Post by Allen on Jul 29, 2014 21:32:28 GMT -8
mTOR Inhibitors
These target a cancer proliferation protein known as the mammalian Target Of Rapamycin (mTOR). Three have already been approved for use in cocktails against other cancers, and are in clinical trials for use against prostate cancer. They could potentially be prescribed now off-label. The approved ones are Sirolimus/rapamycin(Rapamune), Temsirolimus (Toresel), and Everolimus (Afinitor).
Interestingly, one theory about why dairy intake is associated with increased PC incidence is that milk proteins act as mTOR agonists:
The impact of cow´s milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer
They seem to have little efficacy as single agents:
• Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08).
• A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.
• A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer.
In combination with bicalutamide, everolimus had a PSA response in ¾ of men with CRPC, although toxicity was significant:
Everolimus plus bicalutamide in men with castration-resistant prostate cancer (CRPC): Final results of a phase II trial.
This conflicts with an earlier finding:
Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer.
Lab studies suggest that it may be more effective combined with an HDAC inhibitor (see section on HDACIs):
• Inhibitory effects of the HDAC inhibitor valproic acid on prostate cancer growth are enhanced by simultaneous application of the mTOR inhibitor RAD001.
• Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma
... or with a TKI (see section on TKIs) too.
Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis
Some references:
A pharmacodynamic study of rapamycin in men with intermediate to high risk localized prostate cancer
Rapamycin enhances the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to docetaxel
Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
Comparative Study of Rapamycin and Temsirolimus Demonstrates Superimposable Anti-Tumour Potency on Prostate Cancer Cells
RAD001 (Everolimus) Inhibits Growth of Prostate Cancer in the Bone and the Inhibitory Effects Are Increased by Combination With Docetaxel and Zoledronic Acid
They are in clinical trials combined with hormonal therapies like ARN-509 and Xtandi.
Safety
These are all powerful immunosuppressants used to prevent transplant rejection, and may also cause diabetes-like symptoms. Not something to stay on for a long time.
These target a cancer proliferation protein known as the mammalian Target Of Rapamycin (mTOR). Three have already been approved for use in cocktails against other cancers, and are in clinical trials for use against prostate cancer. They could potentially be prescribed now off-label. The approved ones are Sirolimus/rapamycin(Rapamune), Temsirolimus (Toresel), and Everolimus (Afinitor).
Interestingly, one theory about why dairy intake is associated with increased PC incidence is that milk proteins act as mTOR agonists:
The impact of cow´s milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer
They seem to have little efficacy as single agents:
• Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08).
• A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.
• A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer.
In combination with bicalutamide, everolimus had a PSA response in ¾ of men with CRPC, although toxicity was significant:
Everolimus plus bicalutamide in men with castration-resistant prostate cancer (CRPC): Final results of a phase II trial.
This conflicts with an earlier finding:
Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer.
Lab studies suggest that it may be more effective combined with an HDAC inhibitor (see section on HDACIs):
• Inhibitory effects of the HDAC inhibitor valproic acid on prostate cancer growth are enhanced by simultaneous application of the mTOR inhibitor RAD001.
• Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma
... or with a TKI (see section on TKIs) too.
Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis
Some references:
A pharmacodynamic study of rapamycin in men with intermediate to high risk localized prostate cancer
Rapamycin enhances the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to docetaxel
Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
Comparative Study of Rapamycin and Temsirolimus Demonstrates Superimposable Anti-Tumour Potency on Prostate Cancer Cells
RAD001 (Everolimus) Inhibits Growth of Prostate Cancer in the Bone and the Inhibitory Effects Are Increased by Combination With Docetaxel and Zoledronic Acid
They are in clinical trials combined with hormonal therapies like ARN-509 and Xtandi.
Safety
These are all powerful immunosuppressants used to prevent transplant rejection, and may also cause diabetes-like symptoms. Not something to stay on for a long time.
