DF/HCC Program Affiliation

Translational Pharmacology and Early Therapeutic Trials
Neuro-Oncology

Research Abstract

Gene and stem cell therapy has been heralded as a potential revolution in medicine but it is clear that the major limitations to the effectiveness of this new paradigm remain to sufficiently and selectively kill the tumor cells, to monitor gene and stem cell delivery and therapeutic effects in animals, and eventually in human patients. The following are the major aims of my current projects in MGH, Harvard Medical School: 1) To evaluate range of cell death with membrane bound and secreted forms of a therapeutic gene, tumor necrosis factor related apoptosis inducing ligand (TRAIL), delivered via herpes simplex virus (HSV) into glioma cells in culture and in vivo; 2) to simultaneously track the migration of firefly luciferase labeled neural progenitor cells (NPCs) to Renilla luciferase labeled glioma cells and monitor changes in gliomas in the living mouse brains by dual luciferase imaging: 3) to engineer NPCs to express secretable form of TRAIL and use them in NPC/brain tumor therapy paradigm; and 4) to develop protease activatable systems to specifically activate therapeutic proteins and protease activatable near infrared (NIR) optical probes to subsequently monitor therapeutic effect of the TRAIL by NIR optical imaging technology.
The major findings of these studies so far have been the development of secreted form of TRAIL that induces enhanced cell death only in tumor cells while leaving behind the normal cells.We have also developed a dual enzyme substrate (Rluc/Fluc) imaging technology to subsequently image gene delivery via viral vectors and to monitor tumor regression induced by delivery of TRAIL to gliomas in live animals.We have shown that that NPCs expressing firefly luciferase have potent and prominent attraction to brain tumors when administered either by brain parenchymal or intraventricular injections. Furthermore, we have engineered NPCs to express firefly luciferase and secreted form of TRAIL and used them for eradicating Renilla luciferase expressing gliomas. In addition our very recent studies have led to the development of a novel method to image the viral delivery of HSV-1 protease activity in a subcutaneous glioma mouse model in vivo using long circulating graft copolymer autoquenched near-infrared fluorescence (NIRF) probe. NIRF signal was generated by intratumoral viral delivered HSV-1 protease that cleaves the macromolecule, thereby releasing previously quenched fluorochrome. These developed method should find widespread applications for tumor cell killing and for real-time imaging of a variety of viral and NPC delivered therapeutic proteins.

Publications

• Dent P, Yacoub A, Park M, Sarkar D, Shah K, Curiel DT, Grant S.Searching for a cure: Gene therapy for glioblastoma.Cancer Biol Ther 2008 Jun 2;7(9).
  18708757
• Yip S, Shah K.Stem-cell based therapies for brain tumors.Curr Opin Mol Ther 2008 Aug;10(4):334-42.
  18683097
• Kock N, Kasmieh R, Weissleder R, Shah K.Tumor therapy mediated by lentiviral expression of shBcl-2 and S-TRAIL.Neoplasia 2007 May;9(5):435-42.
  17534449
• Shah K, Breakefield XO.HSV Amplicon Vectors for Cancer Therapy.Curr Gene Ther 2006 Jun;6(3):361-70.
  16787187
• Shah K, Tung CH, Breakefield XO, Weissleder R.In vivo imaging of S-TRAIL-mediated tumor regression and apoptosis.Mol Ther 2005 Jun;11(6):926-31.
  15922963
• Shah K, Weissleder R.Molecular optical imaging: applications leading to the development of present day therapeutics.NeuroRx 2005 Apr;2(2):215-25.
  15897946
• Shah K, Hsich G, Breakefield XO.Neural precursor cells and their role in neuro-oncology.Dev Neurosci 2004 Mar-Aug;26(2-4):118-30.
  15711055
• Shah K, Bureau E, Kim DE, Yang K, Tang Y, Weissleder R, Breakefield XO.Glioma therapy and real-time imaging of neural precursor cell migration and tumor regression.Ann Neurol 2005 Jan;57(1):34-41.
  15622535
• Shah K, Tung CH, Yang K, Weissleder R, Breakefield XO.Inducible release of TRAIL fusion proteins from a proapoptotic form for tumor therapy.Cancer Res 2004 May 1;64(9):3236-42.
  15126365
• Shah K, Tung CH, Chang CH, Slootweg E, O'Loughlin T, Breakefield XO, Weissleder R.In Vivo Imaging of HIV Protease Activity in Amplicon Vector-transduced Gliomas.Cancer Res 2004 Jan 1;64(1):273-8.
  14729634
• Tang Y, Shah K, Messerli SM, Snyder E, Breakefield X, Weissleder R.In vivo tracking of neural progenitor cell migration to glioblastomas.Hum Gene Ther 2003 Sep 1;14(13):1247-54.
  12952596