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Vascular targeting of lung tumors

Institution: Sidney Kimmel Cancer Center
Investigator(s): Jan Schnitzer, M.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11RT-0167 Award: $830,563
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Smoking causes most forms of lung cancer, 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. One longstanding approach to cancer therapy has been to create targeting agents that direct drugs specifically to tumor cells. This so-called "magic bullet" strategy of cancer immunotherapy is dependent on the ability of an antibody-conjugate, or “immunotoxin,” to target a drug directly to tumor cells. Although this strategy has worked well 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" on the tumor cells is located on the other side of the blood vessel wall which prevents many intravenous agents from effectively reaching the tumor. An attractive alternative strategy for treating solid tumors is to re-direct antibody probes to targets that reside only in the blood vessels of tumors in key transport vesicles called caveolae. These vascular caveolar target sites can be accessible to agents injected into the bloodstream allowing the efficient targeting of drugs to the tumor and, possibly, also the transport of drugs into and even across the tumor blood vessel wall for specific delivery to the underlying tumor cells. This approach may permit tumor eradication through localized destruction of the tumor vasculature as well as increase the effectiveness of chemotherapeutic drugs in the treatment of lung tumors by improving accessibility to the tumor cells while sparing normal tissues from the toxic side effects associated with conventional chemotherapy.

Our goal is to discover and validate protein targets that reside only in the caveolae of blood vessels of lung tumors that may be useful to permit tumor-specific delivery to cancer cells. We will use a sophisticated identification and targeting strategy to detect accessible vascular targets in vivo by focusing on and purifying transport vesicles, called caveolae, at the blood-tissue interface. We will isolate highly pure caveolae from human lung tumors and then use mass spectrometry to rapidly identify lung tumor-induced targets. Antibodies will be produced to these tumor-induced proteins to develop probes to validate target expression on the blood vessels of lung tumors. In addition, we will continue our analysis of two new promising, apparently lung tumor-specific antibodies identified previously in experiments funded by TRDRP to determine their ability to target specifically blood vessels in lung tumors as well as their ability to direct toxins to lung tumors to cause tumor regression. Those antibodies found to be highly specific for the tumor endothelium will be excellent candidates for future study to determine their usefulness in targeting drugs to primary and metastatic lung tumors after intravenous injection.
Publications

Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy.
Periodical: Nature Index Medicus:
Authors: Oh P, Li Y, Yu J, Durr E, Krasinska K, Carver L, Testa J, Schnitzer J ART
Yr: 2004 Vol: Nbr: Abs: Pg: