"Trojan Horse" Agent Halts Bone Metastasis in Mice
M. D. Anderson News Release 11/15/06
A novel vascular targeting agent completely prevented the development of bone tumors in 50% of the mice tested in a preclinical study, providing early evidence that it could treat, or thwart, growth of tumors in bone, a common destination for a number of cancers when they start to spread.
Researchers at The University of Texas M. D. Anderson Cancer Center reported in the journal Cancer Research that this "Trojan Horse" agent, VEGF121/rGel, stopped specialized cells within the bone from chewing up other bone material to make room for the implanted tumor to grow.
Although this study tested the ability of VEGF121/rGel to halt the growth of human prostate cancer cells in the bones of mice, investigators say it likely could help prevent the growth of other cancers in bones such as breast, multiple myeloma, lung and renal cell.
"Many tumors invade bone in the same way, so these findings suggest it may be possible to shut down this process regardless of the tumor type," says the study's lead author, Michael G. Rosenblum, Ph.D., professor in the Department of Experimental Therapeutics "If that could be done - and we are a long way from determining if it is possible - we may be able to offer the first treatment that specifically targets bone metastasis."
The study also revealed critical information about the role of vascular endothelial growth factor (VEGF) in the development of tumors in bone, says Rosenblum. VEGF is a signaling protein involved in the creation of new blood vessels, but in this study the researchers found that it plays a surprising role in the remodeling of bone tissue.
In the normal maintenance of bones, a balance exists between activity of cells known as osteoclasts, which break down and resorb bone matrix, and osteoblasts, which form new bone. Researchers know that tumor cells that metastasize to bones release VEGF, but what they did not know is whether the protein interrupted bone maintenance or promoted growth of blood vessels to feed the neophyte cancer, Rosenblum said
To find out, Rosenblum designed an experiment with VEGF121/rGel, an agent he and his colleagues began to develop several years ago. They created the drug by fusing the smallest of VEGF proteins (VEGF 121) to a genetically engineered toxin, gelonin, derived from a plant that grows wild in India, and used bacteria to produce the fusion protein. The agent is designed to enter new blood vessel cells in tumors through expressed VEGF receptors and, once inside, the "Trojan Horse" toxin destroys the cell, disrupting the ability of tumors to form blood vessels to supply the nutrients they need to grow. Animal studies previously conducted by the researchers have shown that the protein can selectively destroy blood vessels feeding human solid tumors.
In this study, investigators implanted human prostate cancer cells, which are highly metastatic to bone, directly into the leg bone marrow of experimental mice in order to simulate a bone metastasis. A week later, they treated the animals with five staggered doses of VEGF121/rGel delivered through intravenous injections.
Half of the treated mice did not develop any bone tumors, Rosenblum says. "There was no evidence of cancer growth," he says, adding, "We don't know why the treatment didn't work in the other half of the mice, but we may have started therapy too late."
Rosenblum and his research team then found that VEGF121/rGel dramatically reduced the number of osteoclast cells in the leg bones and further research demonstrated that pre-osteoclast like cells, known as monocytes, had been expressing a receptor, Flt-1, designed to latch on to the VEGF protein secreted by cancer cells.
When activated by maturation factors including VEGF, the pre-osteoclasts differentiated into mature osteoclasts and chew up bone tissue, providing the tumor new space to grow. The mature osteoclast cells themselves do not express the Flt-1 receptor.
According to Rosenblum, the VEGF121/rGel agent entered the immature cells via the Flt-1 receptor and destroyed them, shutting down tumor growth. "This was a surprise to us," he says. "We had not expected these cells to be killed at all because we knew, through our earlier experiments, that VEGF121/rGel destroyed blood vessels by entering a different cell surface receptor, one which is not expressed on pre-osteoclasts."
Thus, in the bone, VEGF121/rGel may be working through two different VEGF receptors. It stops the bone destruction needed for the cancer to grow and may inhibit blood vessel growth to the metastasized tumor, Rosenblum says.
"The fact that this form of VEGF targeting works on different cell receptors in blood vessels and in bone cells is a unique finding that could be clinically significant, not only to treating cancer but other bone disorders," he says. "In the least, this study helps us understand more about how VEGF operates inside the body and how it is involved in bone remodeling."
Rosenblum said that phase I human clinical trials testing VEGF121/rGel are expected to open shortly at M. D. Anderson.
The study was funded by the Clayton Foundation for Research (KAM and MGR), the National Institutes of Health Grant CA96797 (NMN), the Prostate Foundation (NMN), the Prostate SPORE Career Development Award (BGD), and the Gillson Longenbaugh Foundation (PET) and by Peregrine Pharmaceuticals, Inc (PET). Rosenblum's co-authors include, from M. D. Anderson: co-first authors Khalid A. Mohamedali, Ph.D. and Ann T. Poblenz, Ph.D., Charles Sikes, Nora M. Navone, M.D., Ph.D.; Bryant G. Darnay, Ph.D.; and Philip E. Thorpe, Ph.D. from The University of Texas Southwestern Medical Center.