Cell Pathways Identifies Presence of SAANDs Drug Targets and Mechanism of Apoptosis Induction in Breast Cancer Cells; Results Reported At San Antonio Breast Cancer Symposium.

Business Editors & Health/Medical Writers

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HORSHAM, Pa.--(BW HealthWire)--Dec. 13, 2001

Cell Pathways, Inc. (Nasdaq:CLPA) today released data demonstrating the presence, in breast cancer cells, of the cyclic GMP phosphodiesterases (cGMP PDEs) targeted by their selective apoptotic antineoplastic drugs (SAANDs). SAANDs, including Aptosyn(TM) (exisulind) and CP461, inhibit certain cyclic GMP PDEs found to be over-expressed in a variety of tumor types. In doing so, they trigger down-stream pathways leading to programmed cell death, or apoptosis, in the cancer cells. The investigators also demonstrated that inhibition of these cGMP PDEs led to the decrease of another important protein, beta-catenin. The accumulation of beta-catenin within the cell has been implicated in the growth of several types of cancers including, most recently, breast cancer. The new findings were presented today by scientists from Cell Pathways and their collaborators from the University of California at Los Angeles (UCLA) School of Medicine at the annual San Antonio Breast Cancer Symposium.

"While this study confirms the presence of SAANDs targets, cGMP PDEs of the PDE 1 and 5 families, in breast tumor cells, the more important finding is that inhibition of the cGMP PDEs in these breast cancer cells by Aptosyn(TM) and CP461 results in a reduction of the beta-catenin protein in these cells," said Rifat Pamukcu, M.D., Cell Pathways' chief scientific officer. "It is known that the accumulation of beta-catenin significantly contributes to the growth of colon cancer cells. Within the last year, compelling evidence suggests that beta-catenin may also play an important role in the growth of breast cancer. A recent study from Harvard Medical School in the journal Nature Cell Biology suggests that the over-expression of a protein, Pin1, leads to the over-accumulation of beta-catenin in breast cancer cells by preventing its phosphorylation by another protein, APC. Phosphorylation marks beta-catenin for subsequent destruction by other enzymes. Our studies demonstrate that inhibiting the various cGMP PDE targets in breast cancer cells leads to activation of protein kinase G (PKG) and triggers apoptosis. PKG is capable of phosphorylating beta-catenin, independent of APC, leading to its destruction. This is similar to our findings in colon cancer cells, which we reported in the journal Cancer Research last year."

The investigators studied the effects of Aptosyn(TM) and CP461 in MDA-MB-435S and HER2/neu over-expressing MDA-MB-453 breast tumor cells. Like colon tumor cells, both breast cancer cell types contained a cGMP specific PDE5, but MDA-MB-435S cells also harbored PDE1 activity. Aptosyn(TM) and CP461, which induce apoptosis in these cells, inhibited cGMP PDEs as confirmed by persistently increased intracellular cGMP levels. Western blots showed a dose-dependent induction of PKG protein by Aptosyn(TM) and CP461 and a concomitant decrease in cellular beta-catenin and cyclin D1.

"Previous presentations have reported synergistic activity between our SAANDs compounds and both Taxotere(R) and Herceptin(R) in breast cancer cell lines. Based on our findings to date, we believe that Aptosyn(TM) may someday play an important role in combination with other drug therapies for management of breast cancer," said Dr. Pamukcu. He also noted that a Phase I/II clinical trial of Aptosyn(TM) in combination with capecitabine (Xeloda(R)) in patients with metastatic breast cancer was currently ongoing at M.D. Anderson Cancer Center in Houston, Texas.

Cell Pathways, Inc., headquartered in Horsham, Pa., is a development stage pharmaceutical company focused on the research, development and commercialization of novel and unique medications to prevent and treat cancer. For additional information on Cell Pathways, Inc., visit the company's web site at www.cellpathways.com.

Editors Note: Aptosyn(TM) is a trademark of Cell Pathways, Inc. and Xeloda(R) is a registered trademark of Hoffmann-La Roche Inc.

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