Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Existing Drugs Offer New Treatment Options for High-Risk Childhood Leukemia Subtype

15.08.2012
Discovery of the genetic basis of a high-risk subtype of leukemia shows some patients might benefit from existing targeted therapies, advancing the goal of curing all children with the most common childhood cancer

Scientists have identified new genetic alterations underlying a high-risk subtype of the most common childhood cancer that could be effectively targeted with existing leukemia therapies.

The study focused on a subtype of acute lymphoblastic leukemia (ALL) known as Philadelphia chromosome-like ALL (Ph-like ALL). This subgroup accounts for as much as 15 percent of childhood ALL that is associated with a high risk of relapse and a poor outcome. The genetic changes driving the disease were previously unknown for about half of all patients with Ph-like ALL. The work identified new alterations in genes that regulate how cells grow and proliferate. St. Jude Children’s Research Hospital investigators led the research, which appears in the online edition of the journal Cancer Cell.

Investigators also showed that the leukemia cells were sensitive to several targeted therapeutic agents, imatinib and dasatinib, which are already being used against other leukemias, but not this subtype. The findings suggest patients with Ph-like ALL may benefit from the addition of these drugs to current chemotherapy regimens.

“One of the next steps will be to continue work on laboratory tests to rapidly identify patients whose cancer cells carry these alterations and to develop clinical trials to test targeted therapies,” said Charles Mullighan, M.D., Ph.D., an associate member of the St. Jude Department of Pathology, and a corresponding author of the study.

The study involved sequencing the RNA of cancer cells from 15 patients with Ph-like ALL and whole genome sequencing of two of those patients. Whole genome sequencing involves deciphering the DNA molecule, which contains the complete set of instructions for building and maintaining life. Cells use RNA to translate DNA’s instructions into proteins. Sequencing RNA provides a snapshot of gene activity in a cell.

The work was part of the National Cancer Institute’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which aims to use genomics to identify therapeutic targets and spur development of more effective treatments for childhood cancer. NCI is part of the National Institutes of Health. The collaboration included investigators from St. Jude, the Children’s Oncology Group and the British Columbia Genome Sciences Center.

“This work is another example of how a detailed analysis of the genetic changes present in cancer cells can identify the changes that are critical for cancer cells to escape normal growth controls and allow them to resist standard chemotherapy treatments, but also serve as an Achilles’ heel that can be attacked by drugs targeted at these genetic changes. It’s also important to recognize that work like this is only possible because patients with ALL and their parents agreed to participate in clinical trials and linked studies about the genetics of cancer,” said Stephen Hunger, M.D., a professor of pediatrics at the University of Colorado, chairman of the Children’s Oncology Group ALL Committee and a corresponding author of the study.

ALL is the most common childhood cancer. While approximately 90 percent of newly diagnosed ALL patients are cured with current treatments, only 63 percent of children with Ph-like ALL are alive and cancer-free after five years.

Ph-like ALL is named after a chromosomal rearrangement known as the Philadelphia chromosome, which is associated with another subtype of ALL. The two subtypes share similar gene expression profiles, but patients with Ph-like ALL lack the fusion of the BCR and ABL1 genes that is a hallmark of Philadelphia-positive ALL.

To determine the genetic basis of Ph-like ALL, investigators performed transcriptome and whole genome sequencing on cancer cells from young patients with Ph-like ALL. Researchers found the 15 patients harbored genetic alterations, including mutations, chromosomal rearrangements or structural variations, which disrupted tyrosine kinase or cytokine receptor signaling. Kinases are enzymes that function as on-off switches in cells. Cytokine receptors regulate how cells respond to growth factors known as cytokines.

Researchers also found the leukemia cells carried additional mutations or deletions affecting IKZF1 and other genes involved in normal B cell development. “This supports the notion that many subtypes of ALL have at least two key pathways disrupted. One is a block in maturation of immature B cells and the other drives proliferation of those cells,” Mullighan said.

When investigators screened another 436 young patients with high-risk B-cell ALL, they found some patients with Philadelphia-like ALL carried the same alterations. Those changes included the fusion of a gene named EBF1 to the tyrosine kinase gene PDGFRB. This study is the first to link the EBF1-PDGFRB fusion to cancer. Other fusions associated with ALL for the first time involved the genes STRN3-JAK2 and RANBP2-ABL1.

Researchers also showed that expression of EBF1-PDGFRB freed white blood cells from normal controls and allowed them to proliferate in the absence of growth factor. The addition of the tyrosine kinase inhibitors imatinib and dasatinib slowed proliferation and induced cell death.

When human Ph-like ALL cells expressing the NUP214-ABL1 rearrangement were transplanted into mice, the animals responded to treatment with dasatinib. Another mouse model of human Ph-like ALL that included a BCR-JAK2 fusion showed a dramatic reduction of leukemia cells following treatment with the JAK2 inhibitor, ruxolitinib. The drug is approved for use against other blood disorders with mutations in JAK2, a protein involved in cytokine signaling. Together these results suggest that although a wide range of alterations exist in Ph-like ALL, they converge on similar pathways that can be targeted with currently available ABL1 or JAK2 inhibitors.

“Although much work remains to be done, these results suggest most patients with this cancer subtype may respond to treatment with currently available tyrosine kinase inhibitors,” said Kathryn Roberts, Ph.D., a St. Jude postdoctoral fellow. She and Ryan Morin, Ph.D., of the BC Cancer Agency, Vancouver, Canada, are the study’s first authors.

The other corresponding author is Marco Marra, University of British Columbia, Vancouver. The other authors are Jinghui Zhang, Shann-Ching Chen, Debbie Payne-Turner, Michelle Churchman, Xiang Chen, Jared Becksfort, Lei Wei, Jing Ma, Steven Paugh, William E. Evans, Sima Jeha, Ching-Hon Pui and James Downing, all of St. Jude; Xiaoping Su, formerly of St. Jude; Martin Hirst, Yongjun Zhao, Kane Tse, Richard Moore, Steven Jones, Karen Mungall and Inanc Birol, all of BC Cancer Agency; Richard Harvey, I-Ming Chen and Cheryl Willman, all of University of New Mexico, Albuquerque; Corynn Kasap, Neil Shah and Mignon Loh, all of the University of California, San Francisco; Chunhua Yan and Richard Finney, both of the NIH Center for Bioinformatics and Information Technology; David Teachey, Shannon Maude and Stephan Grupp, all of the Children’s Hospital of Philadelphia; Michael Edmonson, Ying Hu and Kenneth Buetow, all of the NIH Laboratory of Population Genetics; William Carroll of New York University; Maria Kleppe and Ross Levine, both of Memorial Sloan Kettering Cancer Center, New York; Guillermo Garcia-Manero, M.D. Anderson Cancer Center, Houston; Eric Larsen, Maine Children’s Cancer Program; Meenakshi Devidas, University of Florida, Gainesville; Gregory Reaman, Children’s National Medical Center, Washington, D.C.; and Malcolm Smith and Daniela Gerhard, both of the NCI Office of Cancer Genomics.

This research was supported in part by grants (CA098543, CA98543, CA98413, CA114766, CA114762 and CA21765) from the NCI, a Leukemia and Lymphoma Society Specialized Center of Research grant, the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Center Genome Project, the St. Baldrick’s Foundation, a Stand Up To Cancer Innovative Research Grant and ALSAC.

St. Jude Children’s Research Hospital
Since opening 50 years ago, St. Jude Children’s Research Hospital has changed the way the world treats childhood cancer and other life-threatening diseases. No family ever pays St. Jude for the care their child receives and, for every child treated here, thousands more have been saved worldwide through St. Jude discoveries. The hospital has played a pivotal role in pushing U.S. pediatric cancer survival rates from 20 to 80 percent overall, and is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. It is also a leader in the research and treatment of blood disorders and infectious diseases in children. St. Jude was founded by the late entertainer Danny Thomas, who believed that no child should die in the dawn of life. To learn more, visit www.stjude.org. Follow us on Twitter @StJudeResearch
The Children’s Oncology Group
The Children’s Oncology Group (www.chidrensoncologygroup.org) is the world’s largest organization devoted exclusively to childhood and adolescent cancer research. The Children’s Oncology Group (COG) unites more than 8,000 experts in childhood cancer at more than 200 leading children’s hospitals, universities, and cancer centers across North America, Australia, New Zealand, and parts of Europe in the fight against childhood cancer. Today, more than 90 percent of the 13,500 children and adolescents diagnosed with cancer each year in the United States are cared for at COG member institutions. Research performed by the Children’s Oncology Group institutions over the past fifty years has transformed childhood cancer from a virtually incurable disease to one with a combined 5-year survival rate of 80 percent. COG’s mission is to improve the cure rate and outcome for all children with cancer.
St. Jude Media Relations Contacts
Summer Freeman
(desk) 901-595-3061
(cell) 901-297-9861
summer.freeman@stjude.org
Carrie Strehlau
(desk) 901-595-2295
(cell) 901-297-9875
carrie.strehlau@stjude.org

Summer Freeman | Newswise Science News
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH

nachricht Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>