“An ideal anti-cancer agent would halt the uncontrolled growth or proliferation of abnormal cells while at the same time selectively promoting apoptosis or programmed cell death,” said Rifat Pamukcu, M.D., chief scientific officer of Cell Pathways, Inc. “This research demonstrates that CP461 acts against cancer cells selectively through both those mechanisms in unison, not only in cancer cells grown in the laboratory but also in a relevant animal model of human NSCLC. Moreover, this compound prevents new blood vessel formation (anti-angiogenic activity) in preclinical models even in the presence of growth stimulators like VEGF. Preventing such new blood vessel formation is also an anti-proliferative effect with potential utility in cancer treatment.”
Cell Pathways is currently conducting Phase I/II clinical investigations with CP461 as a single-agent in a variety of cancer indications. Ongoing studies include clinical trials in chronic lymphocytic leukemia, hormone-refractory prostate cancer and advanced kidney cancer.
Potential Single-Agent Activity in Lung Cancer
In a study comparing the activity of CP461 alone with that of docetaxel in rats implanted with human A459 non-small cell lung cells, groups of 12 animals each received either 10, 25, 50 or 100mg/kg daily of oral CP461 for 10 weeks, 2.5 mg/kg of once-weekly intravenous docetaxel for six consecutive weeks, or placebo. Mean survival times for rats receiving CP461 monotherapy at 25-100 mg/kg doses were statistically significant (p < 0.02, 0.002 and 0.005, respectively) compared to control rats. Also, mean survival times in rats receiving docetaxel were significantly greater than the control rats (p = 0.05). There was no statistical difference in rats receiving CP461 versus docetaxel therapy. Moreover, in addition to higher apoptosis indices, the CP461-treated rats had dose-dependent reductions in proliferation rates as measured by immunohistochemical studies of the NSCLC tumors.
Cell Pathways’ researchers also investigated the mechanisms by which CP461 achieved its anti-cancer effects in the cells used for lung tumor formation, A459 cells. PDE5 and PDE1, the molecular targets of CP461, were higher in lung tissue containing A459 NSCLC cells compared to normal bronchial epithelial and alveolar cells. The researchers also found that CP461 treatment increased both the number of apoptotic cells and the percentage of cells blocked at the G2/M stage of the cell cycle (thus preventing cell division).
“This is the first demonstration of the anti-proliferative effect of CP461 combined with selective apoptotic activity in an animal model of lung cancer,” said Dr. Pamukcu. “These results suggest a strong rationale for the clinical investigation of CP461 as a single-agent in cancer.”
CP461 Disrupts Ability of Cells to Divide
Previous research has shown that CP461 and other SAANDs induce apoptosis in cancer cells. A separate presentation on CP461 provides insight on the mechanism by which the drug achieves its additional anti-proliferative effect. At AACR, Cell Pathways’ scientists and collaborators at Columbia University College of Physicians and Surgeons report that multiple cancer cell lines treated with CP461 become blocked in the cell cycle at prometaphase, preventing their subsequent division and selectively forcing them to undergo apoptosis. Moreover, in the research presented, CP461 did not trigger apoptosis in normal human foreskin fibroblasts or normal human mammary epithelial cells (HMEC).
“Studies showed that CP461 does not directly bind to tubulin or affect its polymerization/ depolymerization properties like some types of conventional chemotherapeutic agents, but instead disrupts microtubule organization and proper spindle formation – cellular structures essential to the process of cell division,” said W. Joseph Thompson, Ph.D., Cell Pathways’ vice president, research and discovery. “This prevents the chromosomes from properly aligning and blocks mitosis.” He noted that the effects of CP461 on chromosome alignment and spindle formation occur at lower concentrations for cancerous over normal cells in these studies.
Target Validation of PDE5 Control of Apoptosis and Cell Proliferation
Prior studies have demonstrated the importance of cGMP phosphodiesterases as targets for Cell Pathways’ SAANDs compounds. New research directed toward target validation presented at AACR used antisense oligonucleotides to create cells in culture with very low PDE5. PDE5 may act as an important modulator of cell cycle progression, notably during the G2/M phase of the cell cycle leading to cell division. Cell Pathways’ researchers and collaborators at the University of South Alabama College of Medicine, demonstrated a positive correlation between PDE5 suppression, increased cGMP content and prolonged doubling times in human colon carcinoma cells stably transfected with the PDE5 antisense.
“In addition to showing much higher rates of apoptosis, the antisense-transfected cells with low PDE5 and high cGMP exhibited a progression time of up to 72 hours versus vector control cells, which progressed to G2/M phase within 24 hours,” said Dr. Thompson. “The antisense inhibition of PDE5 has revealed a novel role for this enzyme to regulate progression during the G2/M phase of the cell cycle. The altered progression during G2/M also appears to enhance the sensitivity of the cancer cells to triggering of the PKG-dependent apoptotic mechanism.”
In related studies also being presented at AACR, Cell Pathways’ collaborators at Columbia University College of Physicians and Surgeons demonstrated cells transfected with constitutively active PKG decreased beta catenin and increased apoptosis in colon tumor cells. Alternatively, cells that stably expressed a dominant negative form of PKG (an inactive form of PKG that dominates over the normal molecule without toxicity to the cell) grew more rapidly and were more resistant to apoptosis induction by SAANDs such as Cell Pathways’ first-generation SAAND, exisulind (Aptosyn®).
“These intact cell data provide substantive in vitro evidence that our proposed mechanism of regulation by SAANDs – cGMP PDE governing cGMP levels governing PKG -- operates in colon tumor cells,” commented Dr. Thompson.
About Cell Pathways
Cell Pathways, Inc., headquartered in Horsham, Pennsylvania, is a development stage pharmaceutical company focused on the research and development of novel and unique medications to treat and prevent cancer, the commercialization of these compounds and the marketing and selling of oncology-related products made by others. For additional information on Cell Pathways, Inc., visit the Company’s web site at http://www.cellpathways.com.
Editors Note: Aptosyn® is a registered trademark of Cell Pathways, Inc. and Taxotere® is a registered trademark of Aventis Pharmaceuticals Inc.
Certain statements in 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: early stage of development; the costs, delays and uncertainties inherent in scientific research, basic pharmaceutical research, drug development, clinical trials and the regulatory approval process, with respect to both our current product candidates and our future product candidates, if any; 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; uncertainty that additional studies, if any, may not be positive; uncertainty of obtaining regulatory approval of any compound for any disease indication whether due to adequacy of the development program, changing regulatory requirements or otherwise; the absence of approved products; history of operating losses and the need for further financing; dependence on the development, regulatory approval and market acceptance of one or more of our product candidates for one or more significant disease indications; the risk that the U.S. Food and Drug Administration (“FDA”) will stop or further delay the Phase III lung cancer study or any other study as a result of safety or otherwise; the risk that the Company does not conduct the clinical studies it may have planned to conduct or does not pursue development plans it may have planned to pursue; the risk that clinical studies do not result in the safety and efficacy necessary to obtain regulatory approvals; the risks of conducting clinical trials, including the risk of conducting clinical trials of our drugs in combination with other drug therapies; the commercial risk and risk of liability in marketing and selling Gelclair™ Concentrated Oral Gel; the commercial risk and risk of liability in providing marketing services promoting NilandronÒ (nilutamide) manufactured by Aventis Pharmaceuticals, Inc.; the risk that the Company may enter into, or may fail to enter into, licensing, partnership or collaborative arrangements or strategic alliances which accord to other companies rights with respect to one or more Company compounds, technologies or programs or in which the Company acquires new rights and obligations; the volatility of the market price of our Common Stock; our ability to sell securities registered under the shelf registration statement; acceptance of any product candidates by physicians and providers of healthcare reimbursement; the actions of competitors; the pace of technological changes in the biopharmaceutical industry; dependence upon third parties; the validity, scope and enforceability of patents; the risk of pending or future class action securities litigation; potential product liability claims; and availability and adequacy of insurance. These and other risks are detailed in our reports filed from time to time under the Securities Act and/or the Securities Exchange Act, including the sections entitled “Business,” “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and “Other Events” in our annual reports on Form 10-K, quarterly reports on Form 10-Q and periodic reports on Form 8-K and in such registration statements on Form S-3 as we may file 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 at http://www.sec.gov and from the Company. Given the uncertainties affecting pharmaceutical companies in the development stage, you 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 our development stage business. We undertake no obligation to update or revise the statements made herein or the risk factors that may relate thereto.
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