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Therapeutic Gene Delivery and Transfection in Human Pancreatic Cancer Cells using Epidermal Growth Factor Receptor-targeted Gelatin Nanoparticles
Published on: January 4, 2012
Activated epidermal growth factor receptor as a novel target in pancreatic cancer therapy
H C Harsha1, Antonio Jimeno, Henrik Molina
1Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.
Abstract:
Pancreatic cancer is one of the most fatal among all solid malignancies. Targeted therapeutic approaches have the potential to transform cancer therapy as exemplified by the success of several tyrosine kinase inhibitors. Prompted by this, comprehensive profiling of tyrosine kinases and their substrates was carried out using a panel of low passage pancreatic cancer cell lines. One of the pancreatic cancer cell lines, P196, which showed dramatic upregulation of tyrosine kinase activity as compared to non-neoplastic cells, was systematically studied using a quantitative proteomic approach called stable isotope labeling with amino acids in cell culture (SILAC). A careful analysis of activated tyrosine kinase pathways revealed aberrant activation of epidermal growth factor receptor pathway in this cell line. Mouse xenograft based studies using EGFR inhibitor erlotinib confirmed EGFR pathway to be responsible for proliferation in these tumors. By a systematic study across low passage pancreatic cancer cell lines and mice carrying pancreatic cancer xenografts, we have demonstrated activated epidermal growth factor receptor as an attractive candidate for targeted therapy in a subset of pancreatic cancers. Further, we propose immunohistochemical labeling of activated EGFR (pEGFR (1068)) as an efficient screening tool to select patients who are more likely to respond to EGFR inhibitors.
Insights
Activated epidermal growth factor receptor (EGFR) drives pancreatic cancer proliferation. Targeting EGFR shows promise for a subset of pancreatic cancers, with pEGFR (1068) serving as a potential screening marker.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Pancreatic cancer is a highly fatal malignancy with limited effective treatments.
- Targeted therapies, such as tyrosine kinase inhibitors, offer promising avenues for cancer treatment.
- Comprehensive profiling of tyrosine kinases is crucial for identifying new therapeutic targets.
Purpose of the Study:
- To identify activated tyrosine kinase pathways in pancreatic cancer.
- To evaluate the potential of targeting activated epidermal growth factor receptor (EGFR) in pancreatic cancer.
- To establish a screening method for patient selection for EGFR-targeted therapy.
Main Methods:
- Quantitative proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) on pancreatic cancer cell lines.
- Systematic study of low passage pancreatic cancer cell lines and mouse xenografts.
- In vivo validation using EGFR inhibitor erlotinib.
Main Results:
- Aberrant activation of the epidermal growth factor receptor (EGFR) pathway was identified in a subset of pancreatic cancer cells.
- EGFR pathway activation was confirmed to drive tumor proliferation in mouse xenograft models.
- Activated EGFR (pEGFR (1068)) was demonstrated as a potential therapeutic target.
Conclusions:
- Activated epidermal growth factor receptor (EGFR) is a viable therapeutic target for a subset of pancreatic cancers.
- Immunohistochemical labeling of activated EGFR (pEGFR (1068)) can serve as an effective screening tool for patient selection.
- Targeted inhibition of EGFR holds potential for improving outcomes in pancreatic cancer patients.
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