Glioma therapy and real‐time imaging of neural precursor cell migration and tumor regression

Despite many refinements in current therapeutic strategies, the overall prognosis for a patient with glioblastoma is dismal. Neural precursor cells (NPCs) are capable of tracking glioma tumors and thus could be used to deliver therapeutic molecules. We have engineered mouse NPCs to deliver a secreted form of tumor necrosis factor–related apoptosis–inducing ligand (S‐TRAIL); S‐TRAIL is optimized to selectively kill neoplastic cells. Furthermore, we have developed means to simultaneously monitor both the migration of NSCs toward gliomas and the changes in glioma burden in real time. Using a highly malignant human glioma model expressing Renilla luciferase (Rluc), intracranially implanted NPC‐FL‐sTRAIL expressing both firefly luciferase (Fluc) and S‐TRAIL was shown to migrate into the tumors and have profound antitumor effects. These studies demonstrate the potential of NPCs as therapeutically effective delivery vehicles for the treatment of gliomas and also provide important tools to evaluate the migration of NPCs and changes in glioma burden in vivo. Ann Neurol 2005;57:34–41

[1]  R. Weissleder,et al.  Inducible release of TRAIL fusion proteins from a proapoptotic form for tumor therapy. , 2004, Cancer research.

[2]  J. Schulz,et al.  Adenoviral (Full-Length) Apo2L/TRAIL Gene Transfer is an Ineffective Treatment Strategy for Malignant Glioma , 2004, Journal of Neuro-Oncology.

[3]  Wafik S El-Deiry,et al.  TRAIL and apoptosis induction by TNF-family death receptors , 2003, Oncogene.

[4]  Ralph Weissleder,et al.  Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo , 2003, Oncogene.

[5]  Ralph Weissleder,et al.  In vivo tracking of neural progenitor cell migration to glioblastomas. , 2003, Human gene therapy.

[6]  G. Fulci,et al.  Viral therapy for glioblastoma. , 2003, Cancer journal.

[7]  A. Ashkenazi,et al.  Apo2L/TRAIL and its death and decoy receptors , 2003, Cell Death and Differentiation.

[8]  Melitta Schachner,et al.  Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons , 2002, Nature Biotechnology.

[9]  F. Beguinot,et al.  Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Death-inducing Signaling Complex and Its Modulation by c-FLIP and PED/PEA-15 in Glioma Cells* , 2002, The Journal of Biological Chemistry.

[10]  H. Fine,et al.  Antitumor activity and prolonged expression from a TRAIL-expressing adenoviral vector. , 2002, Neoplasia.

[11]  R. Weissleder,et al.  MRI of transgene expression: correlation to therapeutic gene expression. , 2002, Neoplasia.

[12]  J. Dong,et al.  The use of Fas Ligand, TRAIL and Bax in gene therapy of prostate cancer. , 2001, Current gene therapy.

[13]  I. Pollack,et al.  Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  K. Hui,et al.  Regression of human mammary adenocarcinoma by systemic administration of a recombinant gene encoding the hFlex-TRAIL fusion protein. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[15]  Erwin G. Van Meir,et al.  Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells. , 2001, Cancer research.

[16]  P. Black,et al.  Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  X. Breakefield,et al.  Prodrug activation enzymes in cancer gene therapy , 2000, The journal of gene medicine.

[18]  B. Gliniak,et al.  Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. , 1999, Cancer research.

[19]  J. Dichgans,et al.  Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. , 1999, Biochemical and biophysical research communications.

[20]  V. Dixit,et al.  Apoptosis control by death and decoy receptors. , 1999, Current opinion in cell biology.

[21]  C. Rauch,et al.  Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo , 1999, Nature Medicine.

[22]  C. Stiles.  Cancer of the central nervous system. Review of an AACR special conference in cancer research with the joint section on tumors of the AANS/CNS (San Diego, CA, June 7-11, 1997). , 1998, Biochimica et biophysica acta.

[23]  X. Breakefield,et al.  Benefits and risks of hosting animal cells in the human brain , 1997, Nature Medicine.

[24]  O. Bogler,et al.  A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. , 1996, Cancer research.

[25]  C A Smith,et al.  Identification and characterization of a new member of the TNF family that induces apoptosis. , 1995, Immunity.

[26]  J. D. Macklis,et al.  Multipotent neural progenitor or stem-like cells may be uniquely suited for therapy for some neurodegenerative conditions. , 1995, Clinical neuroscience.

[27]  C. Cepko,et al.  Establishment and characterization of multipotent neural cell lines using retrovirus vector-mediated oncogene transfer. , 1990, Journal of neurobiology.