(Press-News.org) A new study of acute lymphoblastic leukemia (ALL), a blood cancer that primarily affects young children, has revealed that the disease has two distinct subtypes, and provides preliminary evidence that about 13 percent of ALL cases may be successfully treated with targeted drugs that have proved highly effective in the treatment of lymphomas in adults.
Usually emerging in children between 2 and 5 years of age, ALL occurs when the proliferation of white blood cells known as lymphocytes spirals out of control. The current standard of care for ALL employs high doses of chemotherapy that usually cure the disease, but may also have serious long-term effects on brain development, bone growth and fertility, so there is an unmet need for better therapies.
In addition to discovering the two ALL subtypes, the researchers, led by scientists from UC San Francisco (UCSF) and Oregon Health & Science University (OHSU), developed a simple lab test that determines whether patients fall into the less-common subtype that may respond to targeted therapy. One author of the new study, affiliated with MD Anderson Cancer Center in Texas, is already using this new test to recruit patients for a Phase 1 clinical trial evaluating the use of targeted drugs for ALL.
The research and resulting clinical trial exemplify one of the main goals of precision medicine--improving health by identifying subtypes of disease that can be specifically targeted with drugs or other therapies.
"We hope patients in this newly identified subset can be treated with these targeted drugs, which have worked very well in patients with lymphoma and which are powerfully effective in the mouse experiments we have conducted on ALL," said co-senior author Markus Müschen, MD, PhD, professor of laboratory medicine at UCSF and a member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). "These drugs have essentially no side-effects and relatively few effects on quality of life."
Müschen said the new work, reported online in Cancer Cell on March 9, 2015, grew out of a line of research on new treatments for lymphoma, which usually affects adults. That work, which culminated in papers published in The New England Journal of Medicine in 2013, showed that various forms of lymphoma respond well to treatment with ibrutinib (trade name Imbruvica) or idelalisib (trade name Zydelig), two drugs that precisely target the B-cell antigen receptor, a protein found in white blood cells.
"Because B-cells are also involved in ALL, we essentially recapitulated these studies, starting out with the basic science by studying genetic components of the B-cell antigen receptor in mice," said Müschen. "We were surprised to find that, depending on the initial cancer-causing mutation, B-cell antigen receptor signaling is sometimes present in ALL, which suggested that ALL might also respond to the drugs that had been used in lymphoma."
Led by first authors Huimin Geng, PhD, assistant professor of laboratory medicine at UCSF, postdoctoral fellow Christian Hurtz, PhD, also of UCSF, and Kyle Lenz, research assistant at OHSU, the group found that cells that exhibit B-cell antigen receptor signaling also express very high levels of a protein known as BCL-6. Then, using BCL-6 as a biomarker, the team used several methods to inhibit B-cell antigen receptor signaling, including treating cells with targeted compounds used in human lymphoma. All of these approaches successfully and selectively killed ALL cells, and similar results were seen in a mouse model of ALL.
The research group next studied 830 patients enrolled in four ongoing ALL clinical trials, in part to assess whether testing for BCL-6 expression would be a practical biomarker in the clinic to identify candidates for targeted therapy.
Virtually all of the bone marrow slices from 112 patients (13.5 percent) with active B-cell antigen receptor signaling showed "beautiful staining" of BCL-6 expression, Müschen said (in two patients only weak staining was seen). On the other hand, no BCL-6 staining was observed in patients lacking B-cell antigen receptor signaling. These results suggest that the BCL-6 test may have sufficient sensitivity and specificity to select patients for targeted therapy.
"Children are given high doses of chemotherapy for ALL because they are considered more resilient than adults, but there are long-term consequences that may not be obvious in childhood," Müschen said. "Our idea is that by adding these new drugs we can reduce the amount of conventional chemotherapy or even replace it. In our experiments with mice, both combination therapy with low-dose chemotherapy and single-agent targeted therapy each worked very well. The new clinical trial using the BCL-6 biomarker should begin to bring us the answers."
INFORMATION:
OHSU's Bill Chang, MD, PhD, was co-senior author of the study. The work was funded by the National Institutes of Health, the National Cancer Institute, the Hyundai Hope on Wheels program, the St. Baldrick's Foundation, the Leukemia and Lymphoma Society, Tucker's Toy Box Foundation, the William Lawrence and Blanche Hughes Foundation, the California Institute for Regenerative Medicine, and the U.K.'s Medical Research Council and National Institute for Health Research.
UCSF is the nation's leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and top-tier hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals. Please visit http://www.ucsf.edu.
A process that is too fast to be measured and analysed. Yet a group of international scientists did not lose heart and conceived a sort of highly sophisticated moviola film-editing system, which allowed them to observe - for the first time in a direct manner - an effect underlying high-temperature conductivity. The results of their work have been published in Nature Physics on Monday 9 March 2015.
Superconductors have properties that make them potentially very interesting for technology (examples of application include magnetic levitation trains). The road to a true application ...
Narcoleptics suffer from bouts of sleepiness and sleep attacks, which impair their ability to function in daily life. But the precise cause of narcolepsy has long eluded scientists, and the cure for the devastating neurological disorder afflicting an estimated three million people worldwide -- and one in 3,000 Americans -- remains at bay.
A new study published in Pharmacological Research by the world's leading autoimmune disease expert, Tel Aviv University's Prof. Yehuda Shoenfeld, finds that narcolepsy bears the trademarks of a classic autoimmune disorder and should ...
BOSTON, MA - Healthcare spending is at an all-time high in the U.S., yet young African-American men see little benefit, according to Boston Medical Center (BMC) researchers' Viewpoint commentary published in the current issue of the Journal of the American Medical Association (JAMA).
The researchers note that black men have a life expectancy nearly five years less than white men. While heart disease and cancer contribute to this decreased life expectancy, homicide also plays a large role. From ages 1 to 14, homicide is either the second or third leading cause of death ...
The extraordinary promise of quantum information processing -- solving problems that classical computers can't, perfectly secure communication -- depends on a phenomenon called "entanglement," in which the physical states of different quantum particles become interrelated. But entanglement is very fragile, and the difficulty of preserving it is a major obstacle to developing practical quantum information systems.
In a series of papers since 2008, members of the Optical and Quantum Communications Group at MIT's Research Laboratory of Electronics have argued that optical ...
LINCOLN, NE - Turfgrass professionals have created seed mixes specifically blended to ensure disease and insect resistance, water use efficiency, and tolerance to traffic. For example, a commonly used mixture of kentucky bluegrass (KBG) and perennial ryegrass (PRG) seed offers advantages such as rapid germination and establishment and provides turf cover that can compete with weeds. A new study shows how initial composition of KBG:PRG in the seed mixture affects species composition over multiple years in the Midwest, and offers recommendations about seeding ratios for optimal ...
ROCHESTER, Minn. -- Inhaled Nitric Oxide (iNO) is a drug approved by the Food and Drug Administration that is commonly used in term and near-term neonates who have severe respiratory failure caused by pulmonary hypertension. Over the last decade there have been multiple large studies trying to determine a clinical use for iNO in preterm neonates, but despite evidence of short-term benefit, this drug has not been shown to improve long-term outcomes in preemies. Still, the drug is commonly being used in this population, Mayo Clinic Children's Center and co-authors say in ...
LAWRENCE -- Libya hasn't been terribly hospitable for scientific research lately.
Since the 2011 toppling of Muammar Gaddafi, fighters tied to various tribes, regions and religious factions have sewn chaos across that nation. Most recently, ISIS militants in Libya committed mass beheadings that triggered retaliatory bombings by neighboring Egypt.
"Currently, it is obviously very dangerous to be a Western scientist in Libya," said Christopher Beard, Distinguished Foundation Professor of Ecology and Evolutionary Biology at the University of Kansas. "Even Libyan citizens ...
Lots of potentially useful medical information is getting lost. McGill researchers discovered this when they looked into the lack of reporting of information from "stalled drug" trials in cancer, cardiovascular and neurological diseases.
"Stalled drugs" are drugs that fail to make it to the market either because they prove to be ineffective or unsafe or both. Because only one in ten of the drugs that goes into human testing actually gets licensed, most of the information collected in developing new drugs is currently being lost. This is despite the fact that this information ...
In a study published in the current online issue of JAMA Psychiatry, an international team of scientists, led by researchers at the University of California, San Diego School of Medicine, report finding a highly accurate blood-based measure that could lead to development of a clinical test for autism spectrum disorder (ASD) risk in males as young as one to two years old. The test could be done in community pediatric settings. The degree of accuracy, they said, out performs other behavioral and genetic screens for infants and toddlers with ASD described in literature.
The ...
Eating a vegetarian diet was associated with a lower risk of colorectal cancers compared with nonvegetarians in a study of Seventh-Day Adventist men and women, according to an article published online by JAMA Internal Medicine.
Colorectal cancer is the second leading cause of cancer death in the United States. Although great attention has been paid to screening, primary prevention through lowering risk factors remains an important objective. Dietary factors have been identified as a modifiable risk factor for colorectal cancer, including red meat which is linked to increased ...
