Clocking cancer progression

Collaborative study with Rosetta charts molecular timeline of chronic myeloid leukemia progression, holds promise for improving patient care
Dr. Jerry Radich speaks with study collaborators
Dr. Jerry Radich, of the Clinical Research Division, chats with CML-study collaborators from the Center and Rosetta Inpharmatics, Inc. Pictured from left are Radich and Drs. Hongyue Dai, of Rosetta; Vivian Oehler, Clinical Research Division; Peter Linsley and Jan Schelter, both of Rosetta. Photo by Dean Forbes

A major obstacle to successfully treating cancer is the inability to precisely predict whether a patient would fare better with one type of therapy over another. A new Clinical Research Division study lays the groundwork for a test to predict outcome for patients with a common form of blood cancer, which could enable doctors to customize a patient's treatment precisely to their individual condition and improve their chances of survival.

The research, led by Dr. Jerry Radich and colleagues, focused on chronic myeloid leukemia (CML), a disease that progresses through a characteristic set of stages. By charting the sets of genes that are turned on or off as the disease advances from early to more aggressive phases, the scientists found reproducible genetic "signatures" that could form the basis for tests to predict prognosis and match patients with the best treatment for their illness. The study also identified genes that may be promising targets for new drugs that would be beneficial for patients whose disease is advanced and incurable with currently available therapies.

The study, conducted in collaboration with Seattle-based Rosetta Inpharmatics, Inc., is the first to comprehensively document the numerous genetic changes that occur during CML progression, said Dr. Vivian Oehler, an associate in clinical research and a co-author of the study. "A lot is known about the genetic events that lead to the onset of CML," Oehler said. "What has been missing is an understanding of the events that contribute to progression of CML from early to more advanced stages. The ultimate goal of this work is to use a subset of the genes identified in this study to develop a molecular clock of CML progression. By precisely determining an individual patient's position on the clock at the time of diagnosis, doctors would be able to select the most appropriate treatment for a patient based on stage of their disease."

The findings may be particularly significant for treating certain CML patients who have relapsed after taking the drug imatinib (Gleevec), a so-called targeted therapy developed several years ago that has become an increasingly popular alternative to bone-marrow or stem-cell transplantation, the only demonstrated cure for the disease. The study authors found that the genetic signature associated with relapse after imatinib therapy indicates that such patients have more advanced-stage disease than previously thought.

The results appear in the Feb. 21 issue of the Proceedings of the National Academy of Sciences. Contributors include Drs. Hongyue Dai, Mao Mao, Jan Schelter, Stephen Friend and Peter Linsley of Rosetta, and colleagues at the University of Chicago and the University of New Mexico.

CML is a cancer that affects the stem cells of the blood system and is ultimately fatal if untreated. Unlike most types of cancers, CML is always associated with a single genetic defect (known as the Philadelphia chromosome) and progresses through a distinct series of phases. Patients are usually diagnosed in what is known as the chronic phase, in which their white blood-cell count is elevated. The disease then progresses through an accelerated phase that is accompanied by additional genetic changes followed by the blast-crisis stage, in which cells known as immature blasts greatly increase in number and interfere with the production of all normal blood cells.

"CML is a great model disease for studying progression and devising a molecular clock," Radich said. "In addition, while everyone talks about tailoring treatment for individual cancer patients, CML is among the few diseases right now for which there really are several different treatment options that can work. The trick is figuring out where an individual patient is on the clock and what therapies will work on each patient. The gene-expression array experiments give us a chance to start understanding the biology of CML in a much more detailed way."

Treatment options

Treatment of CML is most successful when given during the chronic phase. Blood stem-cell transplantation, a procedure that can cause serious side effects, is the only known cure. Non-transplant treatments include interferon, which can prolong progression of the disease, and imatinib, a drug that directly targets the protein made by the Philadelphia chromosome. Imatinib successfully induces remission in the majority of patients in chronic phase, but the long-term duration of this remission is currently unknown. A subset of patients becomes resistant to the drug, some of whom rapidly progress into more advanced phases.

In the current study, the researchers analyzed the pattern of gene activity in blood samples from CML patients whose disease was either in chronic, accelerated or blast-crisis phase. Gene activity was measured using a technique known as microarray analysis. Microarrays, or gene chips, allow researchers to analyze thousands of genes in a blood or tissue sample simultaneously. The method provides a snapshot of which genes are switched on or off at a given point in time.

According to this gene-activity analysis, which provides greater resolution than current methods used to stage CML, the researchers found the disease has two rather than three stages: chronic and advanced, which consists of both accelerated and blast-crisis phases.

"What it looks like is that once a patient enters the accelerated phase, a critical shift has occurred," Radich said. "This has clinical implications because it means that patients at this transition stage may benefit from being treated more aggressively." For example, certain patients at this transition phase might be advised not to delay transplantation, which is more likely to fail or cause serious complications after the chronic phase.

The research also yielded new insight into the condition of patients who relapse after treatment with imatinib into what appears to be chronic phase by conventional staging tests. According to their gene-activity profile, such patients actually appeared to have more advanced-stage CML. Because the likelihood of developing resistance to the drug increases with advancing disease stage, the ability to precisely determine the extent of progression before prescribing imatinib could be of major benefit to patients, Oehler said.

Benefits of collaboration

The researchers also compared the pattern of gene activity in progressing CML cells to that of the normal developmental cycle of the healthy cells that can give rise to CML. Although they found relatively few differences between the two cell types, a subset of genes merits further investigation, Radich said.

"Some of the genes we've identified look as though they might be good targets for drugs that would work with more advanced-stage patients," he said. "Right now there are no good therapies for patients in blast crisis, so this could be of huge benefit."

Linsley of Rosetta, which is dedicated to the design and application of microarray technologies, said the project outcomes illustrate the potential benefits of collaborations between academia and industry.

"This collaboration has been a great example of how we are trying to apply technologies like microarray profiling to help develop more effective ways to treat cancer patients," he said. Hutchinson Center research activities for this project were supported by grants from the National Cancer Institute.

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