new agent "Trojan horse" to prevent bone mets--clinical trials to begin within a year

[Lani]

"Trojan Horse" Agent Halts Bone Metastasis in Mice: Human Clinical Trial for Drug Could Open Within a Year [MD Anderson Cancer Center News Room]
A novel vascular targeting agent completely prevented the development of bone tumors in 50 percent 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. mors 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.

[Lani]

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."

[Lani]

ABSTRACT: Inhibition of Prostate Tumor Growth and Bone Remodeling by the Vascular Targeting Agent VEGF121/rGel [Cancer Research; Subscribe]
The pathophysiology of tumor growth following skeletal metastases and the poor response of this type of lesion to therapeutic intervention remains incompletely understood. Vascular endothelial growth factor (VEGF)-A and its receptors play a role in both osteoclastogenesis and tumor growth. Systemic (i.v.) treatment of nude mice bearing intrafemoral prostate (PC-3) tumors with the vascular ablative agent VEGF121/recombinant gelonin (rGel) strongly inhibited tumor growth. Fifty percent of treated animals had complete regression of bone tumors with no development of lytic bone lesions. Immunohistochemical analysis showed that VEGF121/rGel treatment suppressed tumor-mediated osteoclastogenesis in vivo. In vitro treatment of murine osteoclast precursors, both cell line (RAW264.7) and bone marrow-derived monocytes (BMM), revealed that VEGF121/rGel was selectively cytotoxic to osteoclast precursor cells rather than mature osteoclasts. VEGF121/rGel cytotoxicity was mediated by Flt-1, which was down-regulated during osteoclast differentiation. Analysis by flow cytometry and reverse transcription-PCR showed that both BMM and RAW264.7 cells display high levels of Flt-1 but low levels of Flk-1. Internalization of VEGF121/rGel into osteoclast precursor cells was suppressed by pretreatment with an Flt-1 neutralizing antibody or by placenta growth factor but not with an Flk-1 neutralizing antibody. Thus, VEGF121/rGel inhibits osteoclast maturation in vivo and it seems that this process is important in the resulting suppression of skeletal osteolytic lesions. This is a novel and unique mechanism of action for this class of agents and suggests a potentially new approach for treatment or prevention of tumor growth in bone.