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 of the components of these signal-transduction pathways can lead to the development and propagation of malignancies. In addition, human cells exhibit complex responses to DNA damage, including activation of genes involved in cell-cycle arrest, DNA repair, and apoptosis. Recent findings suggest that the cellular response to DNA damage is markedly impaired by deprivation of essential growth factors or by blockage of growth-factor receptors, which suggests that these pathways contribute to the ineffectiveness of chemotherapy and radiation.[1,2] Thus, specific blockade of these pathways in tumor cells may be attractive targets for new cancer therapies, since inhibiting these pathways may induce tumor stasis and/or regression and increase the cytotoxic effects of chemotherapy and radiation.
The ErbB family of growth-factor receptors is well characterized and has generated significant interest as a target for cancer therapeutics. The family consists of epidermal growth factor receptor (EGFR), HER2, HER3, and HER4, and at least 10 ligands that bind and activate family members. Ligand-receptor binding results in receptor dimerization with the same or different family member, autophosphorylation, kinase activation, and the generation of binding sites for downstream adaptor molecules and second messengers.
Because family members can be activated by multiple ligands and ligand-receptor expression determines homo/heterodimerization between receptors as well as rate of receptor internalization and degradation, the efficiency and diversity of signal transduction through these receptor complexes is remarkable. Activation of this family of growth-factor receptors influences cell proliferation, survival, motility, adhesion, invasion, and angiogenesis. Preclinical and clinical data support the involvement of the ligands’ transforming growth factor-alpha and epidermal growth factor and EGFR in the formation and progression of human cancers. Hyperactive receptor signaling promotes deregulated cell growth and subsequent development of malignancy.
EGFR is overexpressed in a significant proportion of human cancers such as breast, lung, and head and neck carcinomas, and glioblastomas.[4,5] In addition, several studies suggest a correlation between receptor and/or ligand expression and poor prognosis. In some studies, EGFR overexpression was associated with poorer prognosis in bladder, head and neck, esophageal, non-small-cell lung, and breast cancer patients.[6-10] Most importantly, EGFR inhibition in EGFR-expressing cancer cells leads to cell cycle arrest, apoptosis, tumor stasis, and even tumor regression in preclinical models.[3,11] Inhibitors of EGFR appear to work additively and/or synergistically with standard cytotoxic agents and radiotherapy.
A number of modalities are being developed to target the ErbB family. These include antibodies to the extracellular domain of the receptors, small molecules that reversibly or irreversibly inhibit receptor autophosphorylation by inhibiting ATP binding, and antisense oligonucleotides. Among these pharmacologic strategies, both antibodies and small molecules directed toward EGFR are currently in clinical development (Table 1). However, only the small molecule ZD1839 (Iressa) and the antibody C225 are presently in phase III trials (see trials).
Given the success of trastuzumab(Drug information on trastuzumab) (Herceptin), a humanized, anti-HER2 murine monoclonal antibody, directed against the extracellular domain of HER2, it is not surprising that a similar approach targeting EGFR is underway. C225, a human/mouse chimeric antibody, binds to the EGFR extracellular domain blocking EGF-ligand binding. In vitro, this antibody blocks ligand-dependent proliferation of tumor cell lines and can induce tumor regression in xenografts. C225 potentiates the effects of ionizing radiation and, similar to trastuzumab, enhances the activity of doxorubicin(Drug information on doxorubicin) and taxanes.
Phase I trials of C225 evaluating single-dose and multi-dose schedules have been reported. In neither study was the maximum tolerated dose reached. In the single dose schedule, patients with various EGFR-overexpressing tumors received 5 to 100 mg/m2 intravenously over 30 minutes. Toxicities included fever, chills, fatigue, hepatic transaminase elevation, nausea, and acneiform skin rash. Receptor-saturating levels were obtained for 7 days. Two patients with head and neck cancer had minor responses. No serious toxicities were seen in patients receiving C225 weekly and antibody doses in the range of 200 to 400 mg/m2 were associated with complete saturation of systemic clearance. Coadministration of cisplatin(Drug information on cisplatin) at 60 mg/m2 once every 4 weeks with C225 doses of 5 to 400 mg/m2 did not alter C225 clearance. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Of 13 patients treated with antibody doses of ³ 50 mg/m2 with cisplatin, 9 completed 12 weeks of therapy, and two partial responses were observed. Concurrent treatment with C225 and radiation in patients with head and neck carcinoma did not enhance radiation-induced toxicity, and all the patients in this phase I study achieved a response. Currently, a phase III study to determine the additional benefit of C225 to radiation is being evaluated in this patient population.
Antibodies can exert a therapeutic effect by hindering receptor-ligand binding or receptor-receptor dimerization. They may also induce antibody-mediated cellular cytotoxicity. However, there are potential disadvantages to the use of antibodies as therapeutic modalities. Antibodies are bulky, which may result in inefficient treatment delivery in the setting of central nervous system malignancies. They bind to the extracellular domain of the receptor and therefore will be inactive against the truncated forms of the molecule that may be present in some percentage of tumors. Finally, antibodies have the potential for generating an immunologic response that may hinder repeated treatment. Despite these theoretical disadvantages, the anti-EGFR antibody C225 has been well tolerated and has shown promising results in early clinical trials.
Small molecule inhibitors of the intracellular tyrosine kinase domain of EGFR are also under clinical evaluation.[3,17,18] Currently available EGFR inhibitors belong to three chemical series: 4-anilinoquinazolines, 4-[ar(alk)ylamino] pyridopyrimidines, and 4-phenylaminopyrrolo-pyrimidines. Two quinazolines that have shown promising antitumor activity in early clinical trials are ZD1839 and OSI-774 (formerly CP-358, 774). These small molecules competitively inhibit ATP binding to EGFR, hindering autophosphorylation, and induce tumor stasis and even tumor regression in some tumor xenograft models.
In addition to their shared mechanism of action, these agents are also administered orally on chronic schedules and have a similar spectrum of toxicity, with diarrhea and skin rash being most common. More recently, potent, irreversible inhibitors of EGFR kinases have been developed such as CI-1033, which inhibits all four EGFR family members. This compound covalently binds to a cysteine(Drug information on cysteine) residue near the ATP binding site. Whether irreversible inhibition will result in an improved therapeutic index or will remove the need for continuous dosing will require further clinical study.
ZD1839 is an anilinoquinazoline that acts as a potent and specific inhibitor of EGFR tyrosine kinase activity by competing with adenosine(Drug information on adenosine) triphosphate for its binding site on the intracellular domain of the receptor. The IC50 of ZD1839 using enzyme extracted from A431 human squamous vulval cell line was 0.023 to 0.079 mM. It is approximately 100-fold less active against ErbB2 kinase and has little or no enzyme inhibitory activity against several other tyrosine and serine-threonine kinases tested. ZD1839 has antitumor activity in a broad range of human tumor xenografts with both tumor stasis and regression seen in xenograft models. However, rapid regrowth of tumors was generally observed when the drug was discontinued, suggesting the need for chronic administration.
Two trials are assessing escalating doses of ZD1839 administered on a continuous daily schedule. Dose-limiting toxicity has not been reached at dose levels of 600 and 800 mg/d. The most frequent adverse events were grade 1 or 2 skin rash, diarrhea, nausea, and vomiting. Grade 3 adverse events included diarrhea, skin rash, increased hepatic transaminases, nausea, and vomiting. Skin toxicity consisted primarily of grade 1 or 2 pustular or acne-like lesions with occasional erythema, or dry skin. The rash was usually located on the face, with involvement of the upper torso at higher doses, and resolved rapidly after discontinuation of the drug. Nausea and/or emesis occurred infrequently and was mild to moderate in severity. Oral doses of 250 and 500 mg/d in combination with standard chemotherapy are being evaluated in ongoing phase III placebo-controlled studies in patients with locally advanced non-small-cell lung cancer.
The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) is currently sponsoring clinical trials of ZD1839 in glioblastoma, squamous cell carcinoma of the head and neck, renal cell carcinoma, transitional cell carcinoma, colorectal carcinoma, and locally advanced non-small-cell lung carcinoma. Other studies are planned in ovarian carcinoma, endometrial carcinoma, and mesothelioma. Research goals include defining optimal combinations with conventional chemotherapeutic agents and with radiation therapy, determining the best therapy candidates, and expanding clinical trials to other tumor types. Details of these trials can be found through the National Cancer Institute’s PDQ Clinical Trials Database (http://cancernet.nci.nih.gov/trialsrch.shtml) available on the Internet through CancerNet, an NCI website that features interactive tools for online searching.