To survive, tumors need a blood supply, and to get that blood supply, they must stimulate the growth of new vessels. Choking off that blood supply has been a successful strategy for fighting cancer, as Avastin (bevacizumab), from Genentech Inc. and ImClone Systems Inc.'s Erbitux (cetuximab,) among others, can attest.
Currently approved anti-angiogenesis drugs target the vascular endothelial growth factor and its interaction with its receptor. But research into alternate ways of starving tumors is ongoing. (See BioWorld Today, Dec 27, 2006.)
In the Dec 6, 2007, issue of Nature, researchers from Genentech presented basic research adding another possible target to the dozens that currently are in the preclinical and clinical pipeline: Bv8, a protein that is secreted by myeloid cells of the bone marrow.
"Over the last several years, there has been growing evidence that bone-marrow derived cells can contribute to cancer," senior author Napoleone Ferrara, Genentech Fellow, told BioWorld Today. "This paper describes a novel molecular mechanism to explain, at least in part, that contribution."
Indeed, bone marrow cells are just one of a number of cells that appear to encourage the growth of tumor blood vessels. While it originally was thought that only tumor cells themselves stimulated such growth, in recent years, scientists have implicated other cell types such as fibroblasts, immune cells and endothelial progenitor cells in stimulating tumor blood vessel growth, as well.
Ferrara and his team focused on myeloid cells expressing the surface markers CD11b and GR1, because previous work had shown that such cells can make tumors resistant to anti-angiogenic therapy targeting VEGF, suggesting they might promote angiogenesis by a separate mechanism.
The team first implanted tumors into mice to see whether the implantation would affect Bv8 in the bone marrow, and found that xenografted tumors significantly increased the levels of Bv8 specifically in myeloid cells expressing CD11b and GR1.
To find out exactly how the tumors signal to bone marrow cells, the scientists next tested the ability of a panel of cytokines and chemokines to induce Bv8 expression in bone marrow cells. They found that a cytokine known as granulocyte colony-stimulating factor, or G-CSF, which is expressed by tumor cells as well as endothelial cells and fibroblasts, strongly increased the expression of Bv8 in myeloid cells.
The scientists conducted both gain-of-function studies, delivering Bv8 to tumors via a viral vector, and loss-of-function studies, blocking it with a monoclonal antibody, to test the effect that Bv8 has on tumor blood vessel growth. Adding Bv8 accelerated tumor growth, while blocking it led to reduced tumor size and fewer vessels.
The researchers wrote in their paper that "in some models, the growth inhibition elicited by anti-Bv8 approached that elicited by anti-VEGF monoclonal antibodies . . . which block both mouse VEGF and human VEGF." Blocking both VEGF and Bv8 had additive effects, suggesting that an eventual therapeutic based on the findings could be "complementary to existing anti-angiogenic agents," Ferrara said.
Avastin is a blockbuster drug, racking up sales of $1.7 billion in 2006. But Ferrara is nevertheless circumspect when asked about the clinical prospects of targeting Bv8: "At this point, this is basic research," he said. "It is too early to think about the clinic."