Serum biomarkers which correlate with failure to respond to immunotherapy and tumor progression in a murine colorectal cancer model

• Published in: Proteomics. Clinical applications Vol. 4; no. 8-9; pp. 682 - 696
• Main Authors: Vafadar-Isfahani, Baharak, Laversin, Stephanie Anne-Sophie, Ahmad, Murrium, Ball, Graham, Coveney, Clare, Lemetre, Christophe, Kathleen Miles, Amanda, van Schalkwyk, Gerhard, Rees, Robert, Matharoo-Ball, Balwir
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.09.2010; WILEY‐VCH Verlag; Wiley
• Subjects: Animals; Biological and medical sciences; Biomarkers, Tumor - blood; Cancer immunotherapy; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colorectal Neoplasms - blood; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Disease Models, Animal; Disease Progression; Diverse techniques; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Immunotherapy - methods; MALDI; Male; Medical sciences; Mice; Mice, Inbred BALB C; Molecular and cellular biology; Neoplasm Staging - methods; Serum biomarkers; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Treatment Outcome; Tumors; Animal model; MALDI; Rodentia; Colorectal cancer; Biological marker; Malignant tumor; Serum biomarkers; Cancer immunotherapy; Vertebrata; Mammalia; Mouse; Immunotherapy; Tumor progression; Proteomics; Serum; Cancer
• ISSN: 1862-8346; 1862-8354
• DOI: 10.1002/prca.200900218

Purpose: To advance our understanding of mechanisms involved in tumor progression/regression, a CT26 colorectal mouse model treated intra‐tumorally with DISC‐herpes simplex virus as immunotherapy was used in the discovery and validation phases to investigate and ultimately identify biomarkers correlating with the failure to respond to immunotherapy. Experimental design: For the discovery phase, serum protein/peptide profiles of a retrospective sample collection (total n=70) were analyzed using MALDI‐TOF‐MS combined with artificial neural networks. Following identification of the key predictive peptides using ESI‐MS/MS, validation of the identified proteins was carried out on serum and tissues collected in an independent sample set (total n=60). Results: Artificial neural network analysis resulted in four discriminatory peaks with an accuracy of 86%, sensitivity of 90% and specificity of 81% between the progressor/regressor groups. Three of the identified discriminatory markers were upregulated and demonstrated a positive correlation with tumor progression following DISC‐herpes simplex virus therapy. Immunovalidation studies corroborated the MALDI‐TOF‐MS findings. Immunohistochemistry revealed that serum amyloid A‐1 and serum amyloid P produced in the liver localized intracellularly in CT26 tumor tissue. Conclusions: MALDI‐TOF‐MS and BI analysis of the serum proteome of tumor‐bearer mice undergoing immunotherapy, identified biomarkers associating with “failure to respond” and biological arrays confirmed these findings.