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Conference Report
11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy
November 7-10, 2000
Amsterdam, The Netherlands

Manuel Hidalgo, MD

[Medscape Hematology-Oncology 3(6), 2000. 2000 Medscape, Inc.]


The transduction of proliferative and survival stimuli such as hormones, growth factors, and cytokines from the extracellular milieu to the nuclei is a complex and highly regulated physiologic phenomenon that is one of the most fundamental processes in living cells. In its most simplistic definition, the basic biological unit of signal transduction consists of a signal receiver, a signal transducer, and a signal amplifier.

Over the last few years, advances in molecular and cellular biology have permitted the deciphering and characterization of some of the principal signal transduction pathways that are crucial for eukaryotic cell proliferation and survival. In addition, emerging data indicate that one of the most common alterations in human cancer consists of the overexpression and amplification of critical signal transduction pathways. Consequently, certain key molecules and elements of the signal transduction cascade have become the target for therapeutic interventions. Recently, a number of new anticancer agents that specifically inhibit or interact with elements of the most relevant signal transduction pathways have been discovered and tested in preclinical models; some have entered clinical development. The epidermal growth factor receptor (EGFR), and its function in a number of signal transduction pathways, have become the target of therapeutic interventions. This article will summarize the use of EGFR in therapeutic interventions as discussed at the 11th National Cancer Institute-European Organization for Research and Treatment of Cancer-American Association for Cancer Research (NCI-EORTC-AACR) Symposium on New Drugs in Cancer Therapy.



Epidermal Growth Factor Signal Transduction Pathway

The EGFR is a Mr 170,000 plasma membrane glycoprotein composed of an extracellular ligand-binding domain, a transmembrane lipophilic segment, and an intracellular tyrosine-kinase (TK) domain. Binding of activating ligands such as the epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) to the extracellular ligand-binding site of the receptor results in receptor dimerization, activation of its intrinsic TK activity, and autophosphorylation of the receptor. These effects activate a signal transduction cascade of biochemical and physiologic changes, which culminate in DNA synthesis and cell division.

There are multiple lines of evidence indicating that dysregulation of the EGFR signal transduction pathway plays a critical role in the process of tumor pathogenesis, growth, and metastasis, and, therefore, represents a potential target for anticancer therapy. Several investigators have described amplification of the EGFR gene and overexpression of the EGFR surface membrane protein in a large number of human cancers, including squamous cell carcinoma of the head and neck, malignant glioma, and lung, renal, breast, colon, and ovarian carcinomas. This enhanced expression has been associated with increased proliferative activity and metastatic potential and has been identified as an independent determinant of poor prognosis in a variety of malignant diseases. By contrast, blockade of the EGFR pathway has been shown to inhibit the proliferation of malignant cells. Specifically, inhibition of ligand-receptor binding by monoclonal antibodies inhibited the growth of human tumor xenografts. More recently, small molecules that selectively inhibit the EGFR-TK inhibited cell proliferation and exhibited antitumor activity in preclinical tumor models. These small molecules bind to the adenosine triphosphate (ATP)-binding site of receptor TK, inhibit receptor phosphorylation, and, ultimately, inhibit activation. A variety of strategies to inhibit EGFR are being actively investigated, including the use of dominant negative EGFR for gene therapy, as well as the use of novel pharmaceutical agents. Dr. G. Giaccone, of the University Hospital Vrije Universiteit in Amsterdam, The Netherlands, presented a general overview of the EGFR inhibitors in clinical development, including C225, ABX-EGF, E7.6.3, EMD 55900, ICR62, ZD1839, OSI-774, PD168393, CGP75166/PKI166, CGP593326A, and BIBX1382



C225: Inhibition of EGFR and Radiosensitization

C225 is a chimeric immunoglobulin G antibody that targets and inhibits the EGFR. Dr. J. Bonner, of the University of Alabama at Birmingham in Birmingham, Alabama, presented data regarding the interaction between C225 and radiation therapy. Exposure of EGFR-overexpressing cells to C225 in vitro resulted in tumor growth inhibition and apoptosis. When cells were exposed to radiation therapy in addition to C225, there was an increase in apoptosis that was larger than the effects achieved by either treatment modality alone. It seems that exposure of cells to C225 and C225/radiation decreases the expression of signal transduction and activation proteins (STAT proteins), an effect that is not observed with radiation therapy alone. In vivo experiments with an A431 cell line corroborated these in vitro findings.

Based on these results, a phase 1/2 trial explored the tolerability of C225 in combination with radiation therapy in patients with squamous cell carcinoma of the head and neck. Responses observed in all treated patients compared favorably with an historical control. A phase 3 randomized clinical trial is underway, and will address whether the addition of C225 to radiation therapy improves the survival of patients with advanced head and neck cancer. Additional data presented at the meeting further supported the use of EGFR blockers in combination with radiation therapy. Exposure of cancer cell lines to ionizing radiation results in activation of the EGFR. This effect has been mechanistically linked to the cytoprotective response of accelerated repopulation. Thus, disruption of the EGFR function can be expected to result in radiosensitization of cells that are EGFR-growth dependent. Dr. R.K. Schmidt-Ullrich, of the Medical College of Virginia in Richmond, Virginia, discussed the effects of EGFR inhibition on radiation therapy radiosensitization. Transfection of cells with a dominant negative EGFR (EGFR-CD533) that lacks the cytoplasmatic 533 carboxy-terminal amino acid and is functionally inert, resulted in a greater than 2-fold radiosensitization of the MDA-MB-231 breast cancer and U-87MG glioblastoma cell lines in both in vitro and in vivo experiments. These data provide the rationale to combine EGFR interacting agents with radiation therapy in tumors in which radiation therapy is the mainstay of treatment.


KB-569: An Irreversible Inhibitor of EGFR and Erb2 Receptor

EKB-569 is a new, 3-cyanoquinoline, small, irreversible inhibitor of EGFR and Erb2 receptor, a related membrane receptor. Dr. Lee Greenberger, of Wyeth-Ayerst, discussed some of the principal preclinical data of this agent. EKB-569 binds covalently to the EGFR at IC concentrations of 1 nM to 33 nM in purified enzyme extracts and 15 nM in cell extracts. Greater than 10-fold higher concentrations are required to inhibit other receptor tyrosine kinases including the Erb2 receptor. However, despite this difference in receptor affinity, the agent is approximately equipotent at inhibiting the growth of cells that overexpress either the EGFR (EC= 14 nM to 66 nM) or c-Erb-2 (IC = 12 nM to 50 nM). This effect seems to be very specific, since 10- to 50-fold higher concentrations are needed to inhibit the growth of cells that do not express either of the receptors.


OSI-774: An EGFR-TK Inhibitor

OSI-774 (formerly known as CP-358,774) is a novel low-molecular-weight quinazolin derivative that inhibits EGFR-TK and exerts antiproliferative effects. The agent specifically inhibits EGFR-TK phosphorylation and, consequently, results in cell cycle arrest and induction of apoptosis. Administration of a single 10 mg/kg dose of OSI-774 to mice bearing the HN5 human head and neck tumor xenograft resulted in a greater than 50% in vivo inhibition of EGFR autophosphorylation in tumor tissues. After a single oral dose of 100 mg/kg, maximum inhibition of EGFR autophosphorylation was evident 1 hour after dosing. This effect persisted over an inhibition range of 75% to 85% for more than 12 hours, and subsequently declined with recovery to baseline function by 24 hours.



ZD-1839: An EGFR-TK Phosphorylation Inhibitor

ZD-1839 is a low molecular weight, specific inhibitor of the ATP-dependent phosphorylation of EGFR-TK. Administration of ZD-1839 to animals with EGFR-expressing neoplasms results in dose- and plasma concentration-dependent inhibition of EGFR-TK in tumors, which is associated with cell cycle arrest, induction of apoptosis, and inhibition of angiogenesis. These effects have ultimately resulted in tumor growth inhibition and tumor responses in preclinical models and in patients, to date. ZD-1839 has demonstrated activity in several preclinical cancer models and is currently undergoing clinical development.




Emerging data indicate that EGFR is a suitable target for cancer therapy. A number of specific inhibitors of EGFR have entered clinical development; data from preclinical and clinical studies look promising. Compounds such as OSI-774 and ZD-1839 are in advanced phases of clinical development and have demonstrated substantial evidence of clinical activity. This area is one of the most exciting and rapidly growing fields of oncology and it is expected to have a major effect on the treatment of patients with cancer.