New Agent May Thwart Bone Metastasis

A novel agent targeting the vascular system completely prevented the development of bone tumors in 50% of the mice tested in a preclinical study, providing early evidence that the agent could treat, or thwart, the growth of tumors in the bone, a common site of metastasis for a number of cancers.

Researchers at M. D. Anderson Cancer Center reported in the November 15 issue of the journal Cancer Research that this agent, VEGF121/rGel, stopped specialized cells within the bone from destroying other bone material; otherwise, the destruction makes room for the implanted tumor to grow.

Although this study specifically 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 other cancers, such as breast cancer, multiple myeloma, lung cancer, and renal cell carcinoma, from metastasizing to bones as well.

“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,” said the study’s lead author, Michael G. Rosenblum, Ph.D., professor in the Department of Experimental Therapeutics. “We’re a long way from determining if it’s possible in humans and in all tumor types; phase I clinical trials are expected to open shortly at M. D. Anderson to explore this. But if we find it can be done, it could lead to 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, said Dr. Rosenblum. VEGF is a signaling protein involved in the creation of new blood vessels, but the researchers found that it plays a surprising role in the remodeling of bone tissue as well.

Because tumor cells that metastasize to bone release VEGF, the researchers did not know whether the protein interrupted bone maintenance or promoted the growth of blood vessels to feed the neophyte cancer, Dr. Rosenblum said.

To find out, Dr. Rosenblum designed an experiment with VEGF121/rGel, an agent designed to enter new blood vessel cells in tumors through expressed VEGF receptors. Once inside, the “Trojan horse” toxin destroys the cell, disrupting the ability of tumors to form the vascular systems necessary for growth. Previous laboratory studies have shown that the protein can selectively destroy blood vessels feeding human solid tumors.

Half of the treated mice did not develop any bone tumors, Dr. Rosenblum said. “We don’t know why the treatment worked in half of the mice and not the others (the cells of which were genetically identical), but we may have started therapy too late in those that didn’t respond,” he said.

Researchers determined that VEGF121/rGel may work through two different VEGF receptors. It stops the bone destruction needed for the cancer to grow and may also inhibit blood vessel growth to the metastasized tumor, Dr. Rosenblum said.

“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 in treating cancer but also in other bone disorders,” he said. “At the very least, this study gives us a better understanding of how VEGF operates and how it is involved in bone remodeling.”

Innovative AML Treatment Proves Promising

Acute myeloid leukemia (AML) is known for its resistance to standard chemotherapy treatment. Now, researchers at M. D. Anderson Cancer Center have found, in laboratory studies, that the experimental drug ABT-737 can destroy AML blast, progenitor, and even stem cells.

The drug was potent in its own right, the researchers said, but they found that some types of AML cells were resistant to ABT-737, so they added another drug, a MAP-kinase inhibitor, that overcame this resistance. Together, these agents hold promise as a new therapy for AML and could eventually form the basis of a new way to treat the cancer, said the scientists, whose study was published in the November 14 issue of the journal Cancer Cell.

“The combination of these two experimental drugs provides the highest synergistic action I have ever seen against acute myeloid leukemia cells,” said the study’s lead author, Michael Andreeff, M.D., Ph.D., professor in the Departments of Stem Cell Transplantation and Leukemia. “ABT-737 would overcome resistance to chemotherapy that we often see in AML therapy, and the MAP-kinase inhibitor would overcome resistance to ABT-737,” he said.

ABT-737 targets the best-known member of the BCL-2 family of proteins, also called BCL-2, which prevents a cell from undergoing apoptosis. ABT-737, however, was engineered to fit tightly on BCL-2, occupying the BCL-2 binding space so that other proteins can promote apoptosis.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, December 2006 issue:

• Curable But Not Conquered: Hodgkin’s Lymphoma Today
• House Call: Big Benefits for Smokers Who Quit

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