CELLULAR TRANSDUCTION FOR DRUG DELIVERY IN CANCER

  • Kasahara, Noriyuki (PI)
  • Lee, A.M.Y. (PI)
  • Declerck, Yves (PI)
  • Dennert, Gunther (PI)
  • Kohn, Donald (PI)
  • Parkman, Robertson (PI)
  • Anderson, W. French (PI)
  • Kedes, Laurence (PI)

Project: Research project

Description

Present clinical gene therapy research in patients with cancer has centered
on two principal areas: 1) marker studies to determine the cellular
trafficking of tumor infiltrating lymphocytes (TIL) cells and the basis for
leukemic relapse following bone marrow transplantation and 2) cytokine gene
transduction to increase immunological responses in patients with melanoma.
In order to have a major impact in the treatment of cancer patients,
however, gene therapy has to be integrated into clinical protocols in the
early stages of therapy and applied to a broader range of cancers. Overall the present proposal "Cellular Transduction For Drug Delivery in
Cancer" is an integrated program between three units of the University of
Southern California School of Medicine: the Kenneth Norris Jr. Cancer
Center, the Institute for Genetic Medicine and the Childrens Hospital Los
Angeles. The integrated program consists of clinical, pre-clinical, and
basic science research into the area of drug delivery utilizing gene
therapy techniques. the proposal represents the establishment of a new,
interactive, gene therapy program and entails the development of new
approaches to the gene therapy of cancer. The central research focus of the proposal is the use of target cells with
capacity for long term gene expression to deliver anti-cancer gene therapy.
The studies center on two such potential cellular delivery systems:
hematopoietic stem cells (HSC) and myoblasts. Pre-clinical and clinical
studies (Project 1) are proposed using HSC transduced with a drug
resistance gene (DRG). The engraftment of DRG transduced HSC would result
in increasing the ability of patients with both hematological malignancies
and solid tumors to tolerate higher doses of chemotherapy without marrow
suppression. Pre-clinical studies with myoblasts (Project 2) transduced
with anti-cancer polypeptide genes (somatostatin analogs) are proposed.
Myoblasts constitutively producing anti-cancer polypeptides would be
expected to be more efficacious and cheaper than the intermittent
administration of the same polypeptide. Central to the use of gene therapy
for the delivery of anti-cancer drugs is the long term expression of the
transduced gene. Some studies with both HSC and myoblasts have exhibited
the phenomenon of "silencing" i.e. the decrease expression of the
transduced gene with time. Basic research into the mechanisms of silencing
are proposed (Project 3) including the possibility that the introduction of
methylation resistant islands in the promoter regions of the transduced
gene may inhibit silencing. Both Project 2 and Project 3 will also
investigate the function and efficacy of novel promoters and enhancers for
the maximal and sustained delivery of recombinant gene products. A vector and animal core is integral to each of the three projects.
Retroviral vectors are pivotal to Projects 1 and 2 and are one of the major
elements of Project 2. The murine gene transfer/bone marrow
transplantation (BMT) studies are fundamental to examining vector silencing
in hematopoietic stem cells (Project 3) and an important element for
evaluating the effects of the MDR-1 gene on conferring drug resistance to
hematopoietic stem cells (Project 1).
StatusFinished
Effective start/end date9/30/922/28/07

Funding

  • National Institutes of Health
  • National Institutes of Health

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Neoplasms
Cell Culture Techniques
Genes
Nude Mice
Prostate
Viruses
Virus Assembly
Retroviridae
Tumor Suppressor Genes
Transgenes
Heterografts
Genetic Therapy
Leukemia
Neoplasm Metastasis
Safety
Injections
Infection

ASJC

  • Medicine(all)