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Published on: March 6, 2018
mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review
Cara M Statz1, Sara E Patterson1, Susan M Mockus2
1The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, USA.
Background:
The progression of prostate cancer to castration-resistant prostate cancer (CRPC) is often a result of somatic alterations in the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway, suggesting that therapies targeting this pathway might lead to improved survival and efficacy. Here, we systematically evaluate the results of clinical trials investigating mTOR inhibition in CRPC and utilize preclinical data to predict clinical outcomes.
Methods:
Trials included in the study were identified through PubMed and via review of conference abstracts cited by relevant review articles. The eligibility of trials was independent of sample size, clinical setting, or date.
Results:
A total of 14 studies were eligible for qualitative analysis. The clinical setting was variable among studies, and all utilized an allosteric mTOR inhibitor as either a monotherapy or in combination. Molecular criteria were evaluated in three trials. Among most studies, the prostate-specific antigen level declined during treatment, but often increased shortly thereafter. Partial responses to treatment were minimal, and no complete responses were reported. Two studies exploring therapy with an mTOR inhibitor in combination with bicalutamide resulted in minimal efficacy. Overall, allosteric mTOR inhibition was deemed to be inadequate for the treatment of CRPC.
Conclusion:
Preclinical data suggest that a reciprocal feedback mechanism between PI3K and androgen receptor signaling is a potential mechanism behind the clinical inefficacy of mTOR inhibitors in CRPC, indicating combinatorial targeting of PI3K, mTORC1/2, and the androgen receptor might be more effective. Comprehensive analysis of preclinical data to assess clinical trial targets and efficacy may reduce the number of unproductive trials and identify potentially beneficial combinatorial therapies for resistant disease.
Insights
Targeting the mammalian target of rapamycin (mTOR) pathway shows limited efficacy in treating castration-resistant prostate cancer (CRPC). Combination therapies targeting PI3K, mTOR, and androgen receptors may offer better outcomes for resistant prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer progression to castration-resistant prostate cancer (CRPC) is linked to PI3K/Akt/mTOR pathway alterations.
- Targeting the PI3K/Akt/mTOR pathway is a potential strategy for improving CRPC treatment outcomes.
Purpose of the Study:
- To systematically evaluate clinical trial results of mTOR inhibition in CRPC.
- To use preclinical data to predict clinical outcomes for mTOR-targeted therapies in CRPC.
Main Methods:
- Systematic review of clinical trials investigating mTOR inhibitors in CRPC.
- Inclusion of trials regardless of sample size, clinical setting, or date.
- Qualitative analysis of 14 eligible studies.
Main Results:
- Allosteric mTOR inhibitors, as monotherapy or combination, showed minimal efficacy in CRPC.
- Most studies reported transient prostate-specific antigen declines, followed by increases.
- No complete responses were observed; partial responses were minimal.
Conclusions:
- Allosteric mTOR inhibition is currently inadequate for treating CRPC.
- Preclinical data suggest a feedback loop between PI3K and androgen receptor signaling contributes to treatment failure.
- Combinatorial targeting of PI3K, mTORC1/2, and androgen receptor may be a more effective strategy for resistant prostate cancer.
