mTOR: Gecrellin mentioned Sirolimus... - Advanced Prostate...

Advanced Prostate Cancer

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mTOR

8 years ago•2 Replies

Gecrellin mentioned Sirolimus [Rapamune, aka Rapamycin] in his recent post; it is an mTOR inhibitor.

Rapamycin was in the news today, because of a dog study [1]. Just why this anti-aging study made the front page of the NY Times is a mystery, since there is coverage elsewhere going back to 2014. Anyway, the premise is that Rapamycin at low dosage might extend the lives of dogs - & therefore, perhaps, of humans.

The only species, other than man, that develops PCa, is the canine. There would be outrage if a PCa study or any other study were to be conducted on dogs in a U.S. lab, but these were all volunteers (thanks to their owners). Of interest, is the use of a low dose, since Rapamycin can have serious side effects.

Rapamycin was named after Rapa Nui [Easter Island], where it was discovered in 1972. In humans (dogs too), it was found to inhibit a protein that was given the amusing name: mammalian target of rapamycin [mTOR].

A PubMed search on <prostate mtor> returns 525 hits. Limiting the search to "mTOR" appearing in the title narrows the hits to 116 - an astonishing number, I feel.

A search of ClinicalTrials.gov using <prostate mtor> returns 23 hits. Again, impressive.

Seems that a lot of time & smart money has been invested in mTOR & its inhibition.

A spoiler paper appeared last month [2]

"mTOR pathway activation is reported in prostate cancer, but clinical trials testing efficacy of mTOR inhibitors were unsuccessful."

"Surprisingly, the mTOR signaling pathway is activated specifically in prostate cancer patients with a favorable outcome."

That doesn't mean that mTOR is our friend, of course. However, mTOR inhibition trials are hardly likely to work in men where the mTOR pathway has not been activated.

In general, the mTOR signaling pathway is actually PI3K/Akt/mTOR. A benefit of PI3K activation is inhibition of the androgen receptor [AR]. Inhibition of PI3K automatically means more AR activity. i.e. it is not a good idea to directly inhibit PI3K as some mTOR inhibition studies have done.

The studies that added Casodex might have done better with Xtandi. In any case, AR inhibition is essential if PI3K is to be inhibited.

A number of non-human studies have occurred that used natural substances:

[N1] Ursolic Acid (from Holy Basil, etc.)

[N2] Quercetin (from onions, etc) - study used an analog.

[N3] Resveratrol (from grape skins)

[N4] Vitamin D + Metformin

[N5] Curcumin (from turmeric)

[N6] DHA (marine omega-3 fatty acid)

[N7] Brassinin (from cabbage)

[N8} Fistetin (from strawberries)

[N9] Licorice

[N10] Honokiol (from Magnolia grandiflora)

& others

Reported mTOR inhibition trials - latest first:

[T1] Everolimus + Casodex in CRPC cases.

"Of 24 patients, 18 ... had a PSA response {at least 30% reduction}, whereas 15 ... had a PSA decrease ≥50%."

"The median overall survival was 28 months ..."

"Fourteen patients ... developed ... adverse events"

[T2] Temsirolimus after Docetaxel in CRPC

"Temsirolimus maintenance therapy after successful docetaxel induction is feasible, does not adversely affect quality of life, and, in this exploratory single-arm phase II study, resulted in a median {time to treatment failure} of 24.3 weeks."

[T3] Phase II Trial of Everolimus, Carboplatin, and Prednisone in Metastatic CRPC.

"The addition of the mTOR inhibitor everolimus to carboplatin demonstrated minimal clinical efficacy"

[T4] Phase I Trial of Ridaforolimus + MK-2206

"No patients with prostate cancer responded" Only 8 PCa cases.

Very disappointing because patients were included based on PI3K pathway dependence. The study design was focussed on the PI3K/Akt/mTOR signaling pathway.

[T5] Phase I/II Trial of Everolimus + gefitinib in patients with metastatic CRPC.

"The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC."

[T6] Phase II study of Temsirolimus in chemotherapy-naïve CRPC.

"Temsirolimus monotherapy has minimal activity in chemotherapy-naïve CRPC."

[T7] Ridaforolimus + Casodex in patients with asymptomatic, metastatic CRPC.

Another bust!

[T8] Phase 2 trial of Everolimus in chemotherapy-naive CRPC.

"Everolimus activity in unselected patients with mCRPC is moderate, but PTEN deletion could be predictive for response. Several serum glycoproteins were able to predict {progression-free survival} at 12 wk. Prospective validation of these potential biomarkers is warranted."

[T9] Phase II trial of RAD001 + Casodex for CRPC.

"The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population."

[T10] Rapamycin in men prior to prostatectomy.

"At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT phosphorylation, tumor proliferation, or apoptosis was observed."

etc.

-Patrick

[1] nytimes.com/2016/05/17/us/a...

[2] impactjournals.com/oncotarg...

[N1] ncbi.nlm.nih.gov/pubmed/265...

[N2] ncbi.nlm.nih.gov/pubmed/264...

[N3] ncbi.nlm.nih.gov/pubmed/259...

[N4] ncbi.nlm.nih.gov/pubmed/259...

[N5] ncbi.nlm.nih.gov/pubmed/264...

[N6] ncbi.nlm.nih.gov/pubmed/238...

[N7] ncbi.nlm.nih.gov/pubmed/236...

[N8] ncbi.nlm.nih.gov/pubmed/205...