HORSHAM, PA (April 3, 2000) -- Scientists from Cell Pathways, Inc. (Nasdaq: CLPA) and their collaborators are presenting new laboratory findings on the novel mechanism of action and anti-cancer activity of the company's selective apoptotic anti-neoplastic drugs (SAANDs) at the annual meeting of the American Association for Cancer Research (AACR) this week in San Francisco. The company's lead drug, Aptosyn (exisulind), and other SAANDs compounds selectively trigger programmed cell death, or apoptosis, in a wide variety of abnormal precancerous and cancerous cells without causing the harmful effects to normal cells associated with conventional chemotherapeutic drugs.
"Poster presentations by company scientists detail research that further demonstrates the ability of Aptosyn and other SAANDs to induce apoptosis through a novel mechanism of action," said Rifat Pamukcu, M.D., Cell Pathways' chief scientific officer and senior vice president of research and development. "Additional studies presented by our collaborators at the Fox Chase Cancer Center and University of Colorado, as well as others, are now tying the SAANDs' upstream effect into other well-known downstream regulators of apoptosis: beta-catenin, Jun kinase and Erk. These downstream regulators are thought to play an important role in the development of precancerous lesions and ultimately cancer. Combining these findings with the broad pro-apoptotic activity seen in preclinical testing across a large number of cancers, and clinical results with Aptosyn in patients with Familial Adenomatous Polyposis (FAP) as well as prostate cancer, we believe that SAANDs target an early, common event in the development of a significant number of cancers."
SAANDs Effect on cGMP Phosphodiesterase
Cell Pathways' research has previously demonstrated that Aptosyn and other SAANDs induce apoptosis in abnormally growing cells by a mechanism involving the inhibition of a novel expression of cyclic GMP phosphodiesterase (cGMP-PDE). As inhibition of cGMP-PDE results in an increase in intracellular cGMP, the company's scientists studied the role of cGMP in apoptosis pathways via cGMP-dependant protein kinase (PKG).
"We found that Aptosyn activates PKG in colon cancer cells, not directly, but by blocking of cGMP-PDE, an enzyme which degrades cGMP. Cyclic GMP is a known activator of PKG," said W. Joseph Thompson, Ph.D., vice president of research at Cell Pathways. "We believe that a sustained rise in cGMP levels, in response to outside signals telling the cell that it is time to die, is blunted by high cGMP-PDE activity in neoplastic cells. If cGMP does not rise, PKG is not activated and the pathway culminating in apoptosis is blocked."
Company scientists also reported new research studying cancer cell responses to cGMP-PDE inhibition by Aptosyn through relative expression of various PDE families. Specifically, they noted that Aptosyn induced the expression of PDE2 by 250% as early as four hours after exposure to the drug and reduced the expression of PDE5 by 50% after 48 hours, with no effect on the other eight families of PDE enzymes.
"It appears from these studies that the cancer cell may try to circumvent the effect of the drug by increasing the production of PDE2, another cGMP phosphodiesterase," said Dr. Pamukcu. "However, we have found that Aptosyn blocks the activity of PDE2. As a result, cancer cells cannot escape the pro-apoptotic increase in cGMP resulting from treatment with Aptosyn."
Effect of Aptosyn® on Downstream Apoptotic Mechanisms
Dr. Margie Clapper at Fox Chase Cancer Center also presented research suggesting Aptosyn's chemoprevention of precancerous colonic polyps in patients with FAP may be due in part to the drug's ability to restore downstream apoptotic signaling to a mutant APC pathway. FAP is caused by a defect in the APC gene that leads to a mutant form of the APC protein. This mutant protein alters the interaction among beta-catenin, GSK-3 and Tcf-4. The result of this altered interaction is that the level of free beta-catenin in cells harboring the mutation is increased. This increase is thought to inhibit apoptosis and possibly stimulate cell proliferation. Thus, the loss of the normal function of the APC protein leads to loss of cellular growth control in patients with FAP. Conversely, a decrease in free beta-catenin levels in APC mutated cells, as seen following Aptosyn treatment, is associated with increased apoptosis.
"Identification of agents, like Aptosyn, which can modulate the level and cellular distribution of beta-catenin, represent a promising strategy for the prevention of not only hereditary and sporadic colon cancer, but also other cancers where the involvement of mutant APC has been implicated," said Dr. Clapper. "The additional pro-apoptotic effects of Aptosyn on downstream regulators of apoptosis, Jun Kinase and Erk, may also contribute to the broad anti-neoplastic activity of the SAANDs."
Aptosyn (exisulind) is the first product candidate from a novel class of compounds under development by Cell Pathways, called Selective Apoptotic Anti-Neoplastic Drugs (SAANDS). SAANDS inhibit cyclic GMP phosphodiesterase and selectively induce apoptosis (programmed cell death) in abnormally growing precancerous and cancerous cells. Because SAANDs do not induce apoptosis in normal cells, they do not produce the serious side effects normally associated with traditional chemotherapeutic agents. They also do not inhibit cyclooxygenase (COX I or COX II) and have not exhibited the gastric and renal toxicities reported to be associated with non-steroidal anti-inflammatory drugs (NSAIDs), including the COX II inhibitors. A New Drug Application for Aptosyn as a treatment for patients with familial adenomatous polyposis, a precancerous condition that often leads to colon cancer, is currently under review by the U.S. Food and Drug Agency (FDA). The compound is also undergoing further clinical evaluation in a variety of additional precancer and cancer indications.
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.
Note to Editors
The specific AACR abstracts discussed in this press release include AACR Publishing IDs 374, 1100, and 3149. Other AACR presentations with ID numbers 3151 and 5435 may also be of interest, as they discuss studies on the apoptotic effect of sulindac sulfone, another chemical name for exisulind.
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 development of Aptosyn exisulind; 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, including uncertainty of approval of the New Drug Application submitted for Aptosyn (exisulind) for familial adenomatous polyposis (a rare disease that puts those afflicted at high risk of developing colon cancer), whether in connection with the adequacy of the data generated in the clinical trials of Aptosyn (exisulind) or otherwise; 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, Form 10-Q for each of the first three quarters of 1999, Form 8-K in the month of August 1999, and Form S-3 filed in December 1999. Given these uncertainties, 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. The Company undertakes no obligation to update or revise the statements made herein or the factors which may relate thereto.