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

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 epitheliumspecific 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.

Defining cellular population dynamics at single-cell resolution during prostate cancer progression

“…Given the widespread use of the Pten fl/fl model ( Ding et al, 2011 ; Svensson et al, 2011 ; Hsieh et al, 2012 ; Garcia et al, 2014 ; Hsieh et al, 2015 ; Ku et al, 2017 ; Allott et al, 2018 ; Antoch et al, 2020 ; Morel et al, 2021 ; Quaglia et al, 2021 ) and our new understanding of cellular dynamics in the context of disease progression, we sought to determine which cell type and context most closely correlated with human prostate cancers that went on to resist androgen deprivation therapy (ADT). To this end, we used a gene signature of ADT resistance derived from human prostate tumors prior to treatment with ADT plus the AR inhibitor enzalutamide, in a neoadjuvant setting ( Figure 4A ) (NCT02430480) ( Karzai et al, 2021 ; Wilkinson et al, 2021 ; Ku et al, 2021 ).…”

Defining cellular population dynamics at single cell resolution during prostate cancer progression

“…Given the widespread use of the Pten fl/fl model (Ding et al, 2011; Svensson et al, 2011; Hsieh et al, 2012; Garcia et al, 2014; Hsieh et al, 2015; Ku et al, 2017; Allott et al, 2018; Antoch et al, 2020; Morel et al, 2021; Quaglia et al, 2021) and our new understanding of cellular dynamics in the context of disease progression, we sought to determine which cell type and context most closely correlated with human prostate cancers that went on to resist androgen deprivation therapy (ADT). To this end we used a gene signature of ADT resistance derived from prostate tumors prior to treatment with ADT plus the AR inhibitor enzalutamide, in a neoadjuvant setting (Fig.…”

Pharmacological inhibition of S6K1 rescues synaptic deficits and attenuates seizures and depression in chronic epileptic rats

“…In summary, we elucidated for the first time that S6K1 has antiepileptic and antidepressive effects in epilepsy and successfully restores low‐frequency power in epileptic rats, providing more evidence for its potential role in the central nervous system. In particular, ongoing phase III clinical trials of S6K1 inhibitors in non‐CNS diseases make them an encouraging potential therapeutic target for CNS diseases, especially when the clinical availability of mTOR inhibitors is limited by a multitude of side effects 48,49 …”