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The EGF receptor family as targets for cancer therapy
1Department of Medicine, The University of Texas, MD Anderson Cancer Center, Houston, 77030-4009, USA.
Abstract:
Human carcinomas frequently express high levels of receptors in the EGF receptor family, and overexpression of at least two of these receptors, the EGF receptor (EGFr) and closely related ErbB2, has been associated with a more aggressive clinical behavior. Further, transfection or activation of high levels of these two receptors in nonmalignant cell lines can lead to a transformed phenotype. For these reasons therapies directed at preventing the function of these receptors have the potential to be useful anti-cancer treatments. In the last two decades monoclonal antibodies (MAbs) which block activation of the EGFr and ErbB2 have been developed. These MAbs have shown promising preclinical activity and 'chimeric' and 'humanized' MAbs have been produced in order to obviate the problem of host immune reactions. Clinical activity with these antibodies has been documented: trastuzumab, a humanized anti-ErbB2 MAb, is active and was recently approved in combination with paclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer; IMC-C225, a chimeric anti-EGFr MAb, has shown impressive activity when combined with radiation therapy and reverses resistance to chemotherapy. In addition to antibodies, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer.
Insights
Targeting the EGF receptor family, including EGFr and ErbB2, with monoclonal antibodies shows promise for cancer therapy. These therapies, like trastuzumab and IMC-C225, are effective against various carcinomas.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Human carcinomas often overexpress EGF receptor family members, particularly EGFr and ErbB2.
- Overexpression of EGFr and ErbB2 correlates with aggressive cancer behavior and can induce a transformed phenotype in nonmalignant cells.
Purpose of the Study:
- To review the development and clinical application of therapies targeting the EGF receptor family for cancer treatment.
- To highlight the potential of monoclonal antibodies and tyrosine kinase inhibitors in combating cancers driven by these receptors.
Main Methods:
- Development of monoclonal antibodies (MAbs) targeting EGFr and ErbB2, including chimeric and humanized forms.
- Evaluation of clinical activity of anti-EGFr and anti-ErbB2 MAbs, such as IMC-C225 and trastuzumab.
- Review of preclinical and early clinical data for direct tyrosine kinase inhibitors.
Main Results:
- Trastuzumab (anti-ErbB2 MAb) is approved for metastatic breast cancer, while IMC-C225 (anti-EGFr MAb) shows efficacy with radiation therapy and reverses chemotherapy resistance.
- Monoclonal antibodies have demonstrated preclinical and clinical activity, with humanized versions reducing host immune reactions.
- Direct tyrosine kinase inhibitors also exhibit promising preclinical and early clinical activity.
Conclusions:
- Therapies targeting the EGF receptor family, including monoclonal antibodies and tyrosine kinase inhibitors, represent a valuable strategy in cancer treatment.
- Ongoing and planned Phase III studies will further define the role of these anti-receptor agents in patient care.