CD13 as target for tissue factor induced tumor vascular infarction in small cell lung cancer
Lars Henning Schmidt1, Janine Stucke-Ring1, Caroline Brand1
1Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
Objectives:
Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease.
Material And Methods:
CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF-NGR on tumor growth were tested.
Results And Conclusion:
In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF-NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection.
Insights
Aminopeptidase N (CD13) is found in small cell lung cancer (SCLC) stroma, not tumor cells. Targeting CD13 with tTF-NGR significantly reduced tumor growth in mice, suggesting its potential for SCLC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Aminopeptidase N (CD13) is a zinc-binding protease expressed on tumor vascular and tumor cells.
- CD13 is a potential target for molecular therapies, such as truncated tissue factor fused with NGR peptide (tTF-NGR), to induce tumor vascular infarction.
- Small cell lung cancer (SCLC) is an aggressive form of lung cancer with limited treatment options.
Purpose of the Study:
- To analyze CD13 expression in a cohort of SCLC patients.
- To evaluate the potential of CD13-targeted therapies in SCLC.
- To assess the efficacy of tTF-NGR in reducing SCLC tumor growth.
Main Methods:
- Immunohistochemical analysis of CD13 expression in 27 SCLC patient samples.
- Correlation of CD13 expression with clinical course and outcome.
- In vivo studies using CD-1 nude mice bearing human SCLC xenotransplants to test the effects of tTF-NGR.
Main Results:
- CD13 was expressed in tumor stroma cells in 52% of SCLC samples; tumor cells were CD13-negative.
- No significant correlation was found between CD13 expression and overall survival in SCLC patients.
- Systemic administration of tTF-NGR significantly reduced tumor growth in SCLC xenografts in mice, with CD13 expression observed in intratumoral vascular and perivascular cells.
Conclusions:
- CD13 is differentially expressed in SCLC, primarily in the stroma and vasculature.
- The CD13-targeting fusion protein tTF-NGR demonstrated significant anti-tumor effects in a preclinical SCLC model.
- Further investigation of tTF-NGR and NGR-peptide targeted therapies is warranted for SCLC.
- Pre-therapeutic CD13 analysis could serve as a predictive biomarker for patient selection in SCLC targeted therapy.
