Novel Inhibitor of mTOR Shrinks Cancers by Starving Them

Novel Inhibitor of mTOR Shrinks Cancers by Starving Them

SAN FRANCISCO—A 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 volume—a 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.


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