The applicant is focused on gene therapy for cancer via retrovirus-mediated gene transfer of two potent angiogenic inhibitors: angiostatin and endostatin. Traditional cancer therapies have limited success because they either address local disease only, have intolerable toxic effects or cancers cells become resistant to chemotherapy. Since tumor growth is strongly dependent upon neo-vessel formation, newly discovered anti-angiogenic agents such as angiostatin and endostatin hold great promise. However, these inhibitors must be administered daily for extended periods in preclinical models and it has prove difficult to produce these recombinant proteins in large amounts in an active form. For these reasons, the applicants are now developing a gene therapy of cancer by retrovirus-mediated long-term systemic delivery of recombinant angiostatins and/or endostatin.
In Specific Aims 1 and 2, they will test the feasibility, toxicity and efficacy of this approach in mice by means of ex-vivo gene transfer protocols involving bone marrow transplantation with transduced bone marrow as vehicle for systemic gene delivery of the angiogenic inhibitors. Transplanted animals will be challenged with syngeneic murine tumors in immunocompetent mice and various human cancers in SCID mice.
In Specific Aim 3, they will evaluate an in-vivo gene transfer protocol in a murine model of ovarian cancer.
NOT AVAILABLE
| Pawliuk, Robert; Bachelot, Thomas; Zurkiya, Omar et al. (2002) Continuous intravascular secretion of endostatin in mice from transduced hematopoietic stem cells. Mol Ther 5:345-51 |
| Jouanneau, E; Alberti, L; Nejjari, M et al. (2001) Lack of antitumor activity of recombinant endostatin in a human neuroblastoma xenograft model. J Neurooncol 51:11-8 |
