Emerging Technologies and the Diagnostic Dilemma

Emily Singer describes the complexity of using new genetic tests in the Biotech section of MIT's Technology Review.

Source: The Impact of Emerging Technologies: The Diagnostic Dilemma - Technology Review.

In the last year, several new genetic diagnostic tests have hit the market: two tests that can predict from a person's genes how well he or she will metabolize certain drugs and a third that forecasts whether lung cancer patients will respond to a specific treatment.

The tests herald the arrival of personalized medicine, which will allow doctors to select treatments and optimize drug doses for individual patients. But, according to many physicians and researchers, such tests alone won't be much help. Rather, doctors will need to learn how to incorporate them into their clinical practices, and scientists will have to figure out what kind of guidelines doctors need to do this properly.

"We need to provide enough context that the average doctor in Idaho can look at the labeling [on a drug that can be genetically targeted] and understand and truly know what to do," says Wayne Rosenkrans, director of scientific and medical strategy at AstraZeneca Pharmaceuticals in Wilmington, DE.

Tarceva, a drug for lung cancer, and its accompanying diagnostic test are often hailed as a model for this intersection of genetics and pharmacology, called pharmacogenomics. In May 2004, scientists discovered a mutation in the gene for the epidermal growth factor receptor (EGFR) that predicts who will respond to the drug. (The drug is more effective in patients whose tumors carry the mutation.) Sixteen months later, in September 2005, a commercially available version of the test was on the market, made by Genzyme Genetics, a diagnostics company based in Westborough, MA.

Doctors can use the Genzyme test to help select the right treatment for a patient -- but the results aren't always black or white, for not all patients who respond well to Tarceva carry the EGFR mutation. "Biological complexity strikes again," says Rosenkrans. "If you want an effective diagnostic, you can’t just look at the EGFR receptor."

via MedGadget

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[Gregory D. Pawelski]

Common Flaws In Oncology Microarray Studies

The heterogeneity of cancer means that a particular drug will rarely be effective against all tumors of a particular type, and the degree of efficacy will vary between patients. Also, as a result of their original mutations, many tumor cells acquire the ability to adapt rapidly to changes in their environment, sometimes by further mutation, often by molecular changes which induce resistance to the drugs used to treat them. Further courses of chemotherapy then select for resistant cells, and the treatment eventually fails to control the tumor.

To overcome the problems of heterogeneity and prevent rapid cellular adaptation, oncologists are able to tailor chemotherapy to individual patients. This is done by testing the tumor cells to see if they are susceptible to particular drugs, before giving them to the patient. DNA microarray work will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell culture assays like the EGFRx™.

Many hope that molecular tests may hold the key to success, particularly as more specific drugs are designed to hit the molecular changes that are responsible for the uncontrolled growth of cancer cells. Like testing breast cancer for the presence of hormone receptors and over-expression of growth factor receptors. However, most drugs cannot be looked at in this way and tests that are now in use have limited predictive accuracy.

So how about exposing cancer cells to the drug and testing their effect? You need to expose the cancer cells to the drugs without altering their behavior from the original tumor. It is not possible to remove the non-cancer cells from the tumor without doing this. But certain assay culture methods can get rid of the non-cancer cells before the end of the culture period. These cell culture assays have contributed to the molecular understanding of chemosensitivity and resistance.

An international study published in the August 5, 2004 issue of the New England Journal of Medicine reported that cell culture assay tests with a cell-death endpoint are effective in identifying gene expression patterns that correlate with clinical drug resistance. The study, titled "Gene Expression Patterns in Drug Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment" employed the cell-death assay to examine drug resistance at the molecular level.

The investigators exposed cells to drugs and cultured in a 96 hour suspension cell culture drug resistance assay (MTT) to define sensitivity and resistance. They used the data to define gene expression patterns associated with sensitivity and resistance to each of 4 drugs commonly used in the treatment of childhood leukemia. They were able to show that the gene expression definitions of sensitivity and resistance were significantly and independently associated with treatment outcome.

This work could not have been done without prior work in more than a thousand cell culture drug resistance test assays from children with leukemia to define sensitivity and resistance for each of the four drugs. Cell culture assays are the Rosetta Stone which allows for identification of clinically relevant gene expression patterns which correlate with clinical drug resistance for different drugs in specific diseases.

In an accompanying editorial, a review of the study findings indicated that the observed gene expression profiles represent fundamental biochemical features and suggests that gene expression profiles could be used to alter therapy instead of in vitro sensitivity testing. They go on to state that there is no single gene whose expression accurately predicts therapy outcome, emphasizing that cancer is a complex disease and needs to be attacked on many fronts.

A number of cell culture assay labs across the country have data from tens of thousands of fresh human tumor specimens, representing virtually all types of human solid and hematologic neoplasms, in which were tested a median of 17 drugs and/or drug combinations under very similar conditions to that of this acute lymphoblastic leukemia study. Cells were exposed to drugs and cultured in suspension for 96 hours and tested simultaneously with two different assays (MTT and DISC). What this means is that these cell culture assay labs have the Rosetta Stone database necessary to define sensitivity and resistance for virtually all of the currently available drugs in virtually all types of human solid and hematologic neoplasms.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

Reference: http://weisenthal.org/ex_targeted_egfr_kinase.pdf