Targeting mTOR

mTOR is a protein with the rather whimsical name "mammalian target of rapamycin".  Rapamycin (aka Sirolimus) is a bacteria discovered on Rapa Nui [Easter Island].  It inhibits mTOR.  So the protein is named after the drug that inhibits it!

mTOR is involved with cancer cell survival, proliferation & metastasis.  It's an excellent target.

Everolimus is a derivative of Sirolimus.  The results of a phase 2 clinical trial of Everolimus plus Bicalutamide (Casodex) for CRPC has just been published (see below).

"The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway."

Hence the rationale for combining Everolimus with Casodex, although I wonder why the people at Davis didn't choose Xtandi.

A "PSA response" was set as >=30%, rather than the usual 50%, although 62.5% did beat 50%.  75% met the 30% target.

"The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation."

However: "A substantial number of patients experienced everolimus-related toxicity."

Which brings to mind PCa research on mTOR using natural substances.  One doesn't expect the dramatic benefits of Everolimus from these substances, but there may be some benefit, & it will likely come without toxicity.

With inhibition of mTOR, we are usually talking about inhibition of the PI3K/Akt/mTOR signaling pathway. Activation of this pathway is implicated in treatment (drug or radiation) resistance.  Attacking PI3K/Akt/mTOR might prolong the effectiveness of a particular therapy.

[1]  Ursolic Acid. ncbi.nlm.nih.gov/pubmed/265...

Ursolic acid [UA] is one of the major constituents of holy basil, which has long been used in Ayurvedic medicine:

swansonvitamins.com/new-cha...

It is a polyphenol (actually, a pentacyclic triterpenoid), & there are currently 31 PubMed hits for <prostate "ursolic acid">. 

"Our study demonstrates that UA not only inhibits cell growth but also induces apoptosis through modulation of the PI3K/Akt/mTOR pathway in human prostate cancer cells. We suggest that UA may be a new chemotherapeutic candidate against prostate cancer."

[2]  Resveratrol. ncbi.nlm.nih.gov/pubmed/259...

Another natural polyphenol (a stilbenoid) & one of the few such recommended by Dr. Myers:

revgenetics.com/store/p-32-...

Resveratrol "treatment ... decreases ER calcium storage and store operated calcium entry (SOCE), which induces endoplasmic reticulum (ER) stress, thereby, activating AMPK and inhibiting the AKT/mTOR pathway."

[3]  Vitamin D + Metformin. ncbi.nlm.nih.gov/pubmed/259...

"Metformin and vitamin D₃ both exhibit a strong antiproliferative action in numerous cancer cell lines, including in human prostate cancer cells. Here we showed that the combination of the two drugs had a much stronger effect on DU145 human prostate cancer cell growth than either drug alone.

This involved:  "activation of phospho-AMPK with subsequent inhibition of downstream mTOR signalling pathway"

[4]  Quercetin. ncbi.nlm.nih.gov/pubmed/230...

A common polyphenol supplement (a flavonol).  "... quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy."

[5]  Fisetin. ncbi.nlm.nih.gov/pubmed/228...

Yet another polyphenol (a flavonoid).

"... we demonstrated that fisetin acts as a dual inhibitor of the PI3K/Akt and the mTOR pathways. This is a significant finding considering the fact that mTOR is phosphorylated and its activation is more frequent in tumors with overexpression of PI3K/Akt. Dual inhibitors of PI3K/Akt and mTOR signaling have been suggested as valuable agents for treating such cancers."  In fact, mTOR is upregulated in 100% of metastases.

The Giovannucci study that started the lycopene industry identified four foods that were PCa-protective.  Three contained tomatoes; the fourth was strawberries.  The protection was likely due to fisetin.  Surprisingly, there was no interest at the time, but with 14 PCa papers since 2010, two fisetin products finally emerged - Novusetin & Cognisetin, both derived from Rhus succedanea:

swansonvitamins.com/swanson...

swansonvitamins.com/doctors...

The above polyphenols can probably be tolerated at high doses &, since polyphenols seem to be unique in their actions, there might be benefit in combining them.

-Patrick

ncbi.nlm.nih.gov/pubmed/270...

Cancer. 2016 Mar 28. doi: 10.1002/cncr.29927. [Epub ahead of print]

A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer.

Chow H1, Ghosh PM2,3,4, deVere White R4, Evans CP4, Dall'Era MA4, Yap SA4, Li Y5, Beckett LA5, Lara PN Jr1, Pan CX1,3,4.

Author information

1Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento, California.

2Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California.

3Veterans Affairs Northern California Health Care System-Mather, Mather, California.

4Department of Urology, University of California Davis, Sacramento, California.

5Department of Public Health Sciences, University of California, Davis, California.

Abstract

BACKGROUND:

The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway.

METHODS:

Patients who were eligible for this study had to have progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment included oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks. The primary endpoint was the prostate-specific antigen (PSA) response (≥30% reduction) from baseline. A sample size of 23 patients would have power of 0.8 and an α error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone.

RESULTS:

Twenty-four patients were enrolled. The mean age was 71.1 years (range, 53.0-87.0 years), the mean PSA level at study entry was 43.4 ng/dL (range, 2.5-556.9 ng/dL), and the mean length of treatment was 8 cycles (range, 1.0-23.0 cycles). Of 24 patients, 18 had a PSA response (75%; 95% confidence interval [CI], 0.53-0.90), whereas 15 (62.5%; 95% CI, 0.41-0.81) had a PSA decrease ≥50%. The median overall survival was 28 months (95% CI, 14.1-42.7 months). Fourteen patients (54%; 95% CI, 0.37-0.78) developed grade 3 (13 patients) or grade 4 (1 patient with sepsis) adverse events that were attributable to treatment.

CONCLUSIONS:

The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity. Cancer 2016. © 2016 American Cancer Society.

© 2016 American Cancer Society. 

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  • Thank you so much for going to the trouble to supply us with so much information.   It will be helpful to many. 

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