Novel Inhibitor of mTOR Shrinks Cancers by Starving Them

SAN FRANCISCO—A novel experimental compound, AP23573, can induce potenttumor shrinkage by inhibiting nutrient uptake in cancer cells and starving them,according to a presentation at the 93rd Annual Meeting of the AmericanAssociation for Cancer Research (abstract LB95). Mice with implanted tumorstreated with AP23573 for 5 days at low doses (0.3 mg/kg/d) showed sustainedreduction 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.

Wide Variety of Tumors

Tumors with a mutated tumor suppressor gene called PTEN are especially sensitive to mTOR inhibition. Mutations and deletions of PTEN are common in a variety of cancers, including pancreatic and ovarian cancers, melanomas, leukemias, and gliomas, Dr. Clackson said. So AP23573 could possibly be used to treat a wide variety of tumor types.

The drug is now undergoing studies required for regulatory filings to initiate clinical trials. "We hope to file the IND [investigational new drug] application by the end of this calendar year," Dr. Clackson said.

In some studies, the ability of AP23573 to shrink tumors exceeded that of rapamycin, its chemical cousin, Dr. Clackson said. AP23573, an analog of rapamycin, was synthesized using structure-based drug design. Unlike rapamycin, it can be given intravenously or orally. "The availability of an orally active mTOR inhibitor represents an important advance in the development of this promising new class of antitumor agents that function by inducing tumor starvation," he concluded.