Tina[a]
16.11.2005
Rapamycin Analog AP23573 Crosses Blood-Brain Barrier and Targets Glioma: Presented at AACR-NCI-EORTC
By Maggie Schwarz
In a dose escalation study performed in patients undergoing debulking surgery for recurrent malignant glioma, the mTOR inhibitor AP23573 showed great promise.
AP23573 is a rapamycin analog that inhibits mammalian target of rapamycin (mTOR). The drug has been shown to cross the blood-brain barrier and induce tumor regression in animal models.
The phase 1 study of AP23573 was presented here at the International Conference on Molecular Targets and Cancer Therapeutics International Conference: Discovery, Biology, and Clinical Applications. The conference is organized by the American Association for Cancer Research - National Cancer Institute - European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC).
David A, Reardon, MD, Associate Professor, Division of Neurosurgery, Clinical Director, Medical Research, Duke University Medical Center, Durham, North Carolina, United States, presented the findings during a presentation on November 15th.
The open-label, dose escalation trial was performed to determine the maximum tolerated dose of AP23573 and whether it crosses the blood-brain barrier and inhibits signaling in target glioma tumors.
The researches characterized the pharmacokinetic profile of AP23573 among patients not receiving enzyme-inducing anticonvulsants, as well as potential pharmacodynamic markers of the drug´s action in the tumor and in peripheral blood mononuclear cells.
They assessed inhibition of mTOR signaling before and after debulking surgery.
Results show that mTOR signaling, as documented by Phospho S6 levels on immunostaining, were dramatically reduced in the glioma tissue in six of eight patients for whom data were available.
A small portion of patients receiving corticosteroids and not receiving enzyme-inducing anticonvulsants exhibited similar pharmacokinetics to those observed in the broader patient population treated with AP23573.
Inclusion of the surgical component limited enrollment and led to early discontinuations due to surgical complications and comorbid conditions, according to the researchers.
Insufficient data were available to assess the efficacy of AP23573 in the glioma population, yet the agent was demonstrated to have crossed the blood-brain barrier and reduced mTOR signaling in the tumor, they said.
"Many agents are not effectively delivered into the brain." Dr. Reardon remarked. He said that advances are being made in the treatment of this difficult-to-treat condition. He and co-investigators are now planning to move forward with an expanded, phase 2 study, he said.
[Presentation title: A Phase I Trial of AP23573, a Novel mTOR Inhibitor, in Patients (Pts) with Recurrent Malignant Glioma. Abstract A195]