BCL2 protein signalling determines acute responses to neoadjuvant chemoradiotherapy in rectal cancer

Flanagan, Lorna; Lindner, Andreas U.; Chaumont, Ciaran de; Kehoe, Joan; Fay, Joanna; Bacon, Orna; Toomey, Sinéad; Huber, Heinrich J.; Hennessy, Bryan T.; Kay, Elaine W.; McNamara, Deborah A.; Prehn, Jochen H.M.

doi:10.1007/s00109-014-1221-7

Cited by 19 publications

(30 citation statements)

References 40 publications

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“…With apoptosis converging on the BCL-2 family to execute the killing decision, understanding BCL-2 family proteins, their interactions and their context within other singling networks, will shed light on the effectiveness of chemotherapies and optimal combinations. The continued development of our BH3 profiling system and other biomarkers 116 (for instance, DR_ MOMP)117, 118, perhaps can help to provide guiding information in patient and drug selection in the future.…”

Section: In Conclusionmentioning

confidence: 99%

How to unleash mitochondrial apoptotic blockades to kill cancers?

Deng

2017

Acta Pharmaceutica Sinica B

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Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.

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Section: In Conclusionmentioning

confidence: 99%

How to unleash mitochondrial apoptotic blockades to kill cancers?

Deng

2017

Acta Pharmaceutica Sinica B

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“…The advantage of using such personalised dynamic models over static biomarkers, has already been demonstrated in several case studies (Fey et al, 2015;Flanagan et al, 2015;Murphy et al, 2013;Lindner et al, 2013). In contrast to previous approaches, the here proposed methodology is not restricted to models in which the total protein concentrations are time-invariant parameters.…”

Section: Discussionmentioning

confidence: 96%

“…Recently, multiple studies have shown that patient-specific differences in the dynamic behaviour of these signalling networks underlie individual pathogenetic changes and disease manifestation (Fey et al, 2015;Flanagan et al, 2015;Lindner et al, 2013;Murphy et al, 2013). For example, a dynamic model of the JNK pathway could predict the survival probabilities of cancer patients in neuroblastoma, a common childhood cancer (Fey et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…In fact, all the personalised models mentioned are based on this simple principle of directly using the measured mRNA or protein concentrations as static parameters in the model (Fey et al, 2015;Flanagan et al, 2015;Lindner et al, 2013;Murphy et al, 2013). Thus, all these personalised models are based on the assumption that the Supported by EU FP7 grant "SynSignal" (No.…”

Section: Introductionmentioning

confidence: 99%

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On the personalised modelling of cancer signalling * *Supported by EU FP7 grant “SynSignal” (No. 613879).

2016

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Dynamic modelling has long been used to understand fundamental principles of cell signalling and its dysregulation in cancer. More recently, these models have also been used to understand the individual risks of cancer patients, and predict their survival probabilities. However, the current methodologies for integrating tumour data and generating patient-specific simulations suffer from the lack of general applicability; they only work for cell signalling models in which only posttranslational protein modifications are considered, so that the total protein concentrations are conserved. Here, we present novel, generally applicable method. The method is based on a simple theoretical framework for modelling gene-regulation, and the indirect estimation of patient-specific parameters from tumour data. Because our method does not require time-invariance of the total-protein concentrations, it can be applied to models of any nature, including the many cancer signalling models involving gene-regulation.

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“…The drug-induced priming changes correlate well with in vivo cytotoxicity. Others have used different methods for measuring the pretreatment apoptosis (23,24). The Prehn laboratory measures absolute protein levels of key BCL-2 family members in pretreatment samples.…”

Section: Pretreatment Apoptotic Parameters Predict Clinical Response mentioning

confidence: 99%

Cell Death and Cancer Therapy: Don't Forget to Kill the Cancer Cell!

Letaï

2015

Clinical Cancer Research

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In our current age of targeted therapies, there is understandably considerable attention paid to the specific molecular targets of pharmaceutical intervention. For a targeted drug to work, it must bind to a target selectively and impair its function. Monitoring biomarkers of the impaired target function can provide vital in vivo pharmacodynamic information. Moreover, genetic changes to the target are often the source of resistance to targeted agents. However, for the treatment of cancer, it is necessary that the therapy not only provide efficient binding and inhibition of the target, but also that this intervention reliably kills the cancer cell. In this CCR Focus section, four articles make the connection between therapies that target T-cell activation, autophagy, IAP proteins, and BCL-2 and the commitment of cancer cells to cell death. Before addressing those exciting classes of targeted therapies, however, an overview is provided to discuss cell death induced by what is arguably still the most successful set of drugs in the history of medical oncology, conventional chemotherapy.

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BCL2 protein signalling determines acute responses to neoadjuvant chemoradiotherapy in rectal cancer

Cited by 19 publications

References 40 publications

How to unleash mitochondrial apoptotic blockades to kill cancers?

How to unleash mitochondrial apoptotic blockades to kill cancers?

On the personalised modelling of cancer signalling * *Supported by EU FP7 grant “SynSignal” (No. 613879).

Cell Death and Cancer Therapy: Don't Forget to Kill the Cancer Cell!

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