SAN FRANCISCOA novel experimental compound, AP23573, can induce potent tumor shrinkage by inhibiting nutrient uptake in cancer cells and starving them, according to a presentation at the 93rd Annual Meeting of the American Association for Cancer Research (abstract LB95). Mice with implanted tumors treated with AP23573 for 5 days at low doses (0.3 mg/kg/d) showed sustained reduction in tumor volumea 46% reduction in treated animals vs a 150% increase in untreated animals.
"This is a new approach to cancer treatment that may be applicable to a range of tumor types and may be less toxic than current standard chemotherapies," said Tim Clackson, PhD, lead researcher and senior vice president, Science and Technology, ARIAD Pharmaceuticals, Cambridge, Massachusetts. "It fools cells into thinking that they are in a starvation environment, and they shut down."
In their first studies of AP23573, Dr. Clackson and his colleagues added it to PTEN-deficient prostate cancer and brain tumor cells in culture. The cells soon stopped growing and dividing. The researchers then grafted human brain tumor cells into mice with defective immune systems. They treated the mice with low-dose injections of the compound for 5 days, followed by 9 days off and another 5 days of treatment. Tumor volume shrank 46% in treated mice whether the drug was given orally or in daily or weekly injections.
In the mouse study, the antitumor effects lasted for 2 weeks beyond the treatment period. The antitumor action of AP23573 can be reinitiated with repeated treatments, resulting in continued reduction of tumor volume.
AP23573 can also be given in intermittent dosing that causes less immunosuppression than current drug-dosing regimens. Such dosing may be appropriate for clinical use, Dr. Clackson said.
The compound AP23573 targets the mTOR protein, which has been shown to play a pivotal role in coordinating the uptake of nutrients in cells for growth and cell division, Dr. Clackson said.
"It is like a master switch that detects the presence of nutrients and helps make the decision whether cells should expand or grow. In the absence of nutrients, the mTOR switch is turned off," he said. The AP23573 compound blocks the action of mTOR, inducing a dramatic metabolic arrest that mimics the cellular response to starvation.