GENETICALLY ENGINEERED VIRUSES TO TREAT MALIGNANT NERVOUS SYSTEM TUMORS

Project: Research project

Project Details

Description

Despite advances in the techniques of surgery, chemotherapy, and
radiotherapy, glioblastomas are almost always fatal due to locally
recurring and invasive tumor. No standard therapeutic modality has
substantially changed the outcome. We are exploring the possibility that
genetically engineered viruses can be used as antineoplastic agents
against glioblastoma and other malignant nervous system tumors. Because
viruses can efficiently enter a cell, express their genomic material, and
cause either cell growth modulation or cell destruction, they are
attractive agents for development. Further, viruses can be designed that
are either cell specific or take advantage of differences between tumor
cells and their normal counterparts. This is especially true for the
brain wherein tumor cells are an actively dividing cell mass within a
post-mitotic neuroglial cell population. both in cell culture and in
animal models using human tumors, we show that certain genetically
engineered mutants of herpes simplex virus (HSV) can kill tumor cells
while sparing surrounding normal brain cells and can cause either
diminished tumor growth or apparent cure. In particular, mutations in
the HSV-thymidine kinase gene or in the gamma 34.5 gene are associated
with a maintained ability to destroy tumor cells yet spare surrounding
normal brain. Evidence is also presented to suggest that this concept
can be extended to other nervous system tumors (medulloblastoma,
neurofibrosarcoma, malignant meningioma, retinoblastoma) and that virus-
induced tumor destruction also is effective in immune competent animals.
We now plan to test a series of double mutants of HSV, specifically,
mutants containing combinations of deletions in HSV-thymidine kinase, DNA
polymerase, and gamma 34.5. These will be tested in cell culture as well
as in subcutaneous and intracerebral models in animals. We expect that
these double mutants will maintain their ability to kill tumor cells but
have decreased neurovirulence and less possibility of reversion to wild-
type. Through these studies we expect to further develop this new
experimental therapeutic method of targeting tumor cells in order to lay
the basic groundwork for possible clinical application.
StatusFinished
Effective start/end date1/1/012/29/96

Funding

  • National Cancer Institute
  • National Cancer Institute

ASJC

  • Oncology
  • Cancer Research
  • Cell Biology
  • Radiation

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