Evaluation of pharmacodynamic biomarkers in a Phase 1a trial of dulanermin (rhApo2L/TRAIL) in patients with advanced tumours
| Autor: | Daniel Branstetter, Roy S. Herbst, Matthew Peach, William Novotny, Huang Cp, Pamela M. Holland, R. Xu, Yang Pan, Eckhardt Sg |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Pathology dulanermin caspase Apoptosis TNF-Related Apoptosis-Inducing Ligand Biology Phase 1a trial 03 medical and health sciences Mice 0302 clinical medicine Internal medicine Neoplasms medicine Biomarkers Tumor Animals Humans Base sequence In patient 030304 developmental biology Dulanermin DNA Primers 0303 health sciences Base Sequence M30 Apo2L/TRAIL Immunohistochemistry Xenograft Model Antitumor Assays APO2L/TRAIL Recombinant Proteins 3. Good health Clinical trial 030220 oncology & carcinogenesis Pharmacodynamics Clinical Study Biomarker (medicine) biomarker |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Background: Dulanermin (rhApo2L/TRAIL) induces apoptosis by binding to death receptors DR4 and DR5, leading to caspase activation and subsequent cell death. A Phase1a trial evaluated the safety and tolerability of dulanermin in patients with advanced tumours. One aim was to develop and validate pharmacodynamic biomarkers to monitor dulanermin activity in patient serum. Methods: We optimised assays to measure the cell-death markers caspase 3/7, cytokeratin 18 and genomic DNA in serum. Mice bearing Colo205 xenografts were treated with dulanermin and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored apoptotic markers in patients who received dulanermin. Results: We detected transient increases in apoptotic markers in mouse sera 8–24 h after dulanermin treatment. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumours. A statistically significant increase in serum caspase 3/7 was detected in cohorts of colorectal and sarcoma patients 24 h after receiving dulanermin dosed above 4 mg kg−1. Conclusion: Owing to limited responses in the Phase 1a study, the changes in circulating cell-death markers were not evaluable. Future studies with dulanermin are needed to determine the utility of these assays with respect to providing evidence of activity or predicting overall response. |
| Databáze: | OpenAIRE |
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