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Published on: March 6, 2018
Targeting the PI3K-AKT-mTOR Pathway in Castration Resistant Prostate Cancer: A Review Article
Jason Cham1, Aparajit Ram Venkateswaran1, Munveer Bhangoo2
1Department of Internal Medicine, Scripps Clinic/Scripps Green Hospital, San Diego, CA.
Background:
Prostate cancer is one of leading causes of cancer death among men worldwide. Androgen deprivation therapy is a central part of the prostate cancer treatment algorithm, however, resistance to androgen deprivation commonly leads to disease progression. Mutations in the phosphoinositide-3-kinase pathway (PI3K) have been implicated in cancer progression and the development of castration-resistance. Thus, inhibitors of this pathway and its downstream signaling partners have been studied as potential therapeutic agents to treat metastatic castration resistant prostate cancer (mCRPC). In this article, we review recent clinical results for novel targeted therapies against the PI3K-AKT-mTOR pathway.
Materials And Methods:
Trials included in this systemic review were identified through conference abstracts, citations in review articles, PubMed, and ClinicalTrials.gov. Trial eligibility was independent of clinical setting or sample size.
Results:
A total of 13 prospective clinical trials between 2012 and 2020 were reviewed: Two trials for pan-PI3K inhibitors, 2 trials for selective PI3K inhibitors, 4 trials for AKT inhibitors, 5 trials for mTOR inhibitors, and 1 for a combined PI3K and mTOR inhibitor. All studies were phase I or II studies with primary outcomes of either safety and tolerability or efficacy.
Conclusion:
Overall, pan-PI3K inhibitors and selective-PI3K inhibitors have not demonstrated clinical efficacy and may have significant adverse effects. AKT inhibitors may have significant adverse effects, but showed some evidence of improved survival. mTORC1 inhibitors show modest efficacy and significant adverse effects.
Insights
Targeted therapies for advanced prostate cancer show limited efficacy. While AKT inhibitors offer some survival benefits, PI3K and mTOR inhibitors have modest results and significant side effects, indicating a need for further research.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer is a leading cause of male cancer deaths globally.
- Androgen deprivation therapy resistance drives disease progression in prostate cancer.
- Phosphoinositide-3-kinase (PI3K) pathway mutations are linked to castration-resistant prostate cancer (mCRPC).
Purpose of the Study:
- To review recent clinical findings on novel targeted therapies for mCRPC.
- To evaluate therapies targeting the PI3K-AKT-mTOR pathway.
Main Methods:
- Systematic review of 13 prospective clinical trials (2012-2020).
- Trials identified via conference abstracts, literature, PubMed, and ClinicalTrials.gov.
- Included Phase I/II studies assessing safety, tolerability, and efficacy.
Main Results:
- Pan-PI3K and selective PI3K inhibitors showed no clinical efficacy and notable adverse effects.
- AKT inhibitors exhibited some survival improvement evidence but had significant adverse effects.
- mTORC1 inhibitors demonstrated modest efficacy with considerable adverse effects.
Conclusions:
- Current PI3K pathway inhibitors have limited clinical benefit in mCRPC.
- Further investigation into AKT inhibitors may be warranted despite adverse effects.
- mTORC1 inhibitors show modest efficacy and significant toxicity.
