Leukemia Survival and Pharmacogenetics
There's a new way to personalize drug therapy. It's pharmacogenetics - using information on genetic differences to tailor treatment.
Deanna Kroetz, PhD, of UCSF's School of Pharmacy is exploring pharmacogenetics in the most common and deadly form of adult leukemia. The cancer is called acute myelogenous leukemia (AML). It stems from immature white blood cells in the bone marrow. AML afflicts 11,000 mostly elderly adults each year.
In cancer, drug effectiveness sometimes depends on normal variations among certain genes we inherit. Scientists call these variations polymorphisms. Likewise, differences among the genetic mutations and other abnormalities that arise within individual cancers also can affect drug responses.
Pharmacogenetics in the Most Deadly Leukemia
Time is of the essence in treating cancers. When oncologists diagnose AML, they often start the patient on chemotherapy the same day. Time lost to trial and error with chemotherapy that is ineffective or that causes unbearable side effects can increase the likelihood that an evasive cancer will eventually grow uncontrollably.
Remarkably, roughly eight out of 10 patients under age 60 who develop AML enter complete remission after an initial course of chemotherapy. This means that treatment leaves no sign of leukemia cells in the blood, and that the bone marrow again makes blood and immune cells in normal amounts.
But just as remarkably, in about half of these patients who initially fare so well, cancer returns, usually within a year. Older patients fare even worse. A new population of leukemia cells grows back from ancestors that survived earlier treatment while remaining undetected. When the leukemia returns, it is resistant to the first-used drug, so oncologists must choose an alternative.
Medical researchers have made strides in classifying AML according to different patterns of chromosome alterations commonly exhibited by cancerous cells. Oncologists already use this information to gauge prognosis and make treatment decisions. But there is much more to be learned from genes and the proteins they encode.
Pumping Information Out of Protein Pumps
In a new AML study funded by the National Institutes of Health, Kroetz and collaborator Maria Baer, MD, of the University of Maryland are looking at genes and the corresponding proteins that cancerous cells use to pump out drugs and thereby avoid the drugs' deadly effects.
Cancers that are resistant to standard AML treatment or that become resistant over time often make large amounts of the pump proteins and, in some cases, extra-active pump proteins.
The researchers are collecting information on AML gene variations, pump protein levels and pumping potency, as well as information on patient survival and side effects for comparison.
To probe the pump genes, the researchers are thawing and examining DNA from living AML cells that were frozen in liquid nitrogen as part of three earlier studies. There are cells from 1,800 AML cases.
The cells were originally collected before the cancers had been treated. After the samples were collected, the patients in those studies completed earlier were treated with standard chemotherapy - a combination of the drugs Ara-C, daunorubicin and etoposide.
Translating Research Findings into Clinical Practice
Pharmaceutical companies have developed, but not marketed, drugs that target a protein pump called P-glycoprotein. In many patients, P-glycoprotein is made in superabundance and put to work by AML and other cancers. These pump-blocking drugs have failed to improve survival in well-designed clinical trials. Even so, they appear to be effective in some patients, Kroetz says.
"Most of the studies were not done by selecting only participants with cancers that over-expressed the protein pump," the patients for whom the drug would be expected to work best, Kroetz says.
Research by Kroetz and Baer could lead to better selection of patients for future clinical trials. But any promising discoveries they make might first be applied by oncologists seeking to choose from among already available treatments.
Any significant associations Kroetz and Baer identify between genetic polymorphisms or protein superabundance on one hand and treatment outcomes on the other - if confirmed through additional study of newly diagnosed AML patients - could lead to the development of a clinical lab test. Such a test could spur a shift away from a trial-and-error approach to AML treatment, Kroetz believes.
When the US Food and Drug Administration mandated a label change for the chemotherapy agent irinotecan, highlighting the role of a key genetic polymorphism on drug response, physicians began ordering the lab test for the key gene much more often, she says.
For AML patients, a different dose, a different drug or, in some cases, bone marrow transplantation might be a better option for those whose cancerous cells pump out standard treatment, Kroetz says.
"If we have tests to avoid it, I don't think patients will be willing to take a drug that they won't respond to, that has significant toxicity and that they will have to be taken off of in a month."
Related Links