#125

An interesting new study where they dosed everolimus in women (with breast cancer) for 1 year at the dose of 10mg/day.

I find this study interesting not because of the outcome, but for the dosing level and side effects. If anyone can get this full study PDF please post it.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer

In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy.

Methods: Patients were randomly assigned 1:1 to physician’s choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC.

Results: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%).

Conclusion: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Paywalled Paper:

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#126

I know that this canker sore wasn’t caused by Rapamycin. It was caused by my accidentally biting my lip while eating. However, the canker sore takes a lot longer to heal on Rapamycin and typically gets bigger than before.

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#127

As long as the FDA / Drug manufacturers leadership’s financial lives are connected at the hip, you will see no long term human trials.

#128

I don’t think its anything so nefarious, the FDA has never actually run clinical trials, especially on generic drugs.

The issue is much larger, there is no financial incentive for any corporation to run an expensive clinical trial for a drug that has no patent-protection.

So, the only group that would reasonably run a clinical trial on a drug with no patent protection is a non-profit, and I don’t know of any nonprofit groups that have ever run a clinical trial such as this, let alone in a new field like longevity drugs. Hevolution (with a budget of up to $1 Billion/yr) is the only group I know of that could reasonably fund such a trial, and sadly, no interest as yet.

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#130

Interesting to speculate how you could achieve that in humans. 15mg w/gfj every 5 days?

#131

Continuing on this speculation… I would tend to avoid GFJ when testing new dosing protocols, simply because you really have no idea what the effect would be from one batch of GFJ or eating a grapefruit, to another (unless you are testing after each dose). For simplicity and repeatability, I’d just go for the tablets alone. Then at least you have a clear baseline to work from, for example if 25mg (from 25 X 1mg sirolimus tablets) raises your trough levels to Xng/ml after 5 days, you at least then have a clear dose/response relationship that you know is repeatable.

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#132

We are still waiting on the results of the Pearl Study of Rapa out of San Diego. Half of the participants are on Rapa and half on a Placebo.

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#133

If enhancing human longevity and healthspan is one aim of certain non-profits, then why do you think we don’t see more billionaire philanthropists funding studies on affordable and accessible treatments and medicines like rapamycin? At least a few of them seem to have more than a passing interest.

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#134

Or, use a consistent form of grapefruit with every dose. I use these cheap grapefruit peel pills to increase rapamycin bioavailability:

https://www.swansonvitamins.com/p/swanson-premium-full-spectrum-grapefruit-peel-600-mg-120-caps

10 pills an hour before rapa seems to consistently raise my effective dose by at least a factor of two, although I have no labs to support this.

#135

How do you know without labs?

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#136

I don’t. “Seems to” is key here. I have experience taking biweekly doses of 12mg, and also 5mg weekly. Taking 5mg with these pills feels like 12mg+ in terms of the mood impacts, exercise recovery, mouth sores, etc.

Yes, I could be wrong.

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#137

@Jjazz Thanks for the further context

#138

You are redefining clinical significance (in my opinion) to be “medically significant in your opinion.”

Antibody titers may be extremely important but they don’t have “a real genuine, palpable, noticeable effect on daily life” whereas, say, pain and shortness of breath upon exertion does. So in the common parlance antibody titers are not clinically significant (although they may be medically important!).

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#139

The following question came up reading other posts in this topic:

  • are peak levels most important to reach our goal of longevity
    – do they need to be above a given value to reach and bind to the target (mTOR1)
    – do they need to be below a given value to avoid important adverse effects
    – will anything above certain values/doses just go down the drain
  • are through levels most important (absent the drug holidays)
    – do they need to be above a given value to create the effect
    – do they need to be below a given value to avoid important adverse effects

or is it the AUC (area under the curve) that is most important.
concentrations either free rapamycin or total (including protein bound fraction)

high peaks can be avoided by spreading intake over multiple doses, and still getting similar or higher through levels depending on the dosing interval…

I would be inclined to go with @RapAdmin and avoid drug interactions as much as possible especially GFJ.

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#140

It’s possible that Acarbose and 17a estradiol help a bit with mTORC2 but I doubt they will help much. I’ve seen many anecdotes of people having signs of mTORC2 inhibition (like elevated lipids and higher blood glucose) despite the fact that they are taking acarbose also.

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#141

This does seem like something we all want to test and see the response on our own bodies. It would be interesting to test (blood sugars and lipids) on a given dose of weekly rapamycin (after you’ve been taking that level/dose for a few weeks), then retest with dosing levels of acarbose - 50mg/meal, 100mg/meal, 200mg/meal, etc. I wonder if there is a good dose reponse relationship with acarbose and mTORC2 activation. The human dose equivalent of acarbose used in the ITP trials is considerably higher than the 100mg per meal that I think is the typical recommended dose of Acarbose for blood glucose control.

Fasting also helps with mTORC2 activation, so perhaps different levels of fasting is another variable we should consider and test.

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#142

Thanks @Olafurpall

Do you have a sense of the dosing sizes of the rapa vs acarbose in those contexts?

My other question is, how strong is the relationship between mTORC2 being the driver of those two issues?
For instance, this thread here suggests that rapa might increase glucose in ways that are independent from mTORC2 via less + damage to beta cells. My CGM data while on Rapamycin - #34 by Neo

#143

These threads are reasonable starting points to investigate the mTORC2 inhibition side effect theories (see also the links to pubs within the twitter posts):

and related:

mTORC2 takes the longevity stAGE

https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25294787/

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#144

Thx for share of that last paper - found this very interesting:

We have determined that mTORC2 is required for the normal lifespan of male, but not female, mice [6].

Chronic treatment with rapamycin, which inhibits both mTORC1 and mTORC2, is more beneficial to females than males, which may be due to the negative influence of mTORC2 inhibition on male lifespan.

Sex-based side effects may be seen during the clinical use of mTOR kinase inhibitors for cancer treatment.

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#145

IMO: The way to easily increase mTORC2 is to upregulate mTORC1 the following day after taking rapamycin by exercising and eating proteins. Amino acids are a positive regulator of mTORC1 activation. This is what I do to modulate mTORC1.

When amino acids are low or become limiting, mTORC1 activity declines.

“Since rapamycin allosterically inhibits mTORC1 but not mTORC2, most of the studies on mTOR pertain to mTORC1.”

“mTORC2 activation is enhanced by withdrawal of amino acids (e.g., glutamine) and by glucose starvation in the presence of serum”

‘Inhibiting mTOR by rapamycin also increases the expression of growth factor receptors such as IGF1R, thus further enhancing PI3K/mTORC2 signaling (124). Elevated mTORC2 signaling feeds back to dampen insulin signals via mTORC2-mediated regulation of IRS-1 turnover, thereby subsequently downregulating mTORC2 (125).’

“An allosteric effect is when a change to one part of a molecule or enzyme (such as effector binding) structurally changes another part of the molecule or enzyme (such as the active site of an enzyme).”

The bottom line is; that we need to find out how much inhibiting mTORC1 affects mTORC2. We are assuming that slow wound healing, mouth sores, etc. after taking rapamycin represents a significant suppression of mTORC2. The anecdotal fact that I never catch anything belies this.

Regulation and metabolic functions of mTORC1 and mTORC2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424549/

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