Researchers at The University of Texas M. D. Anderson Cancer Center in Houston and The University of Texas Southwestern Medical Center at Dallas have demonstrated in mice that a new drug formed by linking a vascular endothelial growth factor to a toxin will target and destroy the blood vessels supplying a malignant tumor.
Dr. Michael Rosenblum, Professor of Medicine at M. D. Anderson, said tests of VEGF121/rGelonin (VEGF/rGel) in mice demonstrated it could selectively destroy blood vessels supplying human solid tumors without harming the vasculature of normal tissue.
"This is like a 'Trojan horse' approach to kill the blood vessels that supply solid tumors. We're using the vascular endothelial growth factor (VEGF) as a carrier to deliver a toxic agent selectively to the tumor's blood supply – in effect, starving the tumor," said Dr. Rosenblum, senior author of the study.
The research, which appears in the June 11 Proceedings of the National Academy of Sciences, was the result of an ongoing collaboration between UT Southwestern and M. D. Anderson. VEGF/rGel was designed jointly and developed at M. D. Anderson and UT Southwestern.
For the study, mice were injected with human melanoma and human prostate cancer cells. The research showed that tumor growth in the mice that received VEGF/rGel was reduced to 16 percent of that of the untreated mice, said Dr. Philip Thorpe, Professor of Pharmacology, who directed tests of VEGF/rGel at UT Southwestern with Dr. Sophia Ran, Assistant Professor of Pharmacology. Both are affiliated with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.
"The anti-tumor effects of the VEGF/rGel fusion construct against both melanoma and human prostate cancer in mouse models was impressive in magnitude and prolonged," Dr. Thorpe said. "These studies suggest that VEGF/rGel has potential as an anti-tumor agent for treating cancer patients."
A clinical trial to test the new technique in patients is expected to begin within the year at M. D. Anderson, Dr. Rosenblum said.
"The significance of this fusion toxin is that it's not specific to one kind of tumor – it has impressive anti-tumor effects in various kinds of tumors – including melanoma and prostate cancers," Dr. Rosenblum said. "We need additional research to determine if it is equally effective in other cancers."
In the mouse study, destruction of the tumor blood vessels was observed as early as 48 hours after administration of the VEGF/rGel. There was no visible damage in any normal organs, including the kidneys, of the treated mice, Dr. Rosenblum said.
VEGF is one of the predominant factors responsible for angiogenesis – the ability of a tumor to create new blood vessels to maintain growth and metastasize.
"The receptors for VEGF are overexpressed on the endothelium of tumor vasculature but are almost undetectable in the adjacent normal tissue, so they make excellent targets for the development of therapeutic agents that inhibit tumor growth and metastatic spread by inhibiting the new blood vessel formation," Dr. Rosenblum said.
The researchers chose the genetically engineered toxin gelonin to link to the VEGF "carrier" because it does not appear to be antigenic in human clinical trials conducted thus far at M. D. Anderson, and it does not cause damage to normal blood vessels as do other toxins that have been explored for use in anti-tumor therapies, Dr. Rosenblum said.
Genetically engineered gelonin was developed in a research program at M. D. Anderson, and related intellectual property rights are owned by Research Development Foundation (RDF). RDF is in the process of licensing the gelonin technology for use with various cell-targeting proteins such as growth factors and antibodies.
Therapies that attack tumor blood vessels have recently been a hot area in cancer research because they appear to bypass the major problem with chemotherapy – the tumor cells' ability to mutate and develop resistance to the drugs.
Other researchers from M. D. Anderson who contributed to the work were Liesbeth M. Veenendaal, Lawrence Cheung, Nora Navone and Hangqing Jin. The Med. Klinik und Poliklinik der Universität Ulm in Germany also contributed to the research.
The work was supported in part by the University of Utrecht and the Dutch Cancer Foundation, Koningen Wilhelmina Funds, the National Institutes of Health and Arcus Therapeutics.
Materials provided by University Of Texas Southwestern Medical Center At Dallas. Note: Content may be edited for style and length.
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