- ONCOLOGY Vol 15 No 6
- Volume 15
- Issue 6
Epidermal Growth Factor Receptor Inhibitors in Clinical Trials
With the understanding of the mechanism of malignant transformation has come the knowledge that oncogene products are frequently growth factors, growth factor receptors, or elements of growth factor signal-transduction pathways. Overexpression
With the understanding of the mechanism ofmalignant transformation has come the knowledge that oncogene products arefrequently growth factors, growth factor receptors, or elements of growth factorsignal-transduction pathways. Overexpression of the components of thesesignal-transduction pathways can lead to the development and propagation ofmalignancies. In addition, human cells exhibit complex responses to DNA damage,including activation of genes involved in cell-cycle arrest, DNA repair, andapoptosis. Recent findings suggest that the cellular response to DNA damage ismarkedly impaired by deprivation of essential growth factors or by blockage ofgrowth-factor receptors, which suggests that these pathways contribute to theineffectiveness of chemotherapy and radiation.[1,2] Thus, specific blockade ofthese pathways in tumor cells may be attractive targets for new cancertherapies, since inhibiting these pathways may induce tumor stasis and/orregression and increase the cytotoxic effects of chemotherapy and radiation.
Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.
It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*
We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.
This month’s installment of Clinical Trials Referral Resource is devoted to studies regarding epidermal growth factor receptor inhibitors.
For patient entry information, see the individual trials.
* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, Internet access is available at
The ErbB family of growth-factor receptors is well characterizedand has generated significant interest as a target for cancer therapeutics. Thefamily consists of epidermal growth factor receptor (EGFR), HER2, HER3, andHER4, and at least 10 ligands that bind and activate family members.[3]Ligand-receptor binding results in receptor dimerization with the sameor different family member, autophosphorylation, kinase activation, and thegeneration of binding sites for downstream adaptor molecules and secondmessengers.
Because family members can be activated by multiple ligands andligand-receptor expression determines homo/heterodimerization between receptorsas well as rate of receptor internalization and degradation, the efficiency anddiversity of signal transduction through these receptor complexes is remarkable.Activation of this family of growth-factor receptors influences cellproliferation, survival, motility, adhesion, invasion, and angiogenesis.[3]Preclinical and clinical data support the involvement of the ligands’transforming growth factor-alpha and epidermal growth factor and EGFR in theformation and progression of human cancers. Hyperactive receptor signalingpromotes deregulated cell growth and subsequent development of malignancy.
EGFR is overexpressed in a significant proportion of humancancers such as breast, lung, and head and neck carcinomas, andglioblastomas.[4,5] In addition, several studies suggest a correlation betweenreceptor and/or ligand expression and poor prognosis. In some studies, EGFRoverexpression was associated with poorer prognosis in bladder, head and neck,esophageal, non-small-cell lung, and breast cancer patients.[6-10] Mostimportantly, EGFR inhibition in EGFR-expressing cancer cells leads to cell cyclearrest, apoptosis, tumor stasis, and even tumor regression in preclinicalmodels.[3,11] Inhibitors of EGFR appear to work additively and/orsynergistically with standard cytotoxic agents and radiotherapy.[12]
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