Hi all, great news !
There are 55 studies ongoing for MND worldwide. Seems only two are mTOR based. Rapamycin the other in a Phase 2 in Italy.
Research shows that reduced p-RPS6KB1 & p-EIF4EBP1 are integral to MND . Remember there are different types of MND , but PAA may be on track to counter SOD1 but not Bulbar from what I can see.
Below is a precis of some studies to explain p-RPS6KB1 & p-EIF4EBP1.
As a substrate and major effector of the mammalian target of rapamycin complex 1 (mTORC1), the biological functions of ribosomal protein S6 kinase (S6K) which the PAA announcement calls p-RPS6KB1 have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, and protein synthesis.
Beyond controlling cell size, S6K simultaneously plays crucial roles in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals. Thus, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for S6K and shed light on S6K as a potential therapeutic target for cancers.
Facts
S6K canonically governs cell size by facilitating mRNA transcription, splicing, and protein synthesis.S6K also plays pivotal role in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals.Diverse stimuli and upstream regulators modulate S6K kinase activity.Targeting S6K individually or in combination is a promising strategy for cancer therapies.How can S6K and its upstream kinases be targeted together to overcome negative feedback regulation?IntroductionThe balance and tight control of cell size and cell numbers are two essential aspects for organ formation biologically and tumor growth pathologically. Of note, cell size has been found to be tightly controlled by mTORC1 by phosphorylating its diverse downstream substrates [1], in particular the S6K kinase, whereas cell numbers have been preliminarily dictated by the Hippo pathway by modulating the key regulator yes-associated protein 1 (YAP) [2]. Interestingly, the cross talk between these two pathways has been recently reported, highlighting the notion that disruption of their balance will result in tumorigenesis
As one of the most well-established mTORC1 downstream effectors, S6K is directly phosphorylated by mTORC1 upon diverse stimuli, such as amino acids [6] and insulin [7]. Many studies have indicated that amino acid availability and insulin stimulation are both required for mTORC1 activation ].
Subsequently, activated mTORC1 phosphorylates S6K and 4E-binding protein 1 (4E-BP1), leading to protein synthesis, cell cycle progression, and glucose homeostasis [9, 10]. Consistent with these findings, dysregulation of PI3K-AKT-mTOR-S6K components is predominantly linked to a large proportion of human malignancies, including breast, kidney, prostate, and liver cancers [11,12,13]. More interestingly, activation of the mTORC1-S6K pathway attenuates insulin-stimulated AKT activity in certain tumors through negative feedback phosphorylation of specific substrates [14].Beyond controlling cell size, S6K has recently attracted more attention due to its important roles in cellular homeostasis [15, 16].
Thus, whether and how other stimuli, except via mTORC1, regulate S6K and how S6K plays distinct roles in addition to controlling cell size by targeting other downstream substrates are not well summarized. Hence, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, and clinical relevance for S6K and highlight employing S6K inhibitors for precision cancer therapy.
Recent studies have suggested that plasma p70S6K is a reliable index for the monitoring of patient response to mTOR inhibitors.
I had a retrospective review of Rapamycin and next paragraph is important.
Therefore, it appears that prolonged rapamycin treatment renders mTORC1 to be rapamycin-resistant specifically toward 4E-BP1, which controls global cap-dependent translation.
So it's exciting clinical news.It could also flow onto Parkinson's as this study shows" 4E-BP1 protects neurones from misfolded protein stress and Parkinson's disease toxicity by inducing the mitochondrial unfolded protein response" Somasish Ghosh 2020
He also did this study.
Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity.
Also , I sent a thankyou email to Dr Mollard, without him we may not have a conditional cure for MND.
Also it's hard to cross reference assay studies on p-RPS6KB1 & p-EIF4EBP1 as they are only related to mTORC1 inhibitors. The other 53 studies don't have it as it's specific to ourselves and Rapamycin. We certainly are in a niche zone.
Kpax
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