Preclinical evaluation of the third-generation, bi-steric mechanistic target of rapamycin complex 1-selective inhibitor RMC-6272 in NF2-deficient models.

Background: NF2-associated meningiomas are progressive, highly morbid, and nonresponsive to chemotherapies, highlighting the need for improved treatments. We have established aberrant activation of the mechanistic target of rapamycin (mTOR) signaling in NF2-deficient tumors, leading to clinical trials with first- and second-generation mTOR inhibitors. However, results have been mixed, showing stabilized tumor growth without shrinkage offset by adverse side effects. To address these limitations, here we explored the potential of third-generation, bi-steric mTOR complex 1 (mTORC1) inhibitors using the preclinical tool compound RMC-6272. Methods: Employing human NF2-deficient meningioma lines, we compared mTOR inhibitors rapamycin (first-generation), INK128 (second-generation), and RMC-6272 (third-generation) using in vitro dose-response testing, cell-cycle analysis, and immunoblotting. Furthermore, the efficacy of RMC-6272 was assessed in NF2-null 3D-spheroid meningioma models, and its in vivo potential was evaluated in 2 orthotopic meningioma mouse models. Results: Treatment of meningioma cells revealed that, unlike rapamycin, RMC-6272 demonstrated superior growth inhibitory effects, cell-cycle arrest, and complete inhibition of phosphorylated 4E-BP1 (mTORC1 readout). Moreover, RMC-6272 had a longer retention time than INK128 and inhibited the expression of several eIF4E-sensitive targets on the protein level. RMC-6272 treatment of NF2 spheroids showed significant shrinkage in size as well as reduced proliferation. Furthermore, in vivo studies in mice revealed effective blockage of meningioma growth by RMC-6272, compared with vehicle controls. Conclusions: Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.

Body focus and cardioceptive accuracy are not associated with physical performance and perceived fatigue in a sample of individuals with regular physical activity.

It is often assumed that distracting attention from unpleasant body sensations evoked by physical exertion can alleviate perceived fatigue and increase physical performance. Also, the higher acuity of perception of heartbeats was associated with less physical performance in one study with sedentary participants. The current study was designed to shed more light on these associations. In a within-subject experiment, 98 students characterized by regular physical activity completed the Schandry-task assessing cardioceptive accuracy and cycled for 15 min on a bicycle ergometer at a convenient pace, listening to their own breathing through a headset (internal attention condition) or to distracting noises (external attention condition). Physical performance (number of pedal turns), physical exertion (heart rate), and self-reported fatigue were assessed for both tasks. Frequentist and Bayesian analyses showed no impact of the direction of attention and cardioceptive accuracy on physical performance, exertion, and perceived fatigue. In fact, the lack of association between cardioceptive accuracy and performance and perceived fatigue was more probable than the alternative hypothesis. Impact of distraction and cardioceptive accuracy on subjective and objective characteristics of physical exercise in the aerobic domain may be different for physically active and sedentary individuals. Future research in this area should systematically explore the background of these differences.