This month's featured paper is from the labs of Drs. Tyner and Druker, and is titled, "Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML." It was published in The New England Journal of Medicine.
"Maxson, et. al., report the remarkable discovery of the genetic mutation that underlies two rare forms of leukemia. This led to essential diagnostic strategies as well as the identification of therapeutic agents that effectively target the molecular pathways affected. Using this information, treatment of a patient led to dramatic clinical improvement. This bellwether study not only presages the future of cancer therapeutics, it is also an important step in the momentous shift in traditional medicine toward a more personalized approach."
-- Eric Orwoll, M.D., associate dean for clinical science
June 12, 2013
Research method used by scientists with the OHSU Knight Cancer Institute shows promise in accelerating advances in personalized cancer medicine
Patients with two forms of leukemia, who currently have no viable treatment options, may benefit from existing drugs developed for different types of cancer, according to a study conducted by researchers at the OHSU Knight Cancer Institute.
The study, published in the May 9 edition of the New England Journal of Medicine, isolated the molecular mutation that causes chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) in some patients. That mutation, occurring in a gene called colony stimulating factor 3 receptor (CSF3R), initiates signaling through SRC, JAK, and TNK2 kinase pathways, which subsequently drives these diseases.
This discovery is promising for patients as it will aid in diagnosing these cancers, which are currently difficult for physicians to distinguish from other leukemias. More importantly, the study results suggest that these patients could be helped by existing FDA-approved drugs designed to inhibit JAK or SRC/TNK2, though clinical trials are needed.
"Our ability to rapidly pinpoint a new cancer-driving mutation demonstrates the power of integrating improved genome sequencing technology. It will accelerate our ability to tailor treatments to individuals and provides insight into the nature of this complex disease," said Jeffrey W. Tyner, Ph.D., an assistant professor with the OHSU Knight Cancer Institute and Cell & Developmental Biology Department, whose lab led the research. "What distinguished this research was our method for matching voluminous amounts of gene sequencing data with drug sensitivity data to quickly deduce which mutations were relevant in causing disease. This allows us to make a difference for patients who don't currently have good therapeutic options."
Tyner and the other researchers who conducted this study used a combination of tests not yet commonly deployed together for research on primary specimens collected from cancer patients. They performed gene sequencing on specimens from patients, creating a profile of the possible genetic causes of these diseases. This enabled them to highlight the important mutations that were common among CNL and aCML patients. As they gathered information on potentially relevant mutations, they simultaneously tested how fresh samples of patients' cancer cells responded to different drugs. This enabled the scientists to link drug efficacy to CSF3R gene mutations.
The two-pronged study approach provided researchers with the ability to quickly home in on and verify a root cause of these rare forms of leukemia. Of the 27 patients in the study, 16, or about 59 percent, had the CSF3R mutation.
"This approach allows us to rapidly discover mutations that are fundamental to cancer growth and identify drugs that might be used to combat them," said Julia Maxson, Ph.D., of the OHSU Knight Cancer Institute, who was first author on the study. "Our findings are not only promising for the treatment of patients with CNL and aCML but also validate our approach to identify new drug targets in cancer."
In fact, during the study period, a CNL patient was treated with the FDA-approved drug ruxolitinib, which inhibits the cancer cell growth initiated by the CSF3R mutation. This treatment resulted in a dramatic improvement in the patient's condition.
CNL and aCML impact several hundred patients in the United States each year. Patients afflicted with these conditions typically live only two to three years. These forms of cancer have also been difficult to diagnose because there wasn't enough known about their genetic drivers. Knowing that they are defined by mutations in CSF3R provides physicians with a means to confirm a diagnosis. Tests for this mutation are already available; the OHSU Knight Diagnostic Laboratories' GeneTrails panel for leukemias has the capability to check for this mutation.
In an editorial that accompanies the study in the New England Journal of Medicine, Jerald Radich, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, wrote that the approach is "an example of what genetically informed treatment may look like in the near future." Radich continued: "This is how we will beat cancer, one gene, one disease at a time."
This study was funded by the Leukemia & Lymphoma Society, The V Foundation, William Lawrence & Blanche Hughes Foundation, Gabrielle's Angel Foundation and the Howard Hughes Medical Institute. Researchers who contributed are also supported by grants (including 5UL1RR024140, 1-K99-CA151670-01A1, 4 R00CA151457-03 and 5P30CA069533-13) offered through the National Institutes of Health, including the National Cancer Institute.
- This article was written by Elisa Williams and first appeared as an OHSU media release.
Pictured above: (left to right) Angela G. Fleischman, M.D., Ph.D.; Christopher A. Eide, B.A.; Marc M. Loriaux, M.D., Ph.D.; Bill H. Chang, M.D., Ph.D; Jeff W. Tyner, Ph.D.; Cristina E. Tognon, Ph.D.; and Julia E. Maxson Ph.D.
In addition to Tyner and Maxson, contributors from OHSU: Angela G. Fleischman, M.D., Ph.D.; Anupriya Agarwal, Ph.D.; Christopher A. Eide, B.A.; Daniel Bottomly, M.S.; Beth Wilmot, Ph.D.; Shannon K. McWeeney, Ph.D.; Cristina E. Tognon, Ph.D.; Bill H. Chang, M.D., Ph.D.; Marc M. Loriaux, M.D., Ph.D. and Brian J. Druker, M.D.
Other contributors are Jason Gotlib, M.D., of Stanford Cancer Institute, Stanford University School of Medicine; Daniel A. Pollyea, M.D., of the University of Colorado School of Medicine; J. Blake Pond, M.S., and Robert H. Collins, M.D., of the University of Texas Southwestern Medical Center; Basem Goueli, M.D., Ph.D., of St. Luke's Regional Cancer Center; Stephen T. Oh, M.D., Ph.D., of Washington University; and Michael W. Deininger, M.D., Ph.D., University of Utah.
About the Paper of the Month
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Senior Associate Dean for Research Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.