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Project W

Project W

 

 

Name:

Alexandru C. Stan, M.D., Ph.D. Professor of Neuropathology

 

Institution:

Institute of Neuropathology

 

Telephone:

0049-511-532-4539

 

Email:

stan.alexmh-hannover.de

 

Research focus:

Brain tumor invasiveness; Glioblastoma angiogenesis; Multidrug resistance; Prodrug therapy

 

Projects:

AIM

 

Our research is focussed onto two major problems encountered in the therapy of glioblastoma. First, glioblastoma is a highly invasive brain tumor. This property obviously determines a lower treatment success rate than might be expected for tumors, which almost never metastasize. In this process, the CD44 adhesion molecule has apparently a major function in regulating the adhesive and locomotory properties of glioblastoma cells, since during invasion, homotypic adhesion is reduced with a concomitant increase in heterotypic adhesion. Second, the multidrug-resistance (MDR) phenotype of glioblastoma is associated with over-expression of P-glycoprotein (P-gp, P-170) encoded by the multidrug-resistance-1 (MDR1) gene. P-gp facilitates active efflux of various xenobiotics, thus significantly lowering their therapeutic efficacy. We have previously demonstrated that local treatment with an anti-CD44s monoclonal antibody can strongly inhibit glioblastoma invasion, thus blocking tumor growth. We have also demonstrated that an enzymatically-engineered doxorubicin-mAb anti-CEA immunoconjugate is about 8-times more efficient in killing colonic carcinoma tumors than doxorubicin itself with virtually no side-effects. We have further demonstrated that doxorubicin can circumvent the P-gp-associated chemoresistance in glioblastoma cells, provided that the drug can persist intracellularly for as long as 24h.

 

GOALS

  1. To target the highly potent chemotherapeutic substance doxorubicin, which is enzymatically engineered on the carbohydrate moieties of a monoclonal antibody to CD44s, the 85-90 kDa standard form of the CD44 adhesion molecule that is over-expressed by glioblastoma cells.
  2. To target anti-sense phosphorothioate oligo-deoxynucleotides, which are likewise enzymatically engineered on the anti-CD44s monoclonal antibody to P-glycoprotein that is over-expressed by endothelial cells within glioblastoma's vasculature. Using this combined therapeutic strategy we expect a dramatic increase of the drug's efficacy in killing tumor cells, which otherwise become resistant to conventional chemotherapy:
  3. High amounts of doxorubicin are shuttled into glioblastoma cells by the antibody due to over-expression of the CD44 adhesion molecule on the cell surface.
  4. High amounts of anti-sense phosphorothioate oligodeoxynucleotides are shuttled into endothelial cells by the antibody due to an improved linking procedure.
  5. High intracellular accumulation of "bio-active" doxorubicin is due to lack of lysosomal degradation of CD44 within glioblastoma cells.
  6. High intracellular retention of "bio-active" doxorubicin is due to suppressed expression of P-glycoprotein within endothelial cells.

 

Group members:

Alexandru C. Stan, M.D., Ph.D., Prof.; Hans H. Wellhoener, M.D., PhD., Prof.;Veronika Thorns, M.D.; Sadanand Gaikwad, M.Sc.; Farid A. Jamai, cand. med.; Stephanie Alm, Technician

 

Methods:

  1. Cell culture and cell transformation
  2. PCR, RT-PCR
  3. Blotting (northern, western)
  4. ELISA (cytotoxicity, apoptosis)
  5. FACS (miscellaneous)
  6. Histology and Immunohistochemistry
  7. Experimental animal treatment (mouse, rat)

 

Key References:

  1. Stan A.C., Radu D.L., Casares S., Bona C.A., and Brumeanu T.-D. Antineoplastic efficacy of Doxorubicin enzymatically assembled on galactose residues of a monoclonal antibody specific for the carcinoembryonic antigen. Cancer Res. 59: 115 - 121 (1999).
  2. Stan, A.C., Casares S., Brumeanu T.-D., Klinman D.M., and Bona C.A. CpG motifs of DNA vaccines induce the expression of chemokines and MHC class II molecules on myocytes. Eur. J. Immunol. 31(1):301 - 310 (2001).
  3. Casares S., Stan A.C., Bona C.A., and Brumeanu T.-D. Antigen-specific downregulation of T cells by doxorubicin delivered through a recombinant MHC II-peptide chimera. Nat. Biotechnol. 19(2): 142 - 147 (2001).

 

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