Request for Funding

Medical Student Research Fellowship for Summer 2004

Mentor: Philip Thorpe, Ph.D.
Department: Simmons Cancer Center
Room #: NC7.304
Mail Code: 8594
Phone #: 8-1809
E-mail: philip.thorpe@utsouthwestern.edu
Project title: Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

Human subjects IRB approved project number (where applicable): No human subjects.
Animal subjects IRB approved project number (where applicable): 0486-03-10-1

Project Type: Animal based-research (primarily mice)

Brief Description of Project:

Tumor neovascular growth depends on a variety of cytokines and growth factors in response to hypoxic conditions. One cytokine designated vascular endothelial growth factor (VEGF) appears to play a central role in tumor neovascularization. A recent study of 260 breast cancer biopsy specimens found 95% had detectable and elevated VEGF levels. More importantly, levels of VEGF were found to be prognostic for both relapse free and overall survival in both univariate and multivariate analyses. In breast tumor biopsy specimens, the KDR receptor for VEGF was found to be over-expressed in vasculature adjacent to breast tumor cells but was not over-expressed in vasculature of normal breast. These studies suggest that neovasculature development in solid tumors particularly in breast cancer may be a critical arena for the development of therapeutic agents. The purpose of this proposal is to design, construct and test specific fusion constructs targeting the breast tumor vasculature. VEGF121 is a 12 kDa peptide containing the receptor binding domain of this cytokine. The recombinant toxin gelonin (rGel) is a 28 kDa protein which acts as an N-glycosidase on rRNA thereby enzymatically inactivating essential protein synthesis. The rGel toxin is extremely cytotoxic once it enters cells, but lacks a cellular entry point. The cDNA for VEGF121 was fused to the cDNA encoding rGel using PCR.The VEGF121/rGel fusion construct was expressed in bacteria and purified to homogeniety. This fusion construct was able to bind to the flk-1 receptor and inhibited cell-free protein synthesis thereby demonstrated biological activity of both VEGF and rGel in the same molecule. These constructs containing human proteins and toxins have the potential of targeting the developing breast tumor vasculature and inhibiting these cells through a selective, receptor-mediated processes. The reduced size of these chimeric constructs may provide for unique therapeutic agents for long-term administration without the risk of developing an immunogenic response. The purpose of this research is to examine the biological properties of these unique constructs in in vitro and in vivo model systems of human breast cancer to determine the feasibility of this approach and to utilize these constructs to examine the biological importance of VEGF and flk-1/KDR receptor in the development and metasteses of human breast cancer. Finally, these studies may provide a critical basis for the further development of VEGF121/rGel fusion constructs as potential therapeutic agents for treatment of patients with metastatic breast cancer.

Previous Research Activities or Publications with Medical Students:

No publications with medical students as authors.

The following people conducted research in the Thorpe laboratory while medical students:

Sarah Edmonson
Dara Eisner
Adrienne Hammill

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