Superior cancer preventive efficacy of low versus high dose of mTOR inhibitor in a mouse model of prostate cancer

// Marina P. Antoch 1 , Michelle Wrobel 2 , Bryan Gillard 1 , Karen K. Kuropatwinski 1 , Ilia Toshkov 2 , Anatoli S. Gleiberman 2 , Ellen Karasik 1 , Michael T. Moser 1 , Barbara A. Foster 1 , Ekaterina L. Andrianova 2 , Olga V. Chernova 2 and Andrei V. Gudkov 3 1 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 2 Everon Biosciences, Inc., Buffalo, NY, USA 3 Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA Correspondence to: Marina P. Antoch, email: marina.antoch@roswellpark.org Keywords: prostate cancer; rapamycin; prevention; mTOR; PTEN Received: February 21, 2020     Accepted: March 14, 2020     Published: April 14, 2020 ABSTRACT The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy. Since mTOR pathway regulation involves multiple feedback mechanisms that may be differentially activated depending on the degree of mTOR inhibition, we investigated whether rapamycin dosing could be adjusted to achieve chemopreventive efficacy without side effects. Thus, we tested the efficacy of two doses of a novel, highly bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer model (male mice with prostate epithelium-specific Pten -knockout). We found that the highest efficacy was achieved by the lowest dose of Rapatar used in the study. While both doses tested were equally effective in suppressing proliferation of prostate epithelial cells, higher dose resulted in activation of feedback circuits that reduced the drug’s tumor preventive efficacy. These results demonstrate that low doses of highly bioavailable mTOR inhibitor, Rapatar, may provide safe and effective cancer prevention.