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Current Data with Mammalian Target of Rapamycin Inhibitors in Advanced Renal Cell Carcinoma
Institution:1. Research Management Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan;2. Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan;1. Unidade de Medicina Tropical, Departamento de Patologia, Universidade Federal do Espirito Santo, Vitoria, ES, Brazil.;2. Programa em Doenças Infecciosas, Centro de Doenças Infecciosas, Universidade Federal do Espirito Santo, Vitoria, ES, Brazil.;3. Laboratório de Imunologia Celular e Bioquímica de Fungos e Protozoários, Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo (UNIFESP), Campus Diadema, Sao Paulo, SP, Brazil.;4. Núcleo de Morfologia e Microscopia, Instituto Adolfo Lutz, Sao Paulo, SP, Brazil.;5. Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, Sao Paulo, SP, Brazil.;6. Parasitology Division, Kimron Veterinary Institute, Israeli Veterinary Service and Animal Health, Ministry of Agriculture and Rural Development Beit Dagan, 5025000, Israel.
Abstract:Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demdemonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTORtargeted therapies in the treatment of advanced-stage RCC.
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