Individuals with chronic myeloid leukemia (CML) are treated first with a drug known as imatinib (Gleevec), which targets the protein known to cause the cancer (BCR-ABL). If their disease returns, because BCR-ABL mutants emerge that are resistant to the effects of imatinib, individuals are treated with a drug known as dasatinib (SPRYCEL), which targets BCR-ABL in a different way. However, patients that relapse after treatment with dasatinib, because BCR-ABL mutants emerge that are resistant to the effects of this drug, are now beginning to be seen in the clinic. Researchers from Memorial Sloan-Kettering Cancer Center, New York, now suggest that treating patients with a combination of the drugs might decrease the chance of the cancer returning, or at the very least increase the time before a relapse occurs
In the study, which appears online on August 16 in advance of publication in the September print issue of the Journal of Clinical Investigation, Charles Sawyers and colleagues show that 2 of 12 patients whose cancer had returned after treatment with dasatinib responded to retreatment with imatinib. Analysis of the BCR-ABL proteins from these patients revealed that their BCR-ABL had only the dasatinib-resistance mutation. By contrast, the BCR-ABL proteins of the other patients had either a single mutation that rendered the protein resistant to both dasatinib and imatinib or had two mutations, one rendering the protein resistant to imatinib and one rendering the protein resistant to dasatinib. A third drug that can target dasatinib- and imatinib-resitant BCR-ABL is currently in clinical trials. The authors therefore suggest that rather than treating CML patients with the drugs that target BCR-ABL sequentially, they should receive all the drugs when they are first diagnosed with the disease so that the emergence of the drug-resistant forms of BCR-ABL might be prevented, or at least delayed.
TITLE: Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency
AUTHOR CONTACT: Charles L. Sawyers Memorial Sloan-Kettering Cancer Center, New York, New York, USA. Phone: (646) 888-2138; Fax: (646) 888-2595; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30890
Contact: Karen Honey
Journal of Clinical Investigation
Review covers 136 countries in US, Canada, UK, France, Germany, Japan and Spain
Leukaemia rates in children and young people are elevated near nuclear facilities, but no clear explanation exists to explain the rise, according to a research review published in the July issue of European Journal of Cancer Care.
Researchers at the Medical University of South Carolina carried out a sophisticated meta-analysis of 17 research papers covering 136 nuclear sites in the UK, Canada, France, the USA, Germany, Japan and Spain.
They found that death rates for children up to the age of nine were elevated by between five and 24 per cent, depending on their proximity to nuclear facilities, and by two to 18 per cent in children and young people up to the age of 25.
Incidence rates were increased by 14 to 21 per cent in zero to nine year olds and seven to ten percent in zero to 25 year-olds.
“Childhood leukaemia is a rare disease and nuclear sites are commonly found in rural areas, which means that sample sizes tend to be small” says lead author Dr Peter J Baker.
“The advantage of carrying out a meta-analysis is that it enables us to draw together a number of studies that have employed common methods and draw wider conclusions.”
Eight separate analyses were performed – including unadjusted, random and fixed effect models – and the figures they produced showed considerable consistency.
But the authors point out that dose-response studies they looked at – which describe how an organism is affected by different levels of exposure – did not show excess rates near nuclear facilities.
“Several difficulties arise when conducting dose-response studies in an epidemiological setting as they rely on a wide range of factors that are often hard to quantify” explains Dr Baker. “It is also possible that there are environmental issues involved that we don’t yet understand.
“If the amount of exposure were too low to cause the excess risk, we would expect leukaemia rates to remain consistent before and after the start-up of a nuclear facility. However, our meta-analysis, consistently showed elevated illness and death rates for children and young people living near nuclear facilities.”
The research review looked at studies carried out between 1984 and 1999, focusing on research that provided statistics for individual sites on children and young people aged from zero to 25.
Four studies covered the UK, with a further three covering just Scotland. Three covered France, two looked at Canada and there was one study each from the USA, Japan, Spain, the former East Germany and the former West Germany.
“Although our meta-analysis found consistently elevated rates of leukaemia near nuclear facilities, it is important to note that there are still many questions to be answered, not least about why these rates increase” concludes Dr Baker.
“Several hypotheses have been proposed to explain the excess of childhood leukaemia in the vicinity of nuclear facilities, including environmental exposure and parental exposure. Professor Kinlen from Oxford University has also put forward a hypothesis that viral transmission, caused by mixing populations in a new rural location, could be responsible.
“It is clear that further research is needed into this important subject.”
Notes to editors
Meta-analysis of standardized incidence and mortality rates of childhood leukaemia in proximity to nuclear facilities. Baker PJ and Hoel D. European Journal of Cancer Care. 16, pages 355-363. July 2007.
The European Journal of Cancer Care provides a medium for communicating multi-professional cancer care across Europe and internationally. The Journal publishes peer-reviewed papers, reviews, reports, features and news, and provides a means of recording lively debate and an exchange of ideas. It is published six times a year by Blackwell Publishing.
Blackwell Publishing is the world’s leading society publisher, partnering with 665 medical, academic, and professional societies. Blackwell publishes over 800 journals and has over 6,000 books in print. The company employs over 1,000 staff members in offices in the US, UK, Australia, China, Singapore, Denmark, Germany and Japan and officially merged with John Wiley & Sons, Inc’s Scientific, Technical and Medical business in February 2007. Blackwell’s mission as an expert publisher is to create long-term partnerships with our clients that enhance learning, disseminate research, and improve the quality of professional practice. For more information on Blackwell Publishing, please visit http://www.blackwellpublishing.com or http://www.blackwell-synergy.com
Contact: Annette Whibley
Blackwell Publishing Ltd.
Contact: Karen Mallet
Fox Chase Cancer Center
Fox Chase Cancer Center researchers described dismantling proteins in journal Cell
Submarines have periscopes. Insects have antennae. And increasingly, biologists are finding that most normal vertebrate cells have cilia, small hair-like structures that protrude like antennae into the surrounding environment to detect signals that control cell growth. In a new study published in the June 29 issue of Cell, Fox Chase Cancer Center researchers describe the strong link between ciliary signaling and cancer and identify the rogue engineers responsible for dismantling the cell’s antenna.
Cilia-based sensing has important roles in sight, smell and motion detection and in helping an embryo develop into a normal baby. Defects in cilia can produce a range of disorders, including kidney cysts, infertility, respiratory problems, reversal of organs (for example, heart on the right) and a predisposition to obesity, diabetes and high blood pressure. In each case, cells fail to appropriately detect growth-controlling signals and develop abnormally. Now, researchers are adding cancer to this list.
“Many cancers arise from defects in cellular signaling systems, and we think we have just identified a really exciting signaling connection,” Fox Chase Cancer Center molecular biologist Erica A. Golemis, Ph.D., points out. In the new study, Golemis and her Fox Chase colleagues found that two proteins with important roles in cancer progression and metastasis, HEF1 and Aurora A, have an unexpected role in controlling the temporary disappearance of cilia during normal cell division, by turning on a third protein, HDAC6. This action causes the “antenna” to be dismantled in an untimely way.
Why cilia come and go on normal cells is not entirely understood, but scientists increasingly suspect that it may play a role in timing the cell division process. Commonly, cancer cells have entirely lost their cilia, and this absence may help explain why tumors fail to respond properly to environmental cues that cause normal cells to stop growing. Hence, the discovery that too much HEF1 and Aurora A cause cilia to disassemble provides important hints into what may be happening in cancers.
Defects in cilia have already been identified in one disease that represents a significant public health burden. Polycystic kidney disease, or PKD, arises from genetic mutations that cause flawed kidney-cell ciliary signaling. PKD is the most common serious hereditary disease, affecting more than 600,000 Americans and 12.5 million people worldwide.
In this incurable syndrome, patients develop numerous, fluid-filled cysts on the kidneys. For many patients, chronic pain is a common problem. PKD leads to kidney failure in about half of cases, requiring kidney dialysis or a kidney transplant.
The proteins involved in dismantling the cilia are no strangers to Golemis and her team. Golemis has been studying HEF1 for over a decade, since she first identified the gene. She first discovered that HEF1 has a role in controlling normal cell movement and tumor cell invasion. Golemis’ laboratory has also shown that Aurora A and HEF1 interact to initiate mitosis (chromosome separation) during cell division.
Suggestively, many cancers produce too much of the Aurora A protein, including breast and colorectal cancers and leukemia. In 2006, excessive production of HEF1 (also known as NEDD9) was found to drive metastasis in over a third of human melanomas, while HEF1 signaling also contributes to the aggressiveness of some brain cancers (glioblastomas).
“Now there’s a new activity for these proteins at cilia,” said co-author Elizabeth P. Henske, M.D., a medical oncologist and genetics researcher who studies the genetic basis of kidney tumors. This complex HEF1 and Aurora A function may mean the increased levels of these proteins in cancer affect cellular response to multiple signaling pathways, rather like a chain reaction highway accident.
The research has significant implications for the understanding and treatment of cancer. The experiments leading to the new paper showed that “small-molecule inhibitors of Aurora A and HDAC6 selectively stabilize cilia,” the authors concluded, “suggesting a novel mode of action for these clinical agents.” Clinical trials of such inhibitors have already begun, so learning more about the mechanisms of their targets is important in understanding how these agents work and who might benefit from them.
“It is also tantalizing to consider that closer connections exist between dysplastic disorders leading to cysts and cancer than have previously been appreciated,” the authors wrote. “Overall, deregulated Aurora A/HEF1/HDAC6 signaling may have broad implications for studies of human development and disease.”
The authors are now investigating possible roles for HEF1 and Aurora A in PKD. They are intrigued by the fact that a study published last year showed that important gene, PKHD1, commonly mutated in PKD has also been found as a target of mutation in colorectal cancer.
In addition to Golemis and Henske, co-authors include Elena N. Pugacheva, Ph.D., Tiffiney Hartman, Ph.D., and Sandra A. Jablonski, Ph.D., all of Fox Chase Cancer Center. Grants from the National Institutes of Health, Department of Defense, Pennsylvania Tobacco Settlement Funds and the Susan B. Komen Foundation supported this research, along with the Cancer Center support grant from NIH and an appropriation from the Commonwealth of Pennsylvania to Fox Chase Cancer Center.
Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation’s first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of cancer prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center’s web site at http://www.fccc.edu or call 1-888-FOX CHASE.
Contact: Summer Freeman
St. Jude Children’s Research Hospital
St. Jude researchers discover that variations in genes that affect the behavior of leukemia chemotherapy drugs in the body are linked to drug toxicity, a finding that will likely help clinicians predict how patients will respond to specific agents
Investigators at St. Jude Children’s Research Hospital have discovered inherited variations in certain genes that make children with acute lymphoblastic leukemia (ALL) susceptible to the toxic side effects caused by chemotherapy medications. The researchers showed that these variations, called polymorphisms, occur in specific genes known to influence pharmacodynamics (how drugs work in the body and how much drug is needed to have its intended effect).
The findings, made during a study of 240 children, are important because these side effects in ALL can be life-threatening and interrupt delivery of treatment, increasing the risk of relapse. The new insights gained in this study could help individualize ALL chemotherapy according to a patient’s inherited tendencies to develop toxic reactions to specific drugs.
“Such individualized therapy would eliminate the time-consuming trial-and-error approach to finding the right dose for a patient,” said Mary Relling, Pharm.D., chair of the Pharmaceutical Sciences department at St. Jude. “When the results of our findings are translated into routine clinical care, we should see less toxicity among children being treated for ALL.” Relling is senior author of a report of this work that appears in the May 15 issue of “Blood.”
The St. Jude team extracted DNA from healthy white blood cells of patients and looked for 16 polymorphisms previously known to be present in genes linked to drug pharmacodynamics. Using a variety of statistical analyses, the investigators identified links between specific polymorphisms and gastrointestinal, infectious, hepatic (liver), and neurologic toxicities during each phase of treatment. The three treatment phases were induction, the initial phase designed to cause remission of the cancer; consolidation, the follow-up after induction; and consolidation, the final phase to ensure comprehensive elimination of cancer cells.
The study showed that some of the 16 genetic polymorphisms are linked to toxic side effects during more than one treatment phase; and some caused more than one type of toxicity. Certain polymorphisms were linked to the pharmacokinetics of specific drugs— how drugs are absorbed by the body, distributed, chemically modified or broken down and eliminated. Variations in pharmacokinetics can alter the levels of drugs in the body, leading to ineffective or toxic levels in individual patients.
For example, during the induction phase, when a variety of different types of chemotherapy drugs are used, polymorphisms in the two genes that were part of a biochemical pathway that breaks down chemotherapy drugs were linked to gastrointestinal toxicity and infection, respectively. In the consolidation phase, when drugs called antifolates were the main treatment, a folate was linked to gastrointestinal toxicity, as it was during the continuation phase. And in all three phases, one polymorphism was linked to hyperbilirubinemia, or jaundice, partly caused by the drug methotrexate.
“Scientists at St. Jude and elsewhere have dramatically improved survival rates from childhood leukemia, but it’s still challenging to find the right dose for each patient,” said Rochelle Long, Ph.D., director of the National Institutes of Health Pharmacogenetics Research Network. “By finding specific genetic variations linked to how individual patients respond to therapy, this work will make medicines safer and more effective for everyone.”
Other authors of this work include Shinji Kishi, Cheng Cheng, Deborah French, Deqing Pei, Nobuko Hijiya, Ching-Hon Pui and William Evans (St. Jude); Soma Das and Edwin Cook (University of Chicago); Carmelo Rizzari (University of Milan, Italy), Gary Rosner (M.D. Anderson Cancer Center, Houston) and Tony Frudakis (DNAPrint Genomics, Sarasota, Fla.).
This work was supported in part by the National Cancer Institute; the National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database; a Center of Excellence grant from the State of Tennessee and ALSAC.
St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.
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