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Print ArticleLike many oncologists, Eric P. Lester, M.D., was faced with a dilemma: seven patients with advanced, incurable cancer, an arsenal of drugs that may or may not help them, and not enough solid proof about treatment efficacy to guide him. So Dr. Lester devised what he called a “simple-minded experiment” that illustrates the promise of personalized medicine. Using DNA microarray “chips,” Dr. Lester analyzed his patients’ tumors for expression of genes associated with good response to various anti-cancer drugs, and based his drug treatment plans on the results. Four out of seven patients with advanced cancer enrolled in the extremely limited study had a better outcome than expected.
The finding, presented today in Atlanta, Ga. at the American Association for Cancer Research’s second International Conference on Molecular Diagnostics in Cancer Therapeutic Development, shows that “a personalized molecular oncology approach, basing chemotherapy on relative gene expression in tumors, holds promise even at the relatively crude level employed here,” said study investigator, Dr. Lester, president of Oncology Care Associates in St. Joseph, Mich.
To obtain and analyze chip data, Dr. Lester worked with Craig Webb, Ph.D., Director of Translational Medicine at the Van Andel Research Institute in Grand Rapids, Mich.
The study is unusual because oncologists don’t yet base most of their treatment decisions on gene profiling, especially when it might involve pairing drugs together in a novel combination or using varied doses, Dr. Lester said. “Much of clinical medicine is an educated guess, and this was an attempt to come up with a better approach by using the technology of a gene chip to make multiple, highly educated guesses simultaneously,” Dr. Lester said.
Dr. Lester added that one of the seven participating patients died before the gene chip was used to direct therapy.
Many current clinical trials involving gene expression examine effectiveness markers for individual drugs rather than combinations of drugs or different doses of agents used together for the first time. To truly help the most patients, Dr. Lester said, all potentially effective drugs and combinations must be matched up against the unique genetic profile of a patient’s tumor, he said.
“Effective cancer treatment depends on understanding the biology driving the cancer, but because each tumor is different, it is very hard to personalize care and do a rigorous scientific experiment at the same time.”
In this study, Dr. Lester said he “stayed within the envelope of a reasonable standard of care” in treating his patients. That standard is often based on what insurance companies will typically reimburse for treatment given published studies about the effectiveness of a drug on a certain tumor type, and whether or not the drug is federally approved for that indication. Dr. Lester and Webb surveyed the scientific literature and compiled a list of genes whose expression levels may predict response to a drug given the tumor type.
In some cases, treatment strategies suggested by the chips varied significantly even for the same type of cancer. For example, one patient whose lung cancer had spread to his brain and bones achieved a “near complete response” when treated with two chemotherapy drugs, in addition to Tarceva and Avastin, while another lung cancer patient responded to third-line drugs such as etoposide.
Acknowledging the risk involved with using novel combinations of drugs where no set safety profile exists, Dr. Lester said that “this is constantly done in medicine. People are taking antibiotics at the same time as using heart and cholesterol pills, and blood pressure medication.”
“This kind of polypharmacy will become more common in cancer, but at the moment, it is hard to figure out the difference between doses that are effective or that could be toxic,” he said.
The best way to get around such issues is to build a database of gene expression data and match them with patient outcomes, he said. “Now when I see new patients I am itching to look at what the genes can tell me,” Dr. Lester said. “It is a smarter way to treat cancer.”
Source : American Association for Cancer Research
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Rational Thought in Cancer Medicine
It's not a case of throwing "targeted" drugs at the problem. It's knowing "what" targeted drugs and "how" to use them in "individual" patients (not average populations). The problem is that few drugs work the way oncologists think they do and few of them take the time to think through what it is they are using them for.
Scientists have conducted a series of pioneering experiments demonstrating a new way of making tumor cells far more susceptible to attack and also the possibility to lower dosage levels to a point where toxic side effects from the drugs are unlikely to occur.
Microarrays (gene chips) can examine gene expression in up to 50,000 different genes at once. It's mainly used for screening/gene discovery work. Out of 50,000 genes, maybe 15 or 20 may be involved in determining sensitivity/resistance to a given drug.
So you screen 50,000 genes to discover an association and then you focus in on only a few hundred or so for more careful study by some other method. The "gold standard" for sensitivity and reproducibility is called real time polymerase chain reaction, or RT-PCR.
Genes make proteins, the molecules that comprise and maintain all the body's tissues. Genes produce their effect by sending molecules called messenger RNA to the protein-making machinery of a cell. They set the protein-making machinery in motion through this gofer messenger RNA (or mRNA).
The technique called RNA interference (RNA-i) allows scientists to "silence" certain genes. In RNA interference, certain molecules trigger the destruction of RNA from a particular gene, so that no protein is produced. Thus, the gene is effectively silenced.
RNA interference is important for regulating the activity of genes (a fundamental mechanism for controlling the flow of genetic information). RNA interference (or RNAi) is a mechanism that interferes with mRNA, a natural molecular switch, regulating gene expression in plants, animals and humans, by "silencing" over-active or malfunctioning genes.
The ability to transfect (introducing foreign DNA into a cell) cultured cells with DNA gene sequences has allowed us to assign functions to different genes and understand the mechanisms that activate or redress their function. It has made gene therapy and stem cell research possible.
Cell culture assay tests with cell-death endpoints are the Rosetta Stone which allows for identification of clinically relevant gene expression patterns which correlate with clinical drug resistance and sensitivity for different drugs in specific diseases. 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. Cell culture assay labs have the 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.
Reference: Various Bio-Assay Laboratories
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