New drug target for inducing apoptosis in abnormal cells published in cancer research
HORSHAM, PA (July 5, 2000) -- Scientists at Cell Pathways, Inc. (Nasdaq: CLPA) and their collaborators have identified a new drug target that may play a key role in cancer cell survival. Exisulind (Aptosyn™) and other compounds in the company's family of selective apoptotic antineoplastic drugs (SAANDs) inhibit this target, cyclic GMP phosphodiesterases of the PDE5 and PDE2 gene families that have been found to be over-expressed in cancerous and precancerous cells of the colon. The inhibition of these target proteins triggers a chain of events which results in the programmed cell death, or apoptosis, of cancerous and precancerous cells, but not normal ones. The drugs have additionally been shown to inhibit the growth of a broad variety of malignant tumor cells beyond colon tumors, in both cell culture and animal models of human cancers.
The new research appears in the July 1 issue of the journal Cancer Research. Cell Pathways scientists and their collaborators at the University of South Alabama College of Medicine, and the University of Colorado authored the paper.
Apoptosis and SAANDs
Apoptosis is the body's response to a normal, orderly sequence of biochemical or physical signals by which damaged or "worn out" cells are eliminated to make way for healthy, new cells. When the mechanism of apoptosis goes awry, cells continue to multiply and grow inappropriately, forming a mass of tissue -- a cancerous tumor. In colon cancer, excessive cell growth occurs as the result of the accumulation of a regulatory protein, beta-catenin, caused by mutations in the adenomatous polyposis coli (APC) gene.
The researchers showed that exisulind and other SAANDs induce apoptosis in colon tumor cells by inhibiting the different forms of cGMP PDE in these cell lines. This results in a sustained increase in cGMP in the cells and the induction of cGMP-dependent protein kinase G (PKG). This rise in PKG activity causes beta-catenin to be degraded in neoplastic cells, thus triggering cell death by apoptosis through well-studied mechanisms. In addition, SAANDs that are better inhibitors of PDE5 and PDE2 than exisulind also show parallel increases in ability to induce apoptosis and inhibit growth of the cancer cells.
"Exisulind and other SAANDs appear to act at an early point in the biochemical pathway that controls apoptosis and survival of cancer cells," said W. Joseph Thompson, Ph.D., vice president of research at Cell Pathways and lead author of the publication. "Our initial data indicates that increased PDE5 expression, and in some cases PDE2, occurs in precancerous and cancerous lesions. This over-expression appears to keep cGMP low in cells that have abnormal proliferation or apoptosis rates. The data indicate that by inhibiting cGMP PDE activity in cancer cells, a sustained rise in cGMP occurs, triggering cell death through protein kinase G. In normal cells, the cGMP pathway does not appear to be important in the regulation of apoptosis. Exisulind and other SAANDs restore the ability of abnormal cells to die by inhibiting that cGMP PDE activity."
New Insights in the Biology of Cancer
Cyclic nucleotide PDEs consist of 11 gene families, each having one or more different members or "isoforms." Each family of PDEs is characterized by their ability to bind and degrade cyclic AMP (cAMP) and/or cGMP, but differs in their immunological, physical and kinetic properties. Only a limited number of PDE isoforms are expressed and used by any single type of cell or tissue to regulate cGMP or cAMP levels. Pharmaceutical developers have been studying these enzymes as potential drug targets to modulated cyclic nucleotide levels in diseases where their levels are important, such as asthma and heart disease. Until now, PDE inhibitors have not been developed as anti-cancer agents. Moreover, the majority of PDE inhibitors investigated to date do not induce apoptosis in tumor cells. Thus, exisulind and SAANDs represent a chemical class of unique PDE inhibitors.
Promising Clinical and Pre-Clinical Results
Cell Pathways has demonstrated the ability of Aptosyn™ (exisulind) and other SAANDs to trigger apoptosis in abnormal cells in over 50 different tumor cell lines, as well as in animal models of a variety of human cancers. Aptosyn™ has demonstrated clinical activity in preventing or treating precancerous colon polyps in individuals with familial adenomatous polyposis (FAP), an inherited disease caused by a defect in the APC gene and the accumulation of beta-catenin in precancerous cells. Further, Aptosyn™ was found to reduce the rise in PSA levels in men with prostate cancer at risk of recurrence after prostatectomy. A New Drug Application (NDA) for Aptosyn™ is currently under review by the Food and Drug Administration (FDA) as a treatment for FAP.
Cell Pathways is conducting additional clinical trials with Aptosyn™, both as a single agent and in combination with traditional chemotherapeutic agents against such cancers and precancerous conditions as prostate, breast and lung cancer, sporadic colon polyps (a precursor to colon cancer), and Barrett's esophagus (a precursor to esophageal cancer). Cell Pathways is also conducting Phase IB safety studies with a second SAAND compound, CPI 461, in cancer patients.
Cell Pathways, Inc., headquartered in Horsham, Pennsylvania, 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 website at http://www.cellpathways.com.
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Journal
Cancer Research