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Vascular targeting of lung tumors

Institution: Sidney Kimmel Cancer Center
Investigator(s): Jan Schnitzer, M.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8RT-0152 Award: $899,686
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
Smoking causes most forms of lung cancer which is a leading cause of death in men and women in the United States. Although key advances have occurred in lung cancer detection and treatment, improvements are needed in the development of both new therapies and ways to enhance early detection and diagnosis of lung cancer not only to extend life and improve the quality of life for men and women with this disease but also to reduce the huge economic cost of this disease. The improved targeting strategy of this project can, with the identification of key targets, provide both diagnostic and therapeutic tools. One longstanding approach to cancer therapy has been to create lethal agents (e.g., immunotoxins) that directly attack tumor cells. This so-called "magic bullet" strategy of cancer immunotherapy is predicated on the ability of an antibody conjugate to target a drug (i.e., a toxin) directly to tumor cells. Although this works on tumor cells grown on a culture dish in the lab, these immuno-bullets have not consistently hit their mark in patients because the "bull's eye" exists on the other side of blood vessel walls, thus preventing many intravenous agents from effectively reaching their target cells, namely the tumor cells inside the tissue. An attractive alternate strategy for immunotherapy of lung cancer is to target agents to the endothelial cells lining the tumor blood vessels (specifically, the “endothelial” cells) rather than to the tumor cells themselves. One key advantage of this approach is that endothelial cells are very accessible to agents injected into the blood whereas the tumor cells are not. Genetically engineered tumor models show that this vascular targeting strategy does indeed work but unfortunately because of technological limitations, the actual pathologically relevant target proteins on the tumor endothelium remain unknown. This project aims to discover such tumor vascular targets by using a new technology that allows direct analysis of the vascular endothelial cell surface membrane as it exists in its native state in the tumor tissue. Tumor growth factors, angiogenesis and other microenvironmental factors in tumors are expected to induce changes in endothelial cell surface protein expression. We propose to identify tumor-induced vascular targets, which may be useful in the treatment of lung cancer, by comparing the proteins found at the endothelial cell surface in normal tissues versus lung tumors. Antibodies will be produced against the tumor endothelial proteins. Novel proteins will be purified for amino acid sequencing. The antibodies will be used to detect tumor growth and to target the tumor vasculature by intravenous injection where they may destroy the local blood supply resulting in tumor starvation and death. Because the tumor vasculature is critical for tumor growth, metastasis, and survival, such non-invasive therapies focusing on the tumor vasculature provide not only an accessible modality but also a specific ablative approach to treating primary and metastatic lung cancer. The vascular targeting strategy is quite distinct from current anti-angiogenesis therapies because the goal of vascular targeting is not stasis by preventing tumor blood vessel growth but rather directly killing the tumor by cutting off its life supply through the rapid and selective destruction of the blood vessels supplying the tumor. This work will provide much new information that should greatly improve our understanding of lung cancer by elucidating the effects of the lung tumor environment on the development of the endothelium in tumor blood vessels and discovering new accessible targets of this smoking-related disease.

Final Report
With the resources made available through the Tobacco-related disease research program, my lab has applied our novel methodology to isolate luminal endothelial cell plasma membranes (P) from normal rat lungs and lung tumors for the purpose of identifying candidate proteins that are specific for lung tumor endothelium. Using a rat lung tumor model, we have compared the endothelial membrane-associated proteins derived from normal and tumor-bearing lungs by 2-D gel electrophoresis revealing several well-separated protein spots that were present solely in the tumor-endothelial membrane fraction. We have begun to characterize 5 protein spots, TE1-5, that appeared to be lung tumor-induced. Using antibodies to TE3, we have discovered that TE3 appears lung tumor-specific by Western analysis, tissue immunostaining, and in vivo targeting. In addition, we have generated monoclonal antibodies (mAb) to tumor P and have identified several promising antibodies, one of which, TC004, appears to be lung tumor-specific. In the last three years, we have progressed significantly in discovering new tumor-induced vascular targets as well as novel tumor-targeting probes. We are continuing this work for three more years as awarded by TRDRP. Details of our progress is discussed below under each of the specific aims defined in the original TRDRP grant application.

Tumor angiogenesis alters caveolae: accessible targets for therapy
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Oh P, Kumer JC, Schnitzer J ABS
Yr: 2000 Vol: 1 Nbr: Abs: 66 Pg:

Tumor vascular targeting of caveolae
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Oh P, Czarny M, Mufleijt M, Schnitzer J ABS
Yr: 2001 Vol: 42 Nbr: Abs: 825 Pg:

Vascular proteomics: identifying accessible tissue- and tumor-specific vascular targets in vivo
Periodical: FASEB Journal Index Medicus:
Authors: Oh P, Kumer JC, Schnitzer J ABS
Yr: 2001 Vol: 15 Nbr: 4 Abs: A484 Pg:

Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo: A pathway to overcome cell barriers to drug and gene delivery.
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: McIntosh DP, Tan XY, Oh P, and Schnitzer JE ART
Yr: 0 Vol: Nbr: Abs: Pg: