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Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors
Epidermal growth factor receptors (EGFR) are typical enzyme-linked receptors, with an exterior ligand that binds with a signaling molecule, and an internal tyrosine kinase enzyme site. Drugs are developed to inhibit expression at either of these sites. Iressa binds to the external ligand, and has shown activity against non-small-cell lung cancer, adenocarcinoma and breast cancer. In the case of breast cancer, Iressa inhibits an overactive HER/neu tyrosine kinase.
Since unregulated signal transduction is a primary characteristic of many types of cancers, researchers are very active in the pursuit of inhibitors that can control the process. These drugs promise to become an essential part of the physician's armament against cancer, particularly those cancers that have developed resistance to other forms of treatment.
However, setbacks with Iressa, that specifically target protein kinases, reflect a lack of validated biomarkers. The next classes of signal transduction inhibitors, the vascular endothelial growth factor receptor (VEGFR) also lack validated biomarkers.
What is needed is to test the concept of targeted cancer drugs with biomarkers as pharmacodynamic endpoints, and with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry.
The importance of mechanistic work around targets as a starting point for drug development should be downplayed in favor of a systems biology (cell function analysis) approach were compounds are first screened in cell-based assays, with mechanistic understanding of the target coming only after validation of its impact on the biology.
The fundamental role of kinases in cancer biology and the success of pioneering therapeutics have prompted intensive efforts to develop kinase inhibitors. However, many of these drugs cry out for validated clinical biomarkers to help set dosage and select people likely to respond.
The Iressa situation is a great argument for pre-screening an individual's tumor. Iressa has been shown to benefit those that are benefitting from it. If the drug is working for some people, then obviously there are others out there who would also benefit. Who are those that benefit from its use? All the more reason to test the tumor first.
Assay-directed therapy is an individualized approach to killing cancer. The bio-marker method is used to determine what precise medications would kill the particular cancer. Doctors have assumed that stopping cell division would stop cancer, because most cancer cells divide and grow rapidly. But the approach didn't always kill the malignant cells. Cancer isn't a case of cells growing out of control, but of cells refusing to die on schedule.
By inhibiting anti-apoptosis with Iressa (small molecule inhibitor of tyrosine kinase, a key intermediary in the EGF cascade pathway), the cells undergo apoptosis and die. This can be detected at the whole cell level and reported out prospectively. It is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.
The EGF system is a target for a number of newer anti-cancer drugs. However, EGF-targeted drugs like Iressa are poorly-predicted by measuring the ostensible target (EGFR), but can be well-predicted by measuring the effect of the drugs on the "function" of live cells. It is an area of cancer research which has been abandoned by the entire cancer research establishment. A bioengineering problem overcomed by a band of private-lab cell biologists.
More and more physicians and patients are turning to individualized therapies to treat cancers. Under this approach, scientists study how an individual's cancerous cells respond to several drugs. Doctors have learned that even when the disease is the same type, different patients' tumors respond differently to chemotherapeutic drugs. Without individualized testing, it's difficult to determine which drugs are best for patients who don't respond to standard therapies.
There are over numerous different therapeutic drug regimens out there. Any one or combination of them can help cancer patients. The system is overloaded with drugs and under loaded with wisdom and expertise for using them. What's needed is to make extensive use of bio-marker tests in treatment decisions.
Literature Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117
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