of brain tumors. J Mag Reson Imaging. 1998. 8: 160-4
108. Kaina B, Christmann M, Naumann S, Roos WP. MGMT: Key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst). 2007. 6: 1079-99
109. Kalofonos HP, Pawlikowska TR, Hemingway A, Courtenay-Luck N, Dhokia B, Snook D. Antibody guided diagnosis and therapy of brain gliomas using radiolabeled monoclonal antibodies against epidermal growth factor receptor and placental alkaline phosphatase. J Nucl Med. 1989. 30: 1636-45
110. Kamoun WS, Ley CD, Farrar CT, Duyverman AM, Lahdenranta J, Lacorre DA. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol. 2009. 27: 2542-52
111. Kanaly CW, Ding D, Heimberger AB, Sampson JH. Clinical applications of a peptide-based vaccine for glioblastoma. Neurosurg Clin N Am. 2010. 21: 95-109
112. Kang TY, Jin T, Elinzano H, Peereboom D. Irinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safety. J Neurooncol. 2008. 89: 113-8
113. Kangasniemi M, McNichols RJ, Bankson JA, Gowda A, Price RE, Hazle JD. Thermal therapy of canine cerebral tumors using a 980 nm diode laser with MR temperature-sensitive imaging feedback. Lasers Surg Med. 2004. 35: 41-50
114. Kendall SE, Najbauer J, Johnston HF, Metz MZ, Li S, Bowers M. Neural stem cell targeting of glioma is dependent on phosphoinositide 3-kinase signaling. Stem Cells. 2008. 26: 1575-86
115. Kikuchi T, Akasaki Y, Abe T, Fukuda T, Saotome H, Ryan JL. Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother. 2004. 27: 452-9
116. Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007. 104: 10152-7
117. Kitahara T, Watanabe O, Yamaura A, Makino H, Watanabe T, Suzuki G. Establishment of interleukin 2 dependent cytotoxic T lymphocyte cell line specific for autologous brain tumor and its intracranial administration for therapy of the tumor. J Neurooncol. 1987. 4: 329-36
118. Kleihues P, Ohgaki H. Primary and secondary glioblastomas: From concept to clinical diagnosis. Neuro Oncol. 1999. 1: 44-51
119. Kootstra NA, Verma IM. Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol. 2003. 43: 413-39
120. Kranzler J, Tyler MA, Sonabend AM, Ulasov IV, Lesniak MS. Stem cells as delivery vehicles for oncolytic adenoviral virotherapy. Curr Gene Ther. 2009. 9: 389-95
121. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009. 27: 740-5
122. Kroeger KM, Muhammad AK, Baker GJ, Assi H, Wibowo MK, Xiong W. Gene therapy and virotherapy: Novel therapeutic approaches for brain tumors. Discov Med. 2010. 10: 293-304
123. Kruse CA, Cepeda L, Owens B, Johnson SD, Stears J, Lillehei KO. Treatment of recurrent glioma with intracavitary alloreactive cytotoxic T lymphocytes and interleukin-2. Cancer Immunol Immunother. 1997. 45: 77-87
124. Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol. 2010. 12: 871-81
125. Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF, Piepmeier JM. Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: A report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol. 2007. 25: 837-44
126. Latchman DS. Gene delivery and gene therapy with herpes simplex virus-based vectors. Gene. 2001. 264: 1-9
127. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006. 9: 391-403
128. Leibel SA, Sheline GE. Radiation therapy for neoplasms of the brain. J Neurosurg. 1987. 66: 1-22
129. Lewis PF, Emerman M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J Virol. 1994. 68: 510-6
130. Li L, Quang TS, Gracely EJ, Kim JH, Emrich JG, Yaeger TE. A Phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme. J Neurosurg. 2010. 113: 192-8
131. Li YM, Hall WA. Targeted toxins in brain tumor therapy. Toxins. 2010. 2: 2645-62
132. Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005. 11: 5515-25
133. Lillehei KO, Mitchell DH, Johnson SD, McCleary EL, Kruse CA. Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery. 1991. 28: 16-23
134. Long Z, Li LP, Grooms T, Lockey C, Nader K, Mychkovsky I. Biosafety monitoring of patients receiving intracerebral injections of murine retroviral vector producer cells. Hum Gene Ther. 1998. 9: 1165-72
135. Long Z, Lu P, Grooms T, Mychkovsky I, Westley T, Fitzgerald T. Molecular evaluation of biopsy and autopsy specimens from patients receiving in vivo retroviral gene therapy. Hum Gene Ther. 1999. 10: 733-40
136. Luptrawan A, Liu G, Yu JS. Dendritic cell immunotherapy for malignant gliomas. Rev Recent Clin Trials. 2008. 3: 10-21
137. Mahaley MS, Mahaley JL, Day ED. The localization of radioantibodies in human brain tumors. II. Radioautography. Cancer Res. 1965. 25: 779-93
138. Markert JM, Liechty PG, Wang W, Gaston S, Braz E, Karrasch M. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther. 2009. 17: 199-207
139. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: Results of a phase I trial. Gene Ther. 2000. 7: 867-74
140. Martinez R, Martin-Subero JI, Rohde V, Kirsch M, Alaminos M, Fernandez AF. A microarray-based DNA methylation study of glioblastoma multiforme. Epigenetics. 2009. 4: 255-64
141. McGirt MJ, Than KD, Weingart JD, Chaichana KL, Attenello FJ, Olivi A. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg. 2009. 110: 583-8
142. Mellinghoff IK, Cloughesy TF, Mischel PS. PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res. 2007. 13: 378-81
143. Merchant RE, Grant AJ, Merchant LH, Young HF. Adoptive immunotherapy for recurrent glioblastoma multiforme using lymphokine activated killer cells and recombinant interleukin-2. Cancer. 1988. 62: 665-71
144. Mesnil M, Yamasaki H. Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: Role of gap-junctional intercellular communication. Cancer Res. 2000. 60: 3989-99
145. Mintz A, Gibo DM, Madhankumar AB, Debinski W. Molecular targeting with recombinant cytotoxins of interleukin-13 receptor alpha2-expressing glioma. J Neurooncol. 2003. 64: 117-23
146. Mintz A, Gibo DM, Slagle-Webb B, Christensen ND, Debinski W. IL-13Ralpha2 is a glioma-restricted receptor for interleukin-13. Neoplasia. 2002. 4: 388-99
147. Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G. Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene. 2003. 22: 2361-73
148. Mitchell DA, Fecci PE, Sampson JH. Immunotherapy of malignant brain tumors. Immunol Rev. 2008. 222: 70-100
149. Mitchell DA, Sampson JH. Toward effective immunotherapy for the treatment of malignant brain tumors. Neurotherapeutics. 2009. 6: 527-38
150. Mohanam S, Sawaya RE, Yamamoto M, Bruner JM, Nicholson GL, Rao JS. Proteolysis and invasiveness of brain tumors: Role of urokinase-type plasminogen activator receptor. J Neurooncol. 1994. 22: 153-60
151. Mohyeldin A, Chiocca EA. Gene and viral therapy for glioblastoma: A review of clinical trials and future directions. Cancer J. 2012. 18: 82-8
152. Msaouel P, Dispenzieri A, Galanis E. Clinical testing of engineered oncolytic measles virus strains in the treatment of cancer: An overview. Curr Opin Mol Ther. 2009. 11: 43-53
153. Mueller S, Polley MY, Lee B, Kunwar S, Pedain C, Wembacher-Schroder E. Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study. J Neurooncol. 2011. 101: 267-77
154. Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF. Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol. 2008. 26: 3015-24
155. Nakamura M, Yang F, Fujisawa H, Yonekawa Y, Kleihues P, Ohgaki H. Loss of heterozygosity on chromosome 19 in secondary glioblastomas. J Neuropathol Exp Neurol. 2000. 59: 539-43
156. Neyns B, Sadones J, Chaskis C, Dujardin M, Everaert H, Lv S. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol. 2011. 103: 491-501
157. Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain JF. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol. 2009. 20: 1596-603
158. Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res. 2009. 15: 6002-7
159. Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL. Genetic pathways to glioblastoma: A population-based study. Cancer Res. 2004. 64: 6892-9
160. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013. 19: 764-72
161. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007. 170: 1445-53
162. Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev. 2004. 15: 275-86
163. Parker JN, Gillespie GY, Love CE, Randall S, Whitley RJ, Markert JM. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc Natl Acad Sci U S A. 2000. 97: 2208-13
164. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008. 321: 1807-12
165. Patel M, Vogelbaum MA, Barnett GH, Jalali R, Ahluwalia MS. Molecular targeted therapy in recurrent glioblastoma: Current challenges and future directions. Expert Opin Investig Drugs. 2012. 21: 1247-66
166. Peereboom DM, Shepard DR, Ahluwalia MS, Brewer CJ, Agarwal N, Stevens GH. Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol. 2010. 98: 93-9
167. Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL. Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res. 2006. 12: 3935-41
168. Perry J, Okamoto M, Guiou M, Shirai K, Errett A, Chakravarti A. Novel therapies in glioblastoma. Neurol Res Int. 2012. 2012:
169. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006. 9: 157-73
170. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006. 444: 761-5
171. Pichlmeier U, Bink A, Schackert G, Stummer W. Resection and survival in glioblastoma multiforme: An RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol. 2008. 10: 1025-34
172. Pitter KL, Galban CJ, Galban S, Tehrani OS, Li F, Charles N. Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma. PloS One. 2011. 6: e14545-
173. Plautz GE, Barnett GH, Miller DW, Cohen BH, Prayson RA, Krauss JC. Systemic T cell adoptive immunotherapy of malignant gliomas. J Neurosurg. 1998. 89: 42-51
174. Plautz GE, Miller DW, Barnett GH, Stevens GH, Maffett S, Kim J. T cell adoptive immunotherapy of newly diagnosed gliomas. Clin Cancer Res. 2000. 6: 2209-18
175. Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell. 2009. 4: 568-80
176. Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009. 27: 579-84
177. Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol. 2006. 8: 67-78
178. Prados MD, McDermott M, Chang SM, Wilson CB, Fick J, Culver KW. Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: A phase I/II multi-institutional trial. J Neurooncol. 2003. 65: 269-78
179. Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro Oncol. 2011. 13: 384-92
180. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997. 57: 4593-9
181. Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011. 17: 1603-15
182. Puri RK. Development of a recombinant interleukin-4-Pseudomonas exotoxin for therapy of glioblastoma. Toxicol Pathol. 1999. 27: 53-7
183. Quattrocchi KB, Miller CH, Cush S, Bernard SA, Dull ST, Smith M. Pilot study of local autologous tumor infiltrating lymphocytes for the treatment of recurrent malignant gliomas. J Neurooncol. 1999. 45: 141-57
184. Rahmathulla G, Hovey EJ, Hashemi-Sadraei N, Ahluwalia MS. Bevacizumab in high-grade gliomas: A review of its uses, toxicity assessment, and future treatment challenges. OncoTargets Ther. 2013. 6: 371-89
185. Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther. 2000. 11: 2389-401
186. Rainov NG, Kramm CM, Banning U, Riemann D, Holzhausen HJ, Heidecke V. Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme. Gene Ther. 2000. 7: 1853-8
187. Rainov NG, Ren H. Clinical trials with retrovirus mediated gene therapy--what have we learned?. J Neurooncol. 2003. 65: 227-36
188. Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 2010. 12: 95-103
189. Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG. A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas. Neuro Oncol. 2010. 12: 87-94
190. Ram Z, Culver KW, Oshiro EM, Viola JJ, DeVroom HL, Otto E. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med. 1997. 3: 1354-61
191. Rand RW, Kreitman RJ, Patronas N, Varricchio F, Pastan I, Puri RK. Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma. Clin Cancer Res. 2000. 6: 2157-65
192. Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert B, Clement PM. Phase II study of imatinib in patients with recurrent gliomas of various histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol. 2008. 26: 4659-65
193. Reardon DA, Dresemann G, Taillibert S, Campone M, van den Bent M, Clement P. Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma. Br J Cancer. 2009. 101: 1995-2004
194. Reardon DA, Egorin MJ, Desjardins A, Vredenburgh JJ, Beumer JH, Lagattuta TF. Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer. 2009. 115: 2188-98
195. Reardon DA, Egorin MJ, Quinn JA, Rich JN, Gururangan S, Vredenburgh JJ. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol. 2005. 23: 9359-68
196. Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008. 26: 5610-7
197. Reardon DA, Nabors LB, Stupp R, Mikkelsen T. Cilengitide: An integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin Investig Drugs. 2008. 17: 1225-35
198. Reardon DA, Vredenburgh JJ, Coan A, Desjardins A, Peters KB, Gururangan S. Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma. J Neurooncol. 2011. 105: 621-7
199. Reijneveld JC, Voest EE, Taphoorn MJ. Angiogenesis in malignant primary and metastatic brain tumors. J Neurol. 2000. 247: 597-608
200. Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature. 2010. 468: 824-8
201. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. 2004. 22: 133-42
202. Riva P, Arista A, Franceschi G, Frattarelli M, Sturiale C, Riva N. Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with 131I: Comparison of the results obtained in recurrent and newly diagnosed tumors. Cancer Res. 1995. 55: 5952-6s
203. Rustamzadeh E, Hall WA, Todhunter DA, Low WC, Liu H, Panoskaltsis-Mortari A. Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice. Int J Cancer. 2006. 118: 2594-601
204. Rustamzadeh E, Hall WA, Todhunter DA, Vallera VD, Low WC, Liu H. Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice. Int J Cancer. 2007. 120: 411-9
205. Rustamzadeh E, Li C, Doumbia S, Hall WA, Vallera DA. Targeting the over-expressed urokinase-type plasminogen activator receptor on glioblastoma multiforme. J Neurooncol. 2003. 65: 63-75
206. Rustamzadeh E, Vallera DA, Todhunter DA, Low WC, Panoskaltsis-Mortari A, Hall WA. Immunotoxin pharmacokinetics: A comparison of the anti-glioblastoma bi-specific fusion protein (DTAT13) to DTAT and DTIL13. J Neurooncol. 2006. 77: 257-66
207. Sampson JH, Akabani G, Archer GE, Bigner DD, Berger MS, Friedman AH. Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol. 2003. 65: 27-35
208. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol. 2008. 20: 267-75
209. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE, Lally-Goss D. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009. 8: 2773-9
210. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010. 28: 4722-9
211. Sandmair AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M. Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther. 2000. 11: 2197-205
212. Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN. Molecularly targeted therapy for malignant glioma. Cancer. 2007. 110: 13-24
213. Scaringi C, Minniti G, Caporello P, Enrici RM. Integrin inhibitor cilengitide for the treatment of glioblastoma: A brief overview of current clinical results. Anticancer Res. 2012. 32: 4213-23
214. Schmidt NO, Westphal M, Hagel C, Ergun S, Stavrou D, Rosen EM. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer. 1999. 84: 10-8
215. Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, Fiedler VU, Niehoff H, Ulrich SD. MR-guided laser irradiation of recurrent glioblastomas. J Magn Reson Imaging. 2005. 22: 799-803
216. Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, Fiedler VU, Niehoff H, Ulrich SD. MR-guided laser-induced interstitial thermotherapy of recurrent glioblastoma multiforme: Preliminary results in 16 patients. Eur J Radiol. 2006. 59: 208-15
217. Schwarzmaier HJ, Yaroslavsky IV, Yaroslavsky AN, Fiedler V, Ulrich F, Kahn T. Treatment planning for MRI-guided laser-induced interstitial thermotherapy of brain tumors--the role of blood perfusion. J Magn Reson Imaging. 1998. 8: 121-7
218. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004. 4: 937-47
219. Shah AC, Benos D, Gillespie GY, Markert JM. Oncolytic viruses: Clinical applications as vectors for the treatment of malignant gliomas. J Neurooncol. 2003. 65: 203-26
220. Shai R, Shi T, Kremen TJ, Horvath S, Liau LM, Cloughesy TF. Gene expression profiling identifies molecular subtypes of gliomas. Oncogene. 2003. 22: 4918-23
221. Shand N, Weber F, Mariani L, Bernstein M, Gianella-Borradori A, Long Z. A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian Study Group. Hum Gene Ther. 1999. 10: 2325-35
222. Shapiro WR, Green SB, Burger PC, Mahaley MS, Selker RG, VanGilder JC. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989. 71: 1-9
223. Shaw RJ, Cantley LC. Ras, PI(3) K and mTOR signalling controls tumour cell growth. Nature. 2006. 441: 424-30
224. Silva R, D’Amico G, Hodivala-Dilke KM, Reynolds LE. Integrins: The keys to unlocking angiogenesis. Arterioscler Thromb Vasc Biol. 2008. 28: 1703-13
225. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003. 63: 5821-8
226. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T. Identification of human brain tumour initiating cells. Nature. 2004. 432: 396-401
227. Sloan AE, Ahluwalia MS, Valerio-Pascua J, Manjila S, Torchia MG, Jones SE. Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma: Clinical article. J Neurosurg. 2013. 118: 1202-19
228. Sloan AE, Dansey R, Zamorano L, Barger G, Hamm C, Diaz F. Adoptive immunotherapy in patients with recurrent malignant glioma: Preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes. Neurosurg Focus. 2000. 9: e9-
229. Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C. Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther. 2003. 7: 851-8
230. Son MJ, Woolard K, Nam DH, Lee J, Fine HA. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell. 2009. 4: 440-52
231. Stiles CD, Rowitch DH. Glioma stem cells: A midterm exam. Neuron. 2008. 58: 832-46
232. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: A randomised controlled multicentre phase III trial. Lancet Oncol. 2006. 7: 392-401
233. Stupp R.editors. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study. Chicago: 2013 ASCO; 2013. p.
234. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009. 10: 459-66
235. Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010. 28: 2712-8
236. Stupp R, Hegi ME, van den Bent MJ, Mason WP, Weller M, Mirimanoff RO. Changing paradigms--an update on the multidisciplinary management of malignant glioma. Oncologist. 2006. 11: 165-80
237. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005. 352: 987-96
238. Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell. 2006. 9: 287-300
239. Teicher BA, Chari RV. Antibody conjugate therapeutics: Challenges and potential. Clin Cancer Res. 2011. 17: 6389-97
240. Terada K, Wakimoto H, Tyminski E, Chiocca EA, Saeki Y. Development of a rapid method to generate multiple oncolytic HSV vectors and their in vivo evaluation using syngeneic mouse tumor models. Gene Ther. 2006. 13: 705-14
241. Thomas AA, Ernstoff MS, Fadul CE. Immunotherapy for the treatment of glioblastoma. Cancer J. 2012. 18: 59-68
242. Tobias A, Ahmed A, Moon KS, Lesniak MS. The art of gene therapy for glioma: A review of the challenging road to the bedside. J Neurol Neurosurg Psychiatry. 2013. 84: 213-22
243. Todhunter DA, Hall WA, Rustamzadeh E, Shu Y, Doumbia SO, Vallera DA. A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model. Protein Eng Des Sel. 2004. 17: 157-64
244. Todo T, Martuza RL, Rabkin SD, Johnson PA. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc Natl Acad Sci U S A. 2001. 98: 6396-401
245. Trask TW, Trask RP, Aguilar-Cordova E, Shine HD, Wyde PR, Goodman JC. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther. 2000. 1: 195-203
246. Tsuboi K, Saijo K, Ishikawa E, Tsurushima H, Takano S, Morishita Y. Effects of local injection of ex vivo expanded autologous tumor-specific T lymphocytes in cases with recurrent malignant gliomas. Clin Cancer Res. 2003. 9: 3294-302
247. Tsurushima H, Liu SQ, Tuboi K, Matsumura A, Yoshii Y, Nose T. Reduction of end-stage malignant glioma by injection with autologous cytotoxic T lymphocytes. Jpn J Cancer Res. 1999. 90: 536-45
248. Uhm JH, Ballman KV, Wu W, Giannini C, Krauss JC, Buckner JC. Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074. Int J Radiat Oncol Biol Phys. 2011. 80: 347-53
249. Ulasov IV, Tyler MA, Rivera AA, Nettlebeck DM, Douglas JT, Lesniak MS. Evaluation of E1A double mutant oncolytic adenovectors in anti-glioma gene therapy. J Med Virol. 2008. 80: 1595-603
250. Ulasov IV, Zhu ZB, Tyler MA, Han Y, Rivera AA, Khramtsov A. Survivin-driven and fiber-modified oncolytic adenovirus exhibits potent antitumor activity in established intracranial glioma. Hum Gene Ther. 2007. 18: 589-602
251. Vallera DA, Li C, Jin N, Panoskaltsis-Mortari A, Hall WA. Targeting urokinase-type plasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT. J Natl Cancer Inst. 2002. 94: 597-606
252. van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009. 27: 1268-74
253. van den Bent MJ, Dubbink HJ, Sanson M, van der Lee-Haarloo CR, Hegi M, Jeuken JW. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: A report from EORTC Brain Tumor Group Study 26951. J Clin Oncol. 2009. 27: 5881-6
254. Van Gool S, Maes W, Ardon H, Verschuere T, Van Cauter S, De Vleeschouwer S. Dendritic cell therapy of high-grade gliomas. Brain Pathol. 2009. 19: 694-712
255. Van Meir EG, Bellail A, Phuphanich S. Emerging molecular therapies for brain tumors. Semin Oncol. 2004. 31: 38-46
256. Vauleon E, Avril T, Collet B, Mosser J, Quillien V. Overview of cellular immunotherapy for patients with glioblastoma. Clin Dev Immunol 2010. 2010. p.
257. Veeravagu A, Liu Z, Niu G, Chen K, Jia B, Cai W. Integrin alphavbeta3-targeted radioimmunotherapy of glioblastoma multiforme. Clin Cancer Res. 2008. 14: 7330-9
258. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010. 17: 98-110
259. Villalva C, Cortes U, Wager M, Tourani JM, Rivet P, Marquant C. O6-Methylguanine-Methyltransferase (MGMT) promoter methylation status in glioma stem-like cells is correlated to temozolomide sensitivity under differentiation-promoting conditions. Int J Mol Sci. 2012. 13: 6983-94
260. Vredenburgh JJ, Desjardins A, Herndon JE, Dowell JM, Reardon DA, Quinn JA. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007. 13: 1253-9
261. Vredenburgh JJ, Desjardins A, Herndon JE, Marcello J, Reardon DA, Quinn JA. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007. 25: 4722-9
262. Vredenburgh JJ, Desjardins A, Kirkpatrick JP, Reardon DA, Peters KB, Herndon JE. Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2012. 82: 58-66
263. Vredenburgh JJ, Desjardins A, Reardon DA, Peters KB, Herndon JE, Marcello J. The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. Clin Cancer Res. 2011. 17: 4119-24
264. Wainwright DA, Nigam P, Thaci B, Dey M, Lesniak MS. Recent developments on immunotherapy for brain cancer. Expert Opin Emerg Drugs. 2012. 17: 181-202
265. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007. 26: 1932-40
266. Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR. Notch promotes radioresistance of glioma stem cells. Stem Cells. 2010. 28: 17-28
267. Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010. 468: 829-33
268. Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996. 6: 217-23
269. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009. 174: 1149-53
270. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008. 359: 492-507
271. Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res. 2006. 12: 4899-907
272. Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003. 5: 79-88
273. Wilcox ME, Yang W, Senger D, Rewcastle NB, Morris DG, Brasher PM. Reovirus as an oncolytic agent against experimental human malignant gliomas. J Natl Cancer Inst. 2001. 93: 903-12
274. Wood GW, Holladay FP, Turner T, Wang YY, Chiga M. A pilot study of autologous cancer cell vaccination and cellular immunotherapy using anti-CD3 stimulated lymphocytes in patients with recurrent grade III/IV astrocytoma. J Neurooncol. 2000. 48: 113-20
275. Xu X, Stockhammer F, Schmitt M. Cellular-based immunotherapies for patients with glioblastoma multiforme. Clin Dev Immunol 2012. 2012. p.
276. Yajima N, Yamanaka R, Mine T, Tsuchiya N, Homma J, Sano M. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin Cancer Res. 2005. 11: 5900-11
277. Yamamoto M, Sawaya R, Mohanam S, Bindal AK, Bruner JM, Oka K. Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo. Cancer Res. 1994. 54: 3656-61
278. Yamanaka R. Cell- and peptide-based immunotherapeutic approaches for glioma. Trends Mol Med. 2008. 14: 228-35
279. Yamanaka R, Abe T, Yajima N, Tsuchiya N, Homma J, Kobayashi T. Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: Results of a clinical phase I/II trial. Br J Cancer. 2003. 89: 1172-9
280. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009. 360: 765-73
281. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004. 64: 4973-9
282. Yu JS, Wheeler CJ, Zeltzer PM, Ying H, Finger DN, Lee PK. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res. 2001. 61: 842-7
283. Zhang J, Stevens MF, Bradshaw TD. Temozolomide: Mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012. 5: 102-14
284. Zhao D, Najbauer J, Garcia E, Metz MZ, Gutova M, Glackin CA. Neural stem cell tropism to glioma: Critical role of tumor hypoxia. Mol Cancer Res. 2008. 6: 1819-29
JESUS FARINAS YANES
Posted January 30, 2020, 12:05 pm
Thanks you for expanding the vision for therapy against this ruthless type of cerebral tumor, I give this article to my residents at the university Hospital of caracas.