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Mutant cell surface receptors as targets for individualized cancer diagnosis and therapy
1Institute of Pathology, Technical University, Trogerstrasse 18, Munich, D-81675, Germany. kf.becker@lrz.tum.de
Abstract:
The catalogue of gene alterations in human cancer is growing rapidly. Alterations in specific genes that play important roles in diverse cellular functions such as cell adhesion, signal transduction, differentiation, development or DNA-repair have been identified. Cancer-associated mutant cell surface molecules are very attractive candidates to target tumor cells because they offer the possibility of minimizing toxic effects to non-tumor cells. The cell adhesion molecule E-cadherin has been shown to play a major role in determining which of the two subtypes of gastric cancer, diffuse or intestinal type, develops. E-cadherin gene mutations typically affect the extracellular portion of the homophilic receptor and are frequently found in patients with diffuse-type tumors. Cancer-specific monoclonal antibodies against the E-cadherin mutational hot spot region are now available. In cell culture and in animal studies we have shown that mutation-specific antibodies exclusively target cells expressing abnormal E-cadherin. Those cells expressing the normal protein were not affected, demonstrating the specificity of our approach. After linking to toxins, drugs or radiolabeled mutation-specific antibodies could serve as very specific agents to treat small tumor deposits. Patients for this novel individualized cancer therapy can be identified within a day using routine immunohistochemistry of biopsies.
Insights
Targeting cancer cells with mutation-specific antibodies offers a novel therapy. These antibodies precisely target abnormal E-cadherin in diffuse-type gastric cancer, sparing healthy cells.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Gene alterations in human cancers are increasingly identified, impacting cellular functions.
- Mutant cell surface molecules are promising targets for cancer therapy due to specificity.
- E-cadherin, a cell adhesion molecule, is crucial in distinguishing gastric cancer subtypes.
Purpose of the Study:
- To investigate the potential of mutation-specific antibodies targeting E-cadherin alterations for cancer therapy.
- To demonstrate the specificity of these antibodies in targeting cancer cells with abnormal E-cadherin.
Main Methods:
- Development of cancer-specific monoclonal antibodies against E-cadherin mutational hotspots.
- Testing antibody specificity in cell culture and animal models.
- Utilizing routine immunohistochemistry for patient identification.
Main Results:
- Mutation-specific antibodies exclusively targeted cells expressing abnormal E-cadherin.
- Cells expressing normal E-cadherin were unaffected, confirming high specificity.
- Potential for individualized therapy using these antibodies.
Conclusions:
- Mutation-specific antibodies against E-cadherin are highly specific for targeting tumor cells.
- These antibodies can be developed into targeted agents for cancer treatment when linked to toxins or drugs.
- Patient identification for this novel therapy is feasible using immunohistochemistry.