New Research Extends Understanding of How SAANDs Trigger Suicide in Cancerous and Precancerous Cells Via Multiple Apoptosis Pathways.

News Editors & Biotechnology/Medical Writers

HORSHAM, Pa.--(BW HealthWire)--Oct. 16, 2000

Clinical Cancer Research Publication Further Describes Mechanism

of Action for a New Class of Anti-Cancer Drugs

Scientists at Columbia University College of Physicians and Surgeons have reported that a new drug target, previously identified by their collaborators at Cell Pathways, Inc. (Nasdaq:CLPA), may affect cancer cell survival by impacting more than one downstream cellular pathway controlling programmed cell death, or apoptosis.

The drug target described consists of the cyclic GMP phosphodiesterases (cGMP PDE) of the PDE5 and PDE2 gene families. Exisulind (Aptosyn(TM)) and other compounds in Cell Pathways' family of selective apoptotic antineoplastic drugs (SAANDs) inhibit these target cGMP PDEs, which the company and its collaborators have found over-expressed in cancerous and precancerous cells of the colon, and cancers of the lung, prostate, breast, bladder and pancreas. This activity leads to the inhibition of growth of a broad variety of malignant tumor cells in both cell culture and animal models of human cancers.

The new research appears in the October issue of the journal Clinical Cancer Research. Columbia University scientists led by Dr. Bernard Weinstein, director emeritus of the Herbert Irving Comprehensive Cancer Center and Dr. Jae-Won Soh and their collaborators at Cell Pathways co-authored the paper.

Research has shown that the inhibition of these target cGMP PDE proteins triggers a chain of events that result in the apoptosis of cancerous and precancerous cells, but not normal ones. Cell Pathways researchers recently reported (Cancer Research July 1, 2000) 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 activation of cGMP-dependent protein kinase (PKG). Increased PKG activity in cancer cells forces the degradation of beta-catenin, an important regulatory protein that accumulates in neoplastic cells, thus triggering cell death by apoptosis through well-studied mechanisms.

"We have expanded those observations by demonstrating that, in addition to beta-catenin, PKG activation also activates another important apoptosis pathway, the JNK-1 pathway," said Dr. Weinstein. "This is an extremely important observation because it indicates that by inhibiting these cGMP PDEs, multiple downstream pathways that regulate cancer cell growth are simultaneously affected increasing the likelihood that even cancer cells with diverse mutations will be killed. Also, CP461 and CP248, which are better inhibitors of PDE5 and PDE2 than exisulind, may be more potent in activating the JNK-1 pathway and in their ability to induce apoptosis and inhibit growth of the cancer cells."

"We are very excited about the results of this study, which expand upon our earlier research findings," said Dr. Rifat Pamukcu, M.D., chief scientific officer and executive vice president of research and development at Cell Pathways, Inc. "Moreover, an independent group of investigators at the University of Missouri recently reported results of an animal study, in the September 15th issue of Cancer Research, demonstrating that the formation of precancerous intestinal polyps was significantly decreased after the triggering of this cGMP-mediated pathway. These studies, combined with our previous published research, substantially validate the use of this cGMP-dependent pathway as an important area for anti-cancer and cancer chemopreventive drug development."

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.

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," said Dr. W. Joseph Thompson, vice president of research at Cell Pathways. "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 exisulind (Aptosyn(TM)) 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. Exisulind (Aptosyn(TM)) 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, exisulind (Aptosyn(TM)) was found to reduce the rise in PSA levels in men with prostate cancer at risk of recurrence after prostatectomy. Cell Pathways is conducting additional clinical trials with exisulind (Aptosyn(TM)), 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 recently completed Phase IB safety studies with a second SAAND compound, CP461, in cancer patients. Other Cell Pathways compounds with greater cGMP PDE inhibitory and pro-apoptotic activity, such as CP248, are in preclinical development.

The research study reported in Clinical Cancer Research was funded by Cell Pathways, Inc.

Cell Pathways, Inc., headquartered in Horsham, 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 http://www.cellpathways.com.

Certain statements made herein, and oral statements made in respect hereof, constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements are those which express plan, anticipation, intent, contingency or future development and/or otherwise are not statements of historical fact. These statements are subject to risks and uncertainties, known and unknown, which could cause actual results and developments to differ materially from those expressed or implied in such statements. Such risks and uncertainties relate to, among other factors, the absence of approved products; history of operating losses; early stage of development; the costs, delays and uncertainties inherent in basic pharmaceutical research, drug development, clinical trials and the regulatory approval process, with respect to both the Company's current product candidates and its future product candidates, if any; dependence on the development and market acceptance of Aptosyn(TM) (exisulind) for one or more significant disease indications; the limitations on, or absence of, the predictive value of data obtained in laboratory tests, animal models and human clinical trials when planning additional steps in product development; the uncertainty of obtaining regulatory approval of any compound for any disease indication; the delay, uncertainty and adversity arising from the recent action of the FDA in issuing a "not approvable" letter with respect to the New Drug Application ("NDA") submitted for Aptosyn(TM) (exisulind) for the orphan drug condition of familial adenomatous polyposis, a rare disease that puts those afflicted at high risk of developing colon cancer; the uncertainty of the effect of product approval, if achieved, on the market price of the Common Stock; the timing and scope of any approval which might be received for any compound for any indication in the future; acceptance by providers of healthcare reimbursement; the validity, scope and enforceability of patents; the actions of competitors; dependence upon third parties; product liability; and the need for further financing. These and other risks are detailed in the Company's reports filed from time to time under the Securities Act of 1933 and/or the Securities Exchange Act of 1934, including the sections entitled "Business," "Risk Factors," "Management's Discussion and Analysis of Financial Condition and Results of Operations" and "Other Events" in the Company's reports on Form 10-K for the year ended December 31, 1999 and Forms 10-Q and 8-K during 2000 and in such registration statements on Form S-3 as may be filed from time to time. You are encouraged to read these filings as they are made. They are available over the Internet from the SEC in its EDGAR database. Given the uncertainties affecting pharmaceutical companies in the development stage, current and prospective investors are cautioned not to place undue reliance on any such forward-looking statements, any of which may turn out to be wrong due to inaccurate assumptions, unknown risks, uncertainties or other factors. No forward-looking statement can be guaranteed; actual future results may vary materially. Both forward-looking statements and statements of historic fact must be understood in the context of the risks referred to above which characterize the Company's development stage business. The Company undertakes no obligation to update or revise the statements made herein or the factors which may relate thereto.