Baseline caspase activity predicts progression free survival of temsirolimus-treated head neck cancer patients

John, Katharina; Rösner, Imme; Keilholz, Ulrich; Gauler, Thomas; Bantel, Heike; Grünwald, Viktor

doi:10.1016/j.ejca.2015.05.021

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…Interestingly, in recent years there is much evidence supporting a role for Caspase-3 in paracrine signalling, which may also influence signal transduction and gene expression changes in neighbouring cells that themselves did not activate caspases. 6 , 26 , 27 Analysis of TMAs of stage 2 and 3 CRC tumours revealed that low levels of active Caspase-3 conferred a significant survival advantage. We found that in patients receiving CT, active Caspase-3 levels gave an even more notable survival advantage, suggesting that while CT is activating Caspase-3, high levels of the active protein may contribute to the eventual relapse.…”

Section: Discussionmentioning

confidence: 99%

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach

et al. 2016

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Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers β-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and β-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a new predictor of CT responsiveness, and inhibition of Caspase-3, or antagonising downstream effectors of Caspase-3 paracrine signalling, such as COX-2 may improve patient outcomes following CT in advanced CRC.

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Section: Discussionmentioning

confidence: 99%

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach

et al. 2016

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“…116 In another study, elevated circulating serum levels of caspase activity correlated with shorter time to progression despite chemotherapy in head and neck cancers. 117 In a third study, activated caspase-3 and increased HMGB1 expression were found in colorectal cancers and were correlated with poor prognosis, independent of their function in metastasis. 43 …”

Section: The Emerging Clinical Significance Of Caspase-driven Aip In mentioning

confidence: 95%

Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease

2017

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Apoptosis is a carefully orchestrated and tightly controlled form of cell death, conserved across metazoans. As the executioners of apoptotic cell death, cysteine-dependent aspartate-directed proteases (caspases) are critical drivers of this cellular disassembly. Early studies of genetically programmed cell death demonstrated that the selective activation of caspases induces apoptosis and the precise elimination of excess cells, thereby sculpting structures and refining tissues. However, over the past decade there has been a fundamental shift in our understanding of the roles of caspases during cell death—a shift precipitated by the revelation that apoptotic cells actively engage with their surrounding environment throughout the death process, and caspases can trigger a myriad of signals, some of which drive concurrent cell proliferation regenerating damaged structures and building up lost tissues. This caspase-driven compensatory proliferation is referred to as apoptosis-induced proliferation (AiP). Diverse mechanisms of AiP have been found across species, ranging from planaria to mammals. In this review, we summarize the current knowledge of AiP and we highlight recent advances in the field including the involvement of reactive oxygen species and macrophage-like immune cells in one form of AiP, novel regulatory mechanisms affecting caspases during AiP, and emerging clinical data demonstrating the critical importance of AiP in cancer.

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“… 414 Baseline caspase 3 activity is inversely correlated with PFS in temsirolimus-treated HNSCC patients, making it a potentially useful noninvasive biomarker of sensitivity to mTOR inhibitors. 499 Recently, studies have focused on exploring effective combination strategies for temsirolimus. In a phase 2 study, temsirolimus plus low-dose chemotherapy (carboplatin and paclitaxel) induced a relatively high response rate (41.7%) and long survival (OS: 12.8 months; PFS: 5.9 months) compared to other treatments in R/M-HNSCC patients.…”

Section: Targeted Therapy In Clinicalmentioning

confidence: 99%

Targeted therapy for head and neck cancer: signaling pathways and clinical studies

Tie

Alu

et al. 2023

Sig Transduct Target Ther

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Head and neck cancer (HNC) is malignant, genetically complex and difficult to treat and is the sixth most frequent cancer, with tobacco, alcohol and human papillomavirus being major risk factors. Based on epigenetic data, HNC is remarkably heterogeneous, and treatment remains challenging. There is a lack of significant improvement in survival and quality of life in patients with HNC. Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy. In addition, resistance to chemotherapy, radiotherapy and some targeted therapies is common. Therefore, it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients. Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies. A well understanding of the pathogenesis of HNC contributes to learning more about its inner association, which provides novel insight into the development of small molecule inhibitors. In this review, we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC, as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy, which may contribute to a more favorable prognosis of HNC. Targeted therapy in combination with other therapies and its limitations were also discussed.

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Baseline caspase activity predicts progression free survival of temsirolimus-treated head neck cancer patients

Cited by 9 publications

References 39 publications

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach

Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease

Targeted therapy for head and neck cancer: signaling pathways and clinical studies

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