CLL Strategies Target Growth Factors Affecting Cell Survival and Proliferation

NEW YORK-Novel treatment strategies targeting specific cytokines may provide an additional therapeutic window for the treatment of chronic lymphocytic leukemia (CLL), Janice L. Gabrilove, MD, of Mount Sinai School of Medicine, New York, said at the Chemotherapy Foundation Symposium XVIII.

Certain cytokines, in vitro, have been shown to promote enhanced CLL cell proliferation. Others may contribute to resistance to programmed cell death in response to an apoptotic stimulus (such as a nucleoside analog). Evidence suggests that delayed apoptosis contributes to the prolonged cell survival seen in this disease.

"Approaches that take advantage of understanding this pathway may be of therapeutic benefit," particularly to patients resistant to standard therapies, Dr. Gabrilove said.

A number of CLL treatments that are accepted today, including use of the nucleoside analog fludarabine (Fludara), actually work by interfering with the impaired apoptosis seen in CLL. By inducing programmed cell death, treatment leads to extinction of the malignant cells.

Tumor necrosis factor-alpha (TNF-alpha) is one cytokine that contributes to enhanced proliferation of malignant cells. Fibroblast growth factor (FGF), on the other hand, contributes to the survival of CLL cells by preventing cell death.

Nine FGF genes have been identified. Dr. Gabrilove and her colleagues have observed that CLL cells express elevated levels of intracellular basic FGF (bFGF) that increase with stage of disease. In vitro, the researchers showed that bFGF contributes to CLL cell resistance to apoptotic stimulus.

In vitro CLL cells exposed to fludara-bine had almost all undergone apoptosis after 5 days of culture; however, with the addition of bFGF, more CLL cells were still viable, suggesting that bFGF confers a "growth advantage" by interfering with the cells’ ability to respond to the apoptotic stimulus provided by the nucleoside analog.

The Bcl-2 protein is commonly over-expressed in CLL, and upregulation of Bcl-2 is associated with delayed programmed cell death. Thus, strategies to interfere with Bcl-2, such as use of novel Bcl-2 antisense compounds, "may prove to be of considerable interest," Dr. Gabrilove said. Fibroblast growth factor also has the ability to promote cell survival by upregulating Bcl-2, she said.

Trial of Thalidomide

A clinical trial of thalidomide (Thalomid) has been initiated by Dr. Gabrilove and her colleagues based on the current understanding of growth-promoting and survival mechanisms.

In the trial, thalidomide, a potent inhibitor of both TNF-alpha and FGF-mediated growth, will be given alone or in combination with fludarabine to CLL patients who have already failed fludarabine treatment or are primarily resistant to fludarabine.