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Antiangiogenics May Hold Promise for Leukemia

Over the past several decades, angiogenesis, the process of blood-vessel formation, has come to assume tremendous importance in cancer research, based on the recognition that cancers grow by increasing their blood supply.

Initially it was believed that anti-angiogenic therapy ñ that is, therapy blocking this blood-supply increase -- would be most relevant to solid tumors. But within the past few years investigators have found links between blood-cell formation and blood-vessel formation that have opened up promising possibilities for antiangiogenic agents in the treatment of blood cancers.

Some of the most important work in this field is currently being carried out at New York Weill Cornell Medical Center.

Today researchers at NewYork Weill Cornell are identifying new ways to target acute myeloid leukemia with antiangiogenic drugs. Investigators believe these agents may have a greater impact on leukemia than on solid tumors, according to Dr. Eric J. Feldman, Director of the Weill Cornell Leukemia Program and Associate Director of its Center for Leukemia and Myeloproliferative Disorders.

ìIn leukemia there may be more compelling reasons why antiangiogenic therapy or targeting mediators of angiogenesis has value,î he says.

In the classic model of angiogenesis, Dr. Feldman explains, tumors secrete a substance called vascular endothelial growth factor (VEGF ñ pronounced vejef). Endothelial cells make up the lining of blood vessels, and VEGF induces them to proliferate and migrate and thereby form blood vessels that support tumor growth.

In the leukemic model, based on the research of NewYork Weill Cornellís Dr. Shahin Rafii, VEGF acts not only on endothelial cells but on the leukemia cells themselves. VEGF receptors have never been described on the surface of solid tumors, observes Dr. Feldman, but on the surface of leukemia cells, there are receptors for VEGF, predominantly VEGFR-1 and VEGFR-2.

ìThatís a point that bears repeating,î says, Dr. Feldman. ìVEGF receptors are not found on solid tumors but they are found on leukemia cells.î This suggests that agents targeting the receptor can kill leukemic cells directly, whereas in solid tumors they act only indirectly, largely through interference with the cancerís blood supply.

In leukemia, two separate pathways (the so-called paracrine and autocrine pathways) feed leukemia growth, while solid tumors are stimulated only through the first of these.

Paracrine involves interaction between cells; autocrine describes a cellís interaction with itself. In the former, cancer cells produce VEGF, which then spurs the growth of endothelial cells when it binds to the receptor protein VEGFR-2. This interaction not only promotes blood-vessel formation but stimulates endothelial-cell release of cytokines (cell-activating factors that spur cancer growth).

But in leukemia, Dr. Feldman explains, there is an additional growth path, because leukemic blast cells have receptors for VEGF. Thus, there is an autocrine process of growth by self-stimulation, whereby the cancer cells release VEGF, which interacts with receptors on the cellsí own surface.

Because two pathways drive leukemia and one drives solid tumor growth, antiangiogenics may prove more effective in leukemia.

These findings are now starting to be put to use in clinical studies. A Phase I trial of an experimental agent that targets VEGFR-2, is being conducted alone and in combination with chemotherapy with patients suffering from AML and myelodysplastic syndrome. Dr. Feldmanís team has not fully analyzed the data, but he reports that the trial appears to be going well.

The group is also about to embark on a Phase I trial employing a humanized monoclonal antibody that targets VEGFR-2.

Dr. Feldman, a member of the CR&T medical advisory board, can be reached at ejf2001@med.cornell.edu. November 2002

For additional information, please contact:
Cancer Research & Treatment Fund
Phone: 212-288-6604
Fax: 212-288-7704 or 212-746-8246
e-mail: director@crt.org