Harnessing system models of cell death signalling for cytotoxic chemotherapy: towards personalised medicine approaches?
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- 作者：Heinrich J. Huber (1) (2) (3)
Ross G. McKiernan (1) (2)
Jochen H. M. Prehn (1) (2) - 关键词：MOMP ; Cytotoxic chemotherapy ; Apoptosis ; Systems modelling ; Personalised oncology ; Molecular medicine
- 刊名：Journal of Molecular Medicine
- 出版年：2014
- 出版时间：March 2014
- 年：2014
- 卷：92
- 期：3
- 页码：227-237
- 全文大小：577 KB
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Ross G. McKiernan (1) (2)
Jochen H. M. Prehn (1) (2)
1. Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen鈥檚 Green, Dublin 2, Ireland
2. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen鈥檚 Green, Dublin 2, Ireland
3. Department of Cardiovascular Science, KU Leuven, Herestraat 49, Box 911, 3000, Leuven, Belgium - ISSN：1432-1440
文摘
Most cytotoxic chemotherapeutics are believed to kill cancer cells by inducing apoptosis. Understanding the factors that contribute to impairment of apoptosis in cancer cells is therefore critical for the development of novel therapies that circumvent the widespread chemoresistance. Apoptosis, however, is a complex and tightly controlled process that can be induced by different classes of chemotherapeutics targeting different signalling nodes and pathways. Moreover, apoptosis initiation and apoptosis execution strongly depend on patient-specific, genomic and proteomic signatures. Here, we will review recent translational studies that suggest a critical link between the sensitivity of cancer cells to initiate apoptosis and clinical outcome. Next we will discuss recent advances in the field of system modelling of apoptosis pathways for the prediction of treatment responses. We propose that initiation of mitochondrial apoptosis, defined as the process of mitochondrial outer membrane permeabilisation (MOMP), is a dose-dependent decision process that allows for a prediction of individual therapy responses and therapeutic windows. We provide evidence in contrast that apoptosis execution post-MOMP may be a binary decision that dictates whether apoptosis is executed or not. We will discuss the implications of this concept for the future use of novel adjuvant therapeutics that specifically target apoptosis signalling pathways or which may be used to reduce the impact of cell-to-cell heterogeneity on therapy responses. Finally, we will discuss the technical and regulatory requirements surrounding the use and implications of system-based patient stratification tools for the future of personalised oncology.