May 11, 2005 - 3:53 am
A class of anti-cancer drugs, called tyrosine kinase inhibitors (TKIs) or anti-EGFR drugs, selectively targets cells within the body that have a specific molecular defect that is believed to cause dangerous cell behaviors such as uncontrolled proliferative growth and high metastatic potential – behaviors that typically are associated with aggressive cancer. The defect occurs within the interior of the cell in a region that is called the tyrosine kinase domain and it involves a complicated chemical process called EGFR signaling.
When tyrosine kinase inhibitors work, they can be highly beneficial, causing tumor shrinkage or promoting stable disease and extending survival. However, as with most of the newer, targeted therapy drugs, tyrosine kinase inhibitors only work for a small percentage of the patients who receive them. In various studies, response rates in single-agent and combined anti-EGFR drug therapy ranged from around 10% to 66%, depending upon the cancer type and the patient population involved. The drugs are expensive and have been associated with toxic side effects. No molecular (gene-based) test has been proven to tell reliably who will benefit from anti-EGFR treatment.
The EGFRx functional profile has been shown to correlate highly with patient response to anti-EGFR treatment and with overall patient survival. Reported prospectively, EGFRx functional profiling results reliably identify patients who do or do not respond to treatment with anti-EGFR drugs and also those who achieved superior survival after treatment.
The EGFRx targeted therapy profile includes analysis of the following targeted drugs: erlotinib (Tarceva), gefitinib (Iressa), sorafenib (Nexavar), and sunitinib (Sutent). For certain types of cancer, a drug called imatinib (Gleevec), which works in a very different way, may be tested.
As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis should be put on matching treatment to the patient. Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.
Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden, April 18, 2007, concluded that "functional profiling" with cell culture assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity of Iressa, Tarceva, Sutent, Nexavar, and Avastin in primary cultures of "fresh" human tumors).
Cell Culture Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.
Many patients are treated not only with a "targeted" therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.
There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell culture assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).
"Funtional profiling" measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, "functional profiling" is measuring them through the surrogate of measuring if the cell is alive or dead.
For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.
As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.
The "funtional profiling" technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.
This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.
Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007