viernes, 7 de septiembre de 2012

Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia || NCI Cancer Bulletin for September 4, 2012 - National Cancer Institute

NCI Cancer Bulletin for September 4, 2012 - National Cancer Institute

Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia

Conceptual illustration showing genetic analysis leading to targeted drugs. (Image by Joshua Stokes, BMC, St. Jude Children’s Research Hospital)
Genomic tools can help match cancer patients to targeted drugs. (Image by Joshua Stokes, BMC, St. Jude Children’s Research Hospital)
Using genomic tools, researchers have uncovered genetic changes associated with a form of leukemia that recurs in some children. The findings, reported last month in Cancer Cell, suggest that some of these young patients may benefit from targeted drugs that are available but currently not used to treat this particular form of the disease.
The study focused on a subtype of acute lymphoblastic leukemia (ALL) known as Philadelphia chromosome-like ALL. Children with this subtype have a higher risk of a recurrence after standard chemotherapy and lower rates of long-term survival than other children with high-risk ALL.
Since the subtype was first described in 2009 (here and here), researchers have identified genetic changes that could explain about half of these cases. Building on this work, a team led by Dr. Charles Mullighan of the St. Jude Children’s Research Hospital analyzed RNA from 15 patients with the subtype and sequenced the genomes of two of these patients.
The results, Dr. Mullighan said, were “striking.” His team found a diverse set of genetic abnormalities linked to cancer, including DNA mutations and chromosomal rearrangements. The biological effects of these changes, however, appeared to be concentrated primarily on two signaling pathways involved in cell growth and proliferation.
Making Use of Available Drugs
“We found a wide range of gene fusions, but they converged on a limited number of pathways,” said Dr. Kathryn Roberts of St. Jude, a study author. These pathways included the proteins ABL1, PDGFRB, and JAK2, which all play a role in cell growth.
In the lab, several drugs that inhibit growth-promoting signals through these pathways—including imatinib (Gleevec), dasatinib (Sprycel), and ruxolitinib (Jakafi)—showed anticancer effects against models of Philadelphia chromosome-like ALL.
“These findings are important because these children frequently have very poor outcomes,” Dr. Mullighan said. Future studies could test whether patients with mutations affecting these pathways could be candidates to receive targeted drugs along with chemotherapy, he added.
Overall, children with high-risk ALL have a greater than 80 percent chance of being cured by standard treatments, but only about 60 percent of children with Philadelphia chromosome-like ALL are alive and free of cancer after 5 years. This subtype, which accounts for about 15 percent of childhood ALL cases, shows similar patterns of gene activity as Philadelphia chromosome-positive ALL, but the BCR-ABL1 fusion gene is absent.
Better Diagnostic Tests Needed
The new results are from the TARGET initiative, an NCI-supported project that brings together experts on childhood cancers and genome analysis to identify genetic alterations that could be targeted by new or existing therapies.
“These are exactly the kind of results this initiative was created to generate,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program and an NCI leader of the TARGET initiative.
Dr. Charles Mullighan (Photo by BMC, St. Jude Children’s Research Hospital)
Dr. Charles Mullighan and his team showed that patients with a high-risk form of leukemia might benefit from existing targeted therapies. (Photo by BMC, St. Jude Children’s Research Hospital)
“At this point there are anecdotal examples of how these findings could be translated for broader application,” Dr. Smith continued. Future challenges include improving diagnostic tests to detect the specific molecular alterations and developing treatments appropriate for each alteration, he noted.
At St. Jude, Dr. Roberts is investigating two approaches for detecting this subtype of ALL at the time of diagnosis. One strategy is to profile the active pathways in the leukemia cells, and the other is to look for signature patterns of gene activity.
These tests could serve as an initial screen for Philadelphia chromosome-like ALL, followed by testing for specific genetic alterations associated with the disease, according to Dr. Christine Harrison of Newcastle University in the United Kingdom, who wrote an accompanying editorial.
She praised the study for providing “a comprehensive genomic definition” of Philadelphia chromosome-like ALL, showing it to be a disease with distinctive genetic alterations that affect a range of proteins involved in cell growth.
The work also illustrates one way that cancer researchers are increasingly using genomic tools, noted co-author Dr. Stephen Hunger of the University of Colorado, who is also chair of the Children’s Oncology Group ALL Disease Committee.
“The first step is to identify the abnormalities driving the development of a particular cancer,” he explained. “Then, you use therapies directed against those abnormalities—either alone or with chemotherapy—to improve the outcomes of patients with the least possible side effects.”
Dr. Smith added, “Targeted agents are already known for some of the molecular alterations in Philadelphia chromosome-like ALL, but for others they will need to be identified.”
Dr. Mullighan agreed that a more complete understanding of the Philadelphia chromosome-like ALL subtype is needed. When his team expanded their analysis to include samples from more than 400 patients, the critical lesions in about 20 percent of the cases were unknown.
“We need to know what the changes are, and no single method of analysis is going to pick up every genetic alteration,” he said.
Knowledge gained from studying Philadelphia chromosome-like ALL in children could prove useful for adolescents and young adults as well. This subtype is thought to be more common with advancing age, and the prognosis may also worsen with age.
Since the study was published, Dr. Mullighan has received inquiries from doctors who want to know whether their patients with ALL might be candidates for the new approach. For the study authors, this has underscored the importance of developing clinically accredited tests.
“We really need to develop the diagnostic tests so that we can identify these patients at the time of diagnosis and direct them to the most appropriate targeted therapy,” Dr. Roberts said.
Edward R. Winstead
Related articles: “Genome Studies Yield Insights into Childhood Leukemia
To see Dr. Roberts discussing her findings, please watch this video Exit Disclaimer.

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