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mTOR Inhibitors in Advanced Biliary Tract Cancers
Chao-En Wu1, Ming-Huang Chen2,3, Chun-Nan Yeh4
1Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan. jiaoen@gmail.com.
International Journal of Molecular Sciences
|January 27, 2019
Summary
Novel treatments targeting the mTOR pathway show promise for advanced biliary tract cancers (BTCs). mTOR inhibitors, including new-generation drugs, offer potential therapeutic benefits for cholangiocarcinoma (CCA) and other BTCs.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have a poor prognosis with limited treatment options.
- Current standard care for advanced BTC is gemcitabine-based chemotherapy, with no established targeted therapies.
- The PI3K/AKT/mTOR signaling pathway is crucial in regulating cancer proliferation and progression and is implicated in BTC tumorigenesis and drug resistance.
Purpose of the Study:
- To review the limitations of current BTC treatments.
- To highlight the significance of mTOR signaling in BTC.
- To explore the potential of mTOR inhibitors as a future therapeutic strategy for advanced BTC.
Main Methods:
- Review of existing literature on BTC treatment, mTOR signaling, and mTOR inhibitors.
- Analysis of in vitro and in vivo studies on rapalogs and new-generation mTOR inhibitors in BTC models.
- Examination of clinical trial data for mTOR inhibitors in advanced BTC patients.
Main Results:
- Rapalogs (e.g., sirolimus, everolimus) partially inhibit mTOR complex 1 (mTORC1) and show anti-cancer activity in BTC models and some clinical activity in patients.
- New-generation mTOR inhibitors targeting the ATP-binding pocket inhibit both TORC1 and TORC2, demonstrating more potent anti-tumor effects in preclinical studies.
- mTOR pathway activation is linked to tumorigenesis and acquired drug resistance in BTC.
Conclusions:
- mTOR signaling plays a critical role in the development and progression of BTC.
- Rapalogs have shown preliminary activity, but new-generation mTOR inhibitors offer greater potential due to broader target inhibition.
- Prospective clinical trials are necessary to establish the efficacy of novel mTOR inhibitors in patients with advanced BTC.
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