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Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.
Highlights
It is widely recognized that one of the major contributors to the observed resistance of GBMs to chemotherapy and radiotherapy is the dysregulation of apoptotic pathways.[6,7]
The anticancer treatment strategies of chemotherapy and radiotherapy typically attempt to engage the intrinsic or mitochondrial pathway of apoptosis to relay their death signals within their target population.[10,11]. In this pathway upon mitochondrial outer membrane permeabilization (MOMP), cytochrome c is released from the mitochondria into the cytosol, triggering formation of the apoptosome, which includes the apoptotic protease activating factor-1 (Apaf-1) and procaspase-9.12,13 Apoptosome formation enables activation of the initiator caspase, procaspase-9 and subsequent activation of the executioner caspases, procaspase-3 and -7.13–15 released from the mitochondria is Smac/
Establishing the basal levels of these apoptotic proteins within GBMs is essential as it determines if these tumor cells have the molecular machinery necessary to undergo apoptosis following MOMP
Summary
It is widely recognized that one of the major contributors to the observed resistance of GBMs to chemotherapy and radiotherapy is the dysregulation of apoptotic pathways.[6,7]. The anticancer treatment strategies of chemotherapy and radiotherapy typically attempt to engage the intrinsic or mitochondrial pathway of apoptosis to relay their death signals within their target population.[10,11] Briefly, in this pathway upon mitochondrial outer membrane permeabilization (MOMP), cytochrome c is released from the mitochondria into the cytosol, triggering formation of the apoptosome, which includes the apoptotic protease activating factor-1 (Apaf-1) and procaspase-9.12,13 Apoptosome formation enables activation of the initiator caspase, procaspase-9 and subsequent activation of the executioner caspases, procaspase-3 and -7.13–15 released from the mitochondria is Smac/. The executioner caspases cleave key regulatory and structural proteins to produce most of the morphological and biochemical changes, characteristic of this type of cell death.[13,15,18,19]
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