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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Baseline caspase activity predicts progression free survival of temsirolimus-treated head neck cancer patients
Katharina John1, Imme Rösner2, Ulrich Keilholz3
1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Abstract:
Squamous cell cancer of the head and neck (SCCHN) is a frequent aggressive malignancy with limited therapeutic options. Increasing evidence suggests that mammalian target of rapamycin (mTOR)-inhibitors might be effective in advanced SCCHN. However, non-invasive biomarkers for early prediction of treatment efficacy are not established in SCCHN. Highly proliferating tumours are characterised by enhanced cell turnover which is associated with enhanced apoptosis. During apoptosis of epithelial cells caspases cleave cytokeratin (CK)-18 can be detected in the blood. In this study we analysed sera from patients with relapsed or metastatic SCCHN patients who have been treated with temsirolimus for caspase-cleaved and total (caspase-cleaved and uncleaved) CK-18 by enzyme-linked immunosorbent assays (ELISAs). In addition, caspase-3 activity was detected by luminometric substrate assay. SCCHN patients revealed higher serum levels of those biomarkers compared to healthy controls. Importantly, patients with short progression-free survival (PFS) showed higher serum levels of caspase-3 activity compared to patients with longer PFS (⩾ 2months). Caspase-3 activity is inversely correlated with PFS. A cut-off value for caspase-3 activity was determined that correctly predicted PFS <2months with a sensitivity of 86% and a specificity of 67%. These data demonstrate that detection of serum caspase-3 activity might be a useful non-invasive biomarker for early identification of SCCHN patients not responding to treatment with novel targeted therapies such as mTOR-inhibitors.
Insights
Serum caspase-3 activity may predict treatment response in head and neck squamous cell cancer (SCCHN). Higher caspase-3 levels indicate poor progression-free survival, aiding early identification of non-responders to targeted therapies like mTOR-inhibitors.
Area of Science:
- Oncology
- Biochemistry
Background:
- Squamous cell cancer of the head and neck (SCCHN) is an aggressive malignancy with limited treatment options.
- Mammalian target of rapamycin (mTOR)-inhibitors show promise for advanced SCCHN, but non-invasive biomarkers for predicting efficacy are lacking.
- Tumor cell turnover and apoptosis are associated with elevated biomarkers in circulation.
Purpose of the Study:
- To investigate serum caspase-cleaved cytokeratin-18 (CK-18) and caspase-3 activity as non-invasive biomarkers for treatment efficacy in SCCHN patients.
- To correlate these biomarkers with progression-free survival (PFS) in patients treated with the mTOR-inhibitor temsirolimus.
Main Methods:
- Serum samples from SCCHN patients treated with temsirolimus were analyzed for caspase-cleaved and total CK-18 using ELISAs.
- Caspase-3 activity was measured using a luminometric substrate assay.
- Biomarker levels were compared between SCCHN patients and healthy controls, and correlated with PFS.
Main Results:
- SCCHN patients exhibited higher serum levels of CK-18 and caspase-3 activity compared to healthy controls.
- Patients with shorter PFS (<2 months) had significantly higher serum caspase-3 activity than those with longer PFS (≥2 months).
- Caspase-3 activity showed an inverse correlation with PFS, with a determined cut-off value predicting PFS <2 months with 86% sensitivity and 67% specificity.
Conclusions:
- Serum caspase-3 activity is a potential non-invasive biomarker for early prediction of treatment response in SCCHN.
- This biomarker can help identify patients unlikely to benefit from targeted therapies such as mTOR-inhibitors, enabling timely treatment adjustments.
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