Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics

Oncogene volume 35, pages 2145–2155 (2016)Cite this article

Subjects

Abstract

Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as ‘GB multiforme’). GB is the most common and aggressive primary malignant brain tumor and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but is upregulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype; (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue; and (iii) TWEAK:Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Chicheportiche Y, Bourdon PR, Xu H, Hsu Y, Scott H, Hession C et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem 1997; 272: 32401–32410.

    CAS  PubMed  Google Scholar 

  2. Meighan-Mantha RL, Hsu DKW, Guo Y, Brown SAN, Feng SY, Peifley KA et al. The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J Biol Chem 1999; 274: 33166–33176.

    CAS  PubMed  Google Scholar 

  3. Feng SY, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR et al. The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am J Pathol 2000; 156: 1253–1261.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V et al. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 2001; 15: 837–846.

    CAS  PubMed  Google Scholar 

  5. Brown SA, Ghosh A, Winkles JA . Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway. J Biol Chem 2010; 285: 17432–17441.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Roos C, Wicovsky A, Muller N, Salzmann S, Rosenthal T, Kalthoff H et al. Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-kappaB pathway. J Immunol 2010; 185: 1593–1605.

    CAS  PubMed  Google Scholar 

  7. Varfolomeev E, Goncharov T, Maecker H, Zobel K, Komuves LG, Deshayes K et al. Cellular inhibitors of apoptosis are global regulators of NF-kappaB and MAPK activation by members of the TNF family of receptors. Sci Signal 2012; 5: ra22.

    PubMed  Google Scholar 

  8. Winkles JA . The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov 2008; 7: 411–425.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Burkly LC, Michaelson JS, Zheng TS . TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunol Rev 2011; 244: 99–114.

    CAS  PubMed  Google Scholar 

  10. Burkly LC . TWEAK/Fn14 axis: The current paradigm of tissue injury-inducible function in the midst of complexities. Semin Immunol 2014; 26: 229–236.

    CAS  PubMed  Google Scholar 

  11. Desplat-Jego S, Creidy R, Varriale S, Allaire N, Luo Y, Bernard D et al. Anti-TWEAK monoclonal antibodies reduce immune cell infiltration in the central nervous system and severity of experimental autoimmune encephalomyelitis. Clin Immunol 2005; 117: 15–23.

    CAS  PubMed  Google Scholar 

  12. Girgenrath M, Weng S, Kostek CA, Browning B, Wang M, Brown SA et al. TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. EMBO J 2006; 25: 5826–5839.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lynch CN, Wang YC, Lund JK, Chen Y, Leal JA, Wiley SR . TWEAK induces angiogenesis and proliferation of endothelial cells. J Biol Chem 1999; 274: 8455–8459.

    CAS  PubMed  Google Scholar 

  14. Ho DH, Vu H, Brown SAN, Donohue PJ, Hanscom HN, Winkles JA . Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. Cancer Res 2004; 64: 8968–8972.

    CAS  PubMed  Google Scholar 

  15. Kawakita T, Shiraki K, Yamanaka Y, Yamaguchi Y, Saitou Y, Enokimura N et al. Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis. Biochem Biophys Res Commun 2004; 318: 726–733.

    CAS  PubMed  Google Scholar 

  16. Gu L, Dai L, Cao C, Zhu J, Ding C, Xu HB et al. Functional expression of TWEAK and the receptor Fn14 in human malignant ovarian tumors: possible implication for ovarian tumor intervention. PLoS One 2013; 8: e57436.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lin BR, Huang MT, Chen ST, Jeng YM, Li YJ, Liang JT et al. Prognostic significance of TWEAK expression in colorectal cancer and effect of its inhibition on invasion. Ann Surg Oncol 2012; 19: S385–S394.

    PubMed  Google Scholar 

  18. Shimada K, Fujii T, Tsujikawa K, Anai S, Fujimoto K, Konishi N . ALKBH3 contributes to survival and angiogenesis of human urothelial carcinoma cells through NADPH oxidase and tweak/Fn14/VEGF signals. Clin Cancer Res 2012; 18: 5247–5255.

    CAS  PubMed  Google Scholar 

  19. Yoriki R, Akashi S, Sho M, Nomi T, Yamato I, Hotta K et al. Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer. Exp Ther Med 2011; 2: 103–108.

    CAS  PubMed  Google Scholar 

  20. Yin J, Liu YN, Tillman H, Barrett B, Hewitt S, Ylaya K et al. AR-regulated TWEAK-FN14 pathway promotes prostate cancer bone metastasis. Cancer Res 2014; 74: 4306–4317.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Culp PA, Choi D, Zhang Y, Yin J, Seto P, Ybarra SE et al. Antibodies to TWEAK receptor inhibit human tumor growth through dual mechanisms. Clin Cancer Res 2010; 16: 497–508.

    CAS  PubMed  Google Scholar 

  22. Lassen UN, Meulendijks D, Siu LL, Karanikas V, Mau-Sorensen M, Schellens JH et al. A phase I monotherapy study of RG7212, a first-in-class monoclonal antibody targeting TWEAK signaling in patients with advanced cancers. Clin Cancer Res 2015; 21: 258–266.

    CAS  PubMed  Google Scholar 

  23. Huang M, Narita S, Tsuchiya N, Ma Z, Numakura K, Obara T et al. Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome. Carcinogenesis 2011; 32: 1589–1596.

    CAS  PubMed  Google Scholar 

  24. Watts GS, Tran NL, Berens ME, Bhattacharyya AK, Nelson MA, Montgomery EA et al. Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma. Int J Cancer 2007; 121: 2132–2139.

    CAS  PubMed  Google Scholar 

  25. Tran NL, McDonough WS, Savitch BA, Fortin SP, Winkles JA, Symons M et al. Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome. Cancer Res 2006; 66: 9535–9542.

    CAS  PubMed  Google Scholar 

  26. Tran NL, McDonough WS, Donohue PJ, Winkles JA, Berens TJ, Ross KR et al. The human Fn14 receptor gene is up-regulated in migrating glioma cells in vitro and overexpressed in advanced glial tumors. Am J Pathol 2003; 162: 1313–1321.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Willis AL, Tran NL, Chatigny JM, Charlton N, Vu H, Brown SA et al. The fibroblast growth factor-inducible 14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity. Mol Cancer Res 2008; 6: 725–734.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chao DT, Su M, Tanlimco S, Sho M, Choi D, Fox M et al. Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb. J Cancer Res Clin Oncol 2013; 139: 315–325.

    CAS  PubMed  Google Scholar 

  29. de Plater L, Vincent-Salomon A, Berger F, Nicolas A, Vacher S, Gravier E et al. Predictive gene signature of response to the anti-TweakR mAb PDL192 in patient-derived breast cancer xenografts. PLoS One 2014; 9: e104227.

    PubMed  PubMed Central  Google Scholar 

  30. Zhou H, Mohamedali KA, Gonzalez-Angulo AM, Cao Y, Migliorini M, Cheung LH et al. Development of human serine protease-based therapeutics targeting Fn14 and identification of Fn14 as a new target overexpressed in TNBC. Mol Cancer Ther 2014; 13: 2688–2705.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Whitsett TG, Cheng E, Inge L, Asrani K, Jameson NM, Hostetter G et al. Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion. Am J Pathol 2012; 181: 111–120.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Li X, Zhu W, Chen Z, Luo L, Huang J, Zhang F et al. Fibroblast growth factor-inducible 14 regulates cell growth and multidrug resistance of small-cell lung cancer through the nuclear factor-kappaB pathway. Anticancer Drugs 2014; 25: 1152–1164.

    CAS  PubMed  Google Scholar 

  33. Zhou H, Ekmekcioglu S, Marks JW, Mohamedali KA, Asrani K, Phillips KK et al. The TWEAK receptor Fn14 is a therapeutic target in melanoma: immunotoxins targeting Fn14 receptor for malignant melanoma treatment. J Invest Dermatol 2013; 133: 1052–1062.

    CAS  PubMed  Google Scholar 

  34. Whitsett TG, Fortin Ensign SP, Dhruv HD, Inge LJ, Kurywchak P, Wolf KK et al. FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion. Clin Exp Metastasis 2014; 31: 613–623.

    CAS  PubMed  Google Scholar 

  35. Cheng E, Armstrong CL, Galisteo R, Winkles JA . TWEAK/Fn14 axis-targeted therapeutics: moving basic science discoveries to the clinic. Front Immunol 2013; 4: 473.

    PubMed  PubMed Central  Google Scholar 

  36. Wajant H . The TWEAK-Fn14 system as a potential drug target. Br J Pharmacol 2013; 170: 748–764.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Blanco-Colio LM . TWEAK/Fn14 axis: a promising target for the treatment of cardiovascular diseases. Front Immunol 2014; 5: 3.

    PubMed  PubMed Central  Google Scholar 

  38. Dohi T, Burkly LC . The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases: focus on inflammatory bowel diseases. J Leukoc Biol 2012; 92: 265–279.

    CAS  PubMed  Google Scholar 

  39. Wisniacki N, Amaravadi L, Galluppi GR, Zheng TS, Zhang R, Kong J et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of anti-TWEAK monoclonal antibody in patients with rheumatoid arthritis. Clin Ther 2013; 35: 1137–1149.

    CAS  PubMed  Google Scholar 

  40. Gladson CL, Prayson RA, Liu WM . The pathobiology of glioma tumors. Annu Rev Pathol 2010; 5: 33–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cloughesy TF, Cavenee WK, Mischel PS . Glioblastoma: from molecular pathology to targeted treatment. Annu Rev Pathol 2014; 9: 1–25.

    CAS  PubMed  Google Scholar 

  42. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114: 97–109.

    PubMed  PubMed Central  Google Scholar 

  43. Wen PY, Kesari S . Malignant gliomas in adults. N Engl J Med 2008; 359: 492–507.

    CAS  PubMed  Google Scholar 

  44. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol 2014; 16: iv1–63.

    PubMed  PubMed Central  Google Scholar 

  45. Huse JT, Holland E, DeAngelis LM . Glioblastoma: molecular analysis and clinical implications. Annu Rev Med 2013; 64: 59–70.

    CAS  PubMed  Google Scholar 

  46. The Cancer Genome Atlas (TCGA) Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061–1068.

    Google Scholar 

  47. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010; 17: 98–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR et al. The somatic genomic landscape of glioblastoma. Cell 2013; 155: 462–477.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 2013; 110: 4009–4014.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Parker NR, Khong P, Parkinson JF, Howell VM, Wheeler HR . Molecular heterogeneity in glioblastoma: potential clinical implications. Front Oncol 2015; 5: 55.

    PubMed  PubMed Central  Google Scholar 

  51. Gill BJ, Pisapia DJ, Malone HR, Goldstein H, Lei L, Sonabend A et al. MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc Natl Acad Sci USA 2014; 111: 12550–12555.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014; 344: 1396–1401.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Meyer M, Reimand J, Lan X, Head R, Zhu X, Kushida M et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc Natl Acad Sci USA 2015; 112: 851–856.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006; 9: 157–173.

    CAS  PubMed  Google Scholar 

  55. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–996.

    CAS  PubMed  Google Scholar 

  56. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC et al. 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: 459–466.

    CAS  PubMed  Google Scholar 

  57. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de TN, Weller M et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003.

    CAS  PubMed  Google Scholar 

  58. Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 2013; 31: 4085–4091.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Giese A, Bjerkvig R, Berens ME, Westphal M . Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 2003; 21: 1624–1636.

    CAS  PubMed  Google Scholar 

  60. Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME . Molecular targets of glioma invasion. Cell Mol Life Sci 2007; 64: 458–478.

    CAS  PubMed  Google Scholar 

  61. Vehlow A, Cordes N . Invasion as target for therapy of glioblastoma multiforme. Biochim Biophys Acta 2013; 1836: 236–244.

    CAS  PubMed  Google Scholar 

  62. van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE . Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Update 2015; 19: 1–12.

    CAS  Google Scholar 

  63. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 2012; 4: 147ra111.

    PubMed  PubMed Central  Google Scholar 

  64. Woodworth GF, Dunn GP, Nance EA, Hanes J, Brem H . Emerging insights into barriers to effective brain tumor therapeutics. Front Oncol 2014; 4: 126.

    PubMed  PubMed Central  Google Scholar 

  65. Allhenn D, Boushehri MA, Lamprecht A . Drug delivery strategies for the treatment of malignant gliomas. Int J Pharm 2012; 436: 299–310.

    CAS  PubMed  Google Scholar 

  66. Obermeier B, Daneman R, Ransohoff RM . Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013; 19: 1584–1596.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pardridge WM . The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005; 2: 3–14.

    PubMed  PubMed Central  Google Scholar 

  68. Wolburg H, Noell S, Fallier-Becker P, Mack AF, Wolburg-Buchholz K . The disturbed blood-brain barrier in human glioblastoma. Mol Aspects Med 2012; 33: 579–589.

    CAS  PubMed  Google Scholar 

  69. Coomber BL, Stewart PA, Hayakawa K, Farrell CL, Del Maestro RF . Quantitative morphology of human glioblastoma multiforme microvessels: structural basis of blood-brain barrier defect. J Neurooncol 1987; 5: 299–307.

    CAS  PubMed  Google Scholar 

  70. Ji Y, Powers SK, Brown JT, Miner R . Characterization of the tumor invasion area in the rat intracerebral glioma. J Neurooncol 1996; 30: 189–197.

    CAS  PubMed  Google Scholar 

  71. Agarwal S, Manchanda P, Vogelbaum MA, Ohlfest JR, Elmquist WF . Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos 2013; 41: 33–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG . Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 2004; 36: 1046–1069.

    CAS  PubMed  Google Scholar 

  73. Nicholson C, Tao L . Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophys J 1993; 65: 2277–2290.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Thorne RG, Nicholson C . In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci USA 2006; 103: 5567–5572.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Sykova E, Nicholson C . Diffusion in brain extracellular space. Physiol Rev 2008; 88: 1277–1340.

    CAS  PubMed  Google Scholar 

  76. Vargova L, Homola A, Zamecnik J, Tichy M, Benes V, Sykova E . Diffusion parameters of the extracellular space in human gliomas. Glia 2003; 42: 77–88.

    PubMed  Google Scholar 

  77. Aryal M, Arvanitis CD, Alexander PM, McDannold N . Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system. Adv Drug Deliv Rev 2014; 72: 94–109.

    CAS  PubMed  Google Scholar 

  78. Juratli TA, Schackert G, Krex D . Current status of local therapy in malignant gliomas—a clinical review of three selected approaches. Pharmacol Ther 2013; 139: 341–358.

    CAS  PubMed  Google Scholar 

  79. Wait SD, Prabhu RS, Burri SH, Atkins TG, Asher AL . Polymeric drug delivery for the treatment of glioblastoma. Neuro Oncol 2015; 17: ii9–ii23.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Mangraviti A, Tyler B, Brem H . Interstitial chemotherapy for malignant glioma: future prospects in the era of multimodal therapy. Surg Neurol Int 2015; 6: S78–S84.

    PubMed  PubMed Central  Google Scholar 

  81. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-Brain Tumor Treatment Group. Lancet 1995; 345: 1008–1012.

    CAS  PubMed  Google Scholar 

  82. Fung LK, Shin M, Tyler B, Brem H, Saltzman WM . Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm Res 1996; 13: 671–682.

    CAS  PubMed  Google Scholar 

  83. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH . Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 1994; 91: 2076–2080.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Healy AT, Vogelbaum MA . Convection-enhanced drug delivery for gliomas. Surg Neurol Int 2015; 6: S59–S67.

    PubMed  PubMed Central  Google Scholar 

  85. Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF, Piepmeier JM et al. 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: 837–844.

    CAS  PubMed  Google Scholar 

  86. Sampson JH, Brady ML, Petry NA, Croteau D, Friedman AH, Friedman HS et al. Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning. Neurosurgery 2007; 60: ONS89–ONS98.

    PubMed  Google Scholar 

  87. Mueller S, Polley MY, Lee B, Kunwar S, Pedain C, Wembacher-Schroder E et al. Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study. J Neurooncol 2011; 101: 267–277.

    PubMed  Google Scholar 

  88. Sampson JH, Archer G, Pedain C, Wembacher-Schroder E, Westphal M, Kunwar S et al. Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg 2010; 113: 301–309.

    PubMed  Google Scholar 

  89. Tanner PG, Holtmannspotter M, Tonn JC, Goldbrunner R . Effects of drug efflux on convection-enhanced paclitaxel delivery to malignant gliomas: technical note. Neurosurgery 2007; 61: E880–E882.

    PubMed  Google Scholar 

  90. Murad GJ, Walbridge S, Morrison PF, Garmestani K, Degen JW, Brechbiel MW et al. Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to Pseudomonas exotoxin. Clin Cancer Res 2006; 12: 3145–3151.

    CAS  PubMed  Google Scholar 

  91. Sampson JH, Brady M, Raghavan R, Mehta AI, Friedman AH, Reardon DA et al. Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans. Neurosurgery 2011; 69: 668–676.

    PubMed  Google Scholar 

  92. Suzuki A, Leland P, Kobayashi H, Choyke PL, Jagoda EM, Inoue T et al. Analysis of biodistribution of intracranially infused radiolabeled interleukin-13 receptor-targeted immunotoxin IL-13PE by SPECT/CT in an orthotopic mouse model of human glioma. J Nucl Med 2014; 55: 1323–1329.

    CAS  PubMed  Google Scholar 

  93. Bernal GM, LaRiviere MJ, Mansour N, Pytel P, Cahill KE, Voce DJ et al. Convection-enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma. Nanomedicine 2014; 10: 149–157.

    CAS  PubMed  Google Scholar 

  94. Shirahata M, Iwao-Koizumi K, Saito S, Ueno N, Oda M, Hashimoto N et al. Gene expression-based molecular diagnostic system for malignant gliomas is superior to histological diagnosis. Clin Cancer Res 2007; 13: 7341–7356.

    CAS  PubMed  Google Scholar 

  95. Li A, Walling J, Ahn S, Kotliarov Y, Su Q, Quezado M et al. Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes. Cancer Res 2009; 69: 2091–2099.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Shirahata M, Oba S, Iwao-Koizumi K, Saito S, Ueno N, Oda M et al. Using gene expression profiling to identify a prognostic molecular spectrum in gliomas. Cancer Sci 2009; 100: 165–172.

    CAS  PubMed  Google Scholar 

  97. Pelekanou V, Notas G, Kampa M, Tsentelierou E, Stathopoulos EN, Tsapis A et al. BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 proteins are related to human glioma tumor grade: immunohistochemistry and public microarray data meta-analysis. PLoS One 2013; 8: e83250.

    PubMed  PubMed Central  Google Scholar 

  98. Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F et al. Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell 2013; 24: 331–346.

    CAS  PubMed  Google Scholar 

  99. Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 2010; 463: 318–325.

    CAS  PubMed  Google Scholar 

  100. Cheng E, Whitsett TG, Tran NL, Winkles JA . The TWEAK receptor Fn14 is an Src-inducible protein and a positive regulator of Src-driven cell invasion. Mol Cancer Res 2015; 13: 575–583.

    CAS  PubMed  Google Scholar 

  101. Halliday J, Helmy K, Pattwell SS, Pitter KL, Laplant Q, Ozawa T et al. In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift. Proc Natl Acad Sci USA 2014; 111: 5248–5253.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Sullivan JP, Nahed BV, Madden MW, Oliveira SM, Springer S, Bhere D et al. Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discov 2014; 4: 1299–1309.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Demuth T, Ross KR et al. Glioma cell motility is associated with reduced transcription of proapoptotic and proliferation genes: a cDNA microarray analysis. J Neurooncol 2001; 53: 161–176.

    CAS  PubMed  Google Scholar 

  104. Fortin SP, Ennis MJ, Savitch BA, Carpentieri D, McDonough WS, Winkles JA et al. Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function. Mol Cancer Res 2009; 7: 1871–1881.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Dhruv HD, McDonough Winslow WS, Armstrong B, Tuncali S, Eschbacher J, Kislin K et al. Reciprocal activation of transcription factors underlies the dichotomy between proliferation and invasion of glioma cells. PLoS One 2013; 8: e72134.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Fortin SP, Ennis MJ, Schumacher CA, Zylstra-Diegel CR, Williams BO, Ross JT et al. Cdc42 and the guanine nucleotide exchange factors Ect2 and Trio mediate Fn14-induced migration and invasion of glioblastoma cells. Mol Cancer Res 2012; 10: 958–968.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Fortin Ensign SP, Mathews IT, Eschbacher JM, Loftus JC, Symons MH, Tran NL . The Src homology 3 domain-containing guanine nucleotide exchange factor is overexpressed in high-grade gliomas and promotes tumor necrosis factor-like weak inducer of apoptosis-fibroblast growth factor-inducible 14-induced cell migration and invasion via tumor necrosis factor receptor-associated factor 2. J Biol Chem 2013; 288: 21887–21897.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Dhruv HD, Whitsett TG, Jameson NM, Patel F, Winkles JA, Berens ME et al. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioblastoma cell chemotaxis via Lyn activation. Carcinogenesis 2014; 35: 218–226.

    CAS  PubMed  Google Scholar 

  109. Cherry EM, Lee DW, Jung JU, Sitcheran R . Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioma cell invasion through induction of NF-kappaB-inducing kinase (NIK) and noncanonical NF-kappaB signaling. Mol Cancer 2015; 14: 9.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Winkles JA, Tran NL, Berens ME . TWEAK and Fn14: new molecular targets for cancer therapy? Cancer Lett 2005; 235: 11–17.

    Google Scholar 

  111. Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA, Berens ME . The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NF-kappaB pathway activation and BCL-XL/BCL-W expression. J Biol Chem 2005; 280: 3483–3492.

    CAS  PubMed  Google Scholar 

  112. Hambardzumyan D, Amankulor NM, Helmy KY, Becher OJ, Holland EC . Modeling adult gliomas using RCAS/t-va technology. Transl Oncol 2009; 2: 89–95.

    PubMed  PubMed Central  Google Scholar 

  113. Winkles JA, Tran NL, Brown SA, Stains N, Cunliffe HE, Berens ME . Role of TWEAK and Fn14 in tumor biology. Front Biosci 2007; 12: 2761–2771.

    CAS  PubMed  Google Scholar 

  114. Brown SA, Cheng E, Williams MS, Winkles JA . TWEAK-independent Fn14 self-association and NF-kappaB activation is mediated by the C-terminal region of the Fn14 cytoplasmic domain. PLoS One 2013; 8: e65248.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Yin X, Luistro L, Zhong H, Smith M, Nevins T, Schostack K et al. RG7212 anti-TWEAK mAb inhibits tumor growth through inhibition of tumor cell proliferation and survival signaling and by enhancing the host antitumor immune response. Clin Cancer Res 2013; 19: 5686–5698.

    CAS  PubMed  Google Scholar 

  116. Michaelson JS, Amatucci A, Kelly R, Su L, Garber E, Day ES et al. Development of an Fn14 agonistic antibody as an anti-tumor agent. MAbs 2011; 3: 362–375.

    PubMed  PubMed Central  Google Scholar 

  117. Salzmann S, Seher A, Trebing J, Weisenberger D, Rosenthal A, Siegmund D et al. Fibroblast growth factor inducible (Fn14)-specific antibodies concomitantly display signaling pathway-specific agonistic and antagonistic activity. J Biol Chem 2013; 288: 13455–13466.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Dhruv H, Loftus JC, Narang P, Petit JL, Fameree M, Burton J et al. Structural basis and targeting of the interaction between fibroblast growth factor-inducible -14 and tumor necrosis factor-like weak inducer of apoptosis. J Biol Chem 2013; 288: 32261–32276.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Gurunathan S, Winkles JA, Ghosh S, Hayden MS . Regulation of fibroblast growth factor-inducible 14 (Fn14) expression levels via ligand-independent lysosomal degradation. J Biol Chem 2014; 289: 12976–12988.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Alewine C, Hassan R, Pastan I . Advances in anticancer immunotoxin therapy. Oncologist 2015; 20: 176–185.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Chandramohan V, Sampson JH, Pastan I, Bigner DD . Toxin-based targeted therapy for malignant brain tumors. Clin Dev Immunol 2012; 2012: 480429.

    PubMed  PubMed Central  Google Scholar 

  122. Li YM, Vallera DA, Hall WA . Diphtheria toxin-based targeted toxin therapy for brain tumors. J Neurooncol 2013; 114: 155–164.

    CAS  PubMed  Google Scholar 

  123. Chandramohan V, Bao X, Kato KM, Kato Y, Keir ST, Szafranski SE et al. Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors. Int J Cancer 2013; 132: 2339–2348.

    CAS  PubMed  Google Scholar 

  124. Kuan CT, Wakiya K, Keir ST, Li J, Herndon JE, Pastan I et al. Affinity-matured anti-glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas. Int J Cancer 2011; 129: 111–121.

    CAS  PubMed  Google Scholar 

  125. Wykosky J, Gibo DM, Debinski W . A novel, potent, and specific ephrinA1-based cytotoxin against EphA2 receptor expressing tumor cells. Mol Cancer Ther 2007; 6: 3208–3218.

    CAS  PubMed  Google Scholar 

  126. 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.

    CAS  PubMed  Google Scholar 

  127. Rustamzadeh E, Hall WA, Todhunter DA, Vallera VD, Low WC, Liu H et al. Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice. Int J Cancer 2007; 120: 411–419.

    CAS  PubMed  Google Scholar 

  128. Weaver M, Laske DW . Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol 2003; 65: 3–13.

    PubMed  Google Scholar 

  129. Liu TF, Hall PD, Cohen KA, Willingham MC, Cai J, Thorburn A et al. Interstitial diphtheria toxin-epidermal growth factor fusion protein therapy produces regressions of subcutaneous human glioblastoma multiforme tumors in athymic nude mice. Clin Cancer Res 2005; 11: 329–334.

    CAS  PubMed  Google Scholar 

  130. Sampson JH, Akabani G, Archer GE, Berger MS, Coleman RE, Friedman AH et al. Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. Neuro Oncol 2008; 10: 320–329.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Beers R, Chowdhury P, Bigner D, Pastan I . Immunotoxins with increased activity against epidermal growth factor receptor vIII-expressing cells produced by antibody phage display. Clin Cancer Res 2000; 6: 2835–2843.

    CAS  PubMed  Google Scholar 

  132. 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: 2157–2165.

    CAS  PubMed  Google Scholar 

  133. Weber F, Asher A, Bucholz R, Berger M, Prados M, Chang S et al. Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol 2003; 64: 125–137.

    PubMed  Google Scholar 

  134. Rustamzadeh E, Hall WA, Todhunter DA, Low WC, Liu H, Panoskaltsis-Mortari A et al. Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice. Int J Cancer 2006; 118: 2594–2601.

    CAS  PubMed  Google Scholar 

  135. Kioi M, Seetharam S, Puri RK . Targeting IL-13Ralpha2-positive cancer with a novel recombinant immunotoxin composed of a single-chain antibody and mutated Pseudomonas exotoxin. Mol Cancer Ther 2008; 7: 1579–1587.

    CAS  PubMed  Google Scholar 

  136. Chandramohan V, Bao X, Keir ST, Pegram CN, Szafranski SE, Piao H et al. Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy. Clin Cancer Res 2013; 19: 4717–4727.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol 2010; 12: 871–881.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Jarboe JS, Johnson KR, Choi Y, Lonser RR, Park JK . Expression of interleukin-13 receptor alpha2 in glioblastoma multiforme: implications for targeted therapies. Cancer Res 2007; 67: 7983–7986.

    CAS  PubMed  Google Scholar 

  139. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A . ‘Go or grow’: the key to the emergence of invasion in tumour progression? Math Med Biol 2012; 29: 49–65.

    CAS  PubMed  Google Scholar 

  140. Xie Q, Mittal S, Berens ME . Targeting adaptive glioblastoma: an overview of proliferation and invasion. Neuro Oncol 2014; 16: 1575–1584.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhou H, Marks JW, Hittelman WN, Yagita H, Cheung LH, Rosenblum MG et al. Development and characterization of a potent immunoconjugate targeting the Fn14 receptor on solid tumor cells. Mol Cancer Ther 2011; 10: 1276–1288.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhou H, Hittelman WN, Yagita H, Cheung LH, Martin SS, Winkles JA et al. Antitumor activity of a humanized, bivalent immunotoxin targeting Fn14-positive solid tumors. Cancer Res 2013; 73: 4439–4450.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Giannini C, Sarkaria JN, Saito A, Uhm JH, Galanis E, Carlson BL et al. Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol 2005; 7: 164–176.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Joo KM, Kim J, Jin J, Kim M, Seol HJ, Muradov J et al. Patient-specific orthotopic glioblastoma xenograft models recapitulate the histopathology and biology of human glioblastomas in situ. Cell Rep 2013; 3: 260–273.

    CAS  PubMed  Google Scholar 

  145. Lewis GK Jr, Schulz ZR, Pannullo SC, Southard TL, Olbricht WL . Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly: laboratory investigation. J Neurosurg 2012; 117: 1128–1140.

    PubMed  Google Scholar 

  146. Lipsman N, Mainprize TG, Schwartz ML, Hynynen K, Lozano AM . Intracranial applications of magnetic resonance-guided focused ultrasound. Neurotherapeutics 2014; 11: 593–605.

    PubMed  PubMed Central  Google Scholar 

  147. Diaz RJ, McVeigh PZ, O'Reilly MA, Burrell K, Bebenek M, Smith C et al. Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: potential for targeting experimental brain tumors. Nanomedicine 2014; 10: 1075–1087.

    CAS  PubMed  Google Scholar 

  148. Chen ZG . Small-molecule delivery by nanoparticles for anticancer therapy. Trends Mol Med 2010; 16: 594–602.

    CAS  PubMed  Google Scholar 

  149. Jain RK, Stylianopoulos T . Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 2010; 7: 653–664.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Wang AZ, Langer R, Farokhzad OC . Nanoparticle delivery of cancer drugs. Annu Rev Med 2012; 63: 185–198.

    CAS  PubMed  Google Scholar 

  151. Chauhan VP, Jain RK . Strategies for advancing cancer nanomedicine. Nat Mater 2013; 12: 958–962.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Xu X, Ho W, Zhang X, Bertrand N, Farokhzad O . Cancer nanomedicine: from targeted delivery to combination therapy. Trends Mol Med 2015; 21: 223–232.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Hu CM, Zhang L . Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem Pharmacol 2012; 83: 1104–1111.

    CAS  PubMed  Google Scholar 

  154. Danhier F, Feron O, Preat V . To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 2010; 148: 135–146.

    CAS  PubMed  Google Scholar 

  155. Maeda H, Nakamura H, Fang J . The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev 2013; 65: 71–79.

    CAS  PubMed  Google Scholar 

  156. Prabhakar U, Maeda H, Jain RK, Sevick-Muraca EM, Zamboni W, Farokhzad OC et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res 2013; 73: 2412–2417.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC . Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev 2014; 66: 2–25.

    CAS  PubMed  Google Scholar 

  158. Torchilin VP . Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov 2014; 13: 813–827.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. van der Meel R, Vehmeijer LJ, Kok RJ, Storm G, van Gaal EV . Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv Drug Deliv Rev 2013; 65: 1284–1298.

    CAS  PubMed  Google Scholar 

  160. Akhtar MJ, Ahamed M, Alhadlaq HA, Alrokayan SA, Kumar S . Targeted anticancer therapy: overexpressed receptors and nanotechnology. Clin Chim Acta 2014; 436C: 78–92.

    Google Scholar 

  161. Chauhan VP, Stylianopoulos T, Boucher Y, Jain RK . Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu Rev Chem Biomol Eng 2011; 2: 281–298.

    CAS  PubMed  Google Scholar 

  162. Tailor TD, Hanna G, Yarmolenko PS, Dreher MR, Betof AS, Nixon AB et al. Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther 2010; 9: 1798–1808.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Allard E, Passirani C, Benoit JP . Convection-enhanced delivery of nanocarriers for the treatment of brain tumors. Biomaterials 2009; 30: 2302–2318.

    CAS  PubMed  Google Scholar 

  164. Tzeng SY, Green JJ . Therapeutic nanomedicine for brain cancer. Ther Deliv 2013; 4: 687–704.

    CAS  PubMed  Google Scholar 

  165. Del Burgo LS, Hernandez RM, Orive G, Pedraz JL . Nanotherapeutic approaches for brain cancer management. Nanomedicine 2014; 10: 905–919.

    CAS  Google Scholar 

  166. Xi G, Robinson E, Mania-Farnell B, Vanin EF, Shim KW, Takao T et al. Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomedicine 2014; 10: 381–391.

    CAS  PubMed  Google Scholar 

  167. Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng MQ, Duong N et al. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proc Natl Acad Sci USA 2013; 110: 11751–11756.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Nance EA, Woodworth GF, Sailor KA, Shih TY, Xu Q, Swaminathan G et al. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med 2012; 4: 149ra119.

    PubMed  PubMed Central  Google Scholar 

  169. Nance E, Zhang C, Shih TY, Xu Q, Schuster BS, Hanes J . Brain-penetrating nanoparticles improve paclitaxel efficacy in malignant glioma following local administration. ACS Nano 2014; 8: 10655–10664.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Schneider CS, Perez JG, Cheng E, Zhang C, Mastorakos P, Hanes J et al. Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells. Biomaterials 2015; 42: 42–51.

    CAS  PubMed  Google Scholar 

  171. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 2009; 16: 510–520.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Agemy L, Friedmann-Morvinski D, Kotamraju VR, Roth L, Sugahara KN, Girard OM et al. Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma. Proc Natl Acad Sci USA 2011; 108: 17450–17455.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Teesalu T, Sugahara KN, Ruoslahti E . Tumor-penetrating peptides. Front Oncol 2013; 3: 216.

    PubMed  PubMed Central  Google Scholar 

  174. Pang Z, Gao H, Yu Y, Guo L, Chen J, Pan S et al. Enhanced intracellular delivery and chemotherapy for glioma rats by transferrin-conjugated biodegradable polymersomes loaded with doxorubicin. Bioconjug Chem 2011; 22: 1171–1180.

    CAS  PubMed  Google Scholar 

  175. Kim SS, Rait A, Kim E, Pirollo KF, Chang EH . A tumor-targeting p53 nanodelivery system limits chemoresistance to temozolomide prolonging survival in a mouse model of glioblastoma multiforme. Nanomedicine 2015; 11: 301–311.

    CAS  PubMed  Google Scholar 

  176. Hadjipanayis CG, Machaidze R, Kaluzova M, Wang L, Schuette AJ, Chen H et al. EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer Res 2010; 70: 6303–6312.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Madhankumar AB, Slagle-Webb B, Wang X, Yang QX, Antonetti DA, Miller PA et al. Efficacy of interleukin-13 receptor-targeted liposomal doxorubicin in the intracranial brain tumor model. Mol Cancer Ther 2009; 8: 648–654.

    CAS  PubMed  Google Scholar 

  178. Sanz AB, Sanchez-Nino MD, Carrasco S, Manzarbeitia F, Ruiz-Andres O, Selgas R et al. Inflammatory cytokines and survival factors from serum modulate Tweak-induced apoptosis in PC-3 prostate cancer cells. PLoS One 2012; 7: e47440.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2: 401–404.

    PubMed  Google Scholar 

  180. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6: l1.

    Google Scholar 

Download references

Acknowledgements

We thank Drs David Hersh and Rudi Castellani (University of Maryland School of Medicine) for the GB patient MRI images and Fn14 IHC data, respectively. Research in the authors’ laboratories is supported, in part, by NIH R01 CA177796 and The Ben & Catherine Ivy Foundation (NLT), The Clayton Foundation for Research (MGR), NIH T32 CA154274 (NPC), NIH K25 EB018370 (AJK), NIH K08 NS090430 (GFW) and DOD CDMRP Lung Cancer Research Program IDEA Award W81XWH-14-1-0324 (JAW).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA

    J G Perez, C S Schneider, N P Connolly, A J Kim & G F Woodworth

  2. Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA

    N L Tran

  3. Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA

    M G Rosenblum

  4. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

    A J Kim

  5. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    A J Kim, G F Woodworth & J A Winkles

  6. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

    J A Winkles

  7. Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA

    J A Winkles

Authors
  1. J G Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N L Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M G Rosenblum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C S Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N P Connolly
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G F Woodworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J A Winkles
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J A Winkles.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Perez, J., Tran, N., Rosenblum, M. et al. The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics. Oncogene 35, 2145–2155 (2016). https://doi.org/10.1038/onc.2015.310

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.310

This article is cited by

Search

Advanced search

Quick links