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RESEARCHTarget: bneuroblastomaScientists close in on method tofi ght deadly childhood cancerBy John PastorAmulticenter team of researchers,including scientists from UF, hasdiscovered a way to potentially blockthe growth of neuroblastoma, a type ofcancer responsible for 15 percent of all cancerdeaths in children.Working with human cell lines and tissue samples, researchersdescribed online in the journal Nature how they were able to shortcircuitgenetic processes that apparently contribute to neuroblastomas— tumors that arise from the developing nervous system in childrenand often appear in the abdomen, chest or neck.Concentrating on a gene known as ALK, the scientists used asmall-molecule inhibitor — a technique common to many drugs — toblock abnormalities that apparently cause neuroblastomas.Neuroblastomas are extremely rare, appearing in about 600 patientsannually in the United States, according to the National Institutes ofHealth. About half of the patients with neuroblastoma are diagnosedbefore the age of 18 months. In 40 percent of cases, the cancer hasspread to other parts of the body by the time doctors discover it.Treatment usually involves surgery, chemotherapy and radiation, andtransplantation for high-risk patients.“We need to find a home run for these kids,” said Wendy B. London,Ph.D., a research associate professor of epidemiology, biostatistics andhealth policy research at the UF College of Medicine and a member ofthe UF Shands Cancer Center. “A targeted therapy to treat patients withALK mutations would be a realbreakthrough.”Led by Dana-Farber CancerInstitute researchers Rani E. George,M.D., an assistant professor ofpediatrics at Harvard MedicalSchool, and A. Thomas Look, M.D.,a professor of pediatrics at Harvard,the scientists analyzed the ALK genein 94 tumors representative ofgeneral neuroblastomas and 30neuroblastoma cell lines.WENDY B. LONDON, Ph.D.Scientists discovered that ALKabnormalities in a subset ofneuroblastoma cells appear to interfere with the natural cell-deathprocesses. Furthermore, they found some of the ALK mutationswere sensitive to a tiny organic molecule known as TAE684, adiscovery that may be useful in efforts to create drugs to staunchcancer growth.In addition, researchers used gene-transfer techniques to initiateALK-related cancer in rodent cells. These transducedneuroblastomas also appear vulnerable to the small molecule,known as an ALK inhibitor.The tumor samples were obtained from the Children’s OncologyGroup Neuroblastoma Tumor Bank. COG is an NIH/NationalCancer Institute cooperative research coalition that conductspediatric cancer clinical and biological trials, including specimencollection and statistical analyses. UF is one of three sites of theCOG Statistics and Data Center, where the study design, datacollection and statistical analyses of the data take place.The current findings dovetail with the recent discovery of therole of ALK mutations in both inherited and non-inheritedversions of neuroblastoma published Aug. 24 in Nature byresearchers from The Children’s Hospital of Philadelphia.“This research group looked at neuroblastoma in a totallydifferent and complementary way to ours and came up with similarresults, validating the role of ALK mutations,” said pediatriconcologist Yael P. Mosse, M.D., of The Children’s Hospital ofPhiladelphia. “A unique aspect of their work is they proved in amodel system that these mutations can indeed be cancer-causing.”With samples they had collected from families for the past 15years, as well as additional data from COG, Children’s Hospital ofPhiladelphia scientists traced the genetic roots of manyneuroblastomas to ALK mutations — findings that open the doorto genetic screenings for the disease as well as possible therapies.Ultimately, researchers hope drug treatments can be developedto disrupt the cancer cell-signaling process. They are designing aclinical trial that would test small molecules against the cancercausingmutations in the gene.“This is the epitome of translational research,” said London,who is also the principal investigator of the COG Statistics andData Center at UF. “We will use what we have learned about thesensitivity of ALK mutations to an ALK inhibitor and attempt totranslate this knowledge to the development of targeted therapy fortreatment of neuroblastoma patients in the clinic.” PPOST 11•088 POSTVisit us online @ http://news.health.ufl.edu for the latest news and HSC events.
RESEARCHTFructose hampers hormone thatcontrols appetite, UF study fi ndsBy April Frawley BirdwellCould all those years chewing candy andslurping sugary sodas come back to hauntyou? Perhaps. A new UF study in ratsshows that a fructose-filled diet blocks the appetitecontrollinghormone leptin from doing its job,setting the body up for future obesity.Leptin is critical in controlling appetite andenergy expenditure, and scientists have long linkedleptin resistance to obesity. And several studies haveshown that overconsumption of fructose, a sugarfound in everything from apples to cookies, could beplaying a significant role in the obesity epidemic.But the UF study, recently published in theAmerican Journal of Physiology — Regulatory,Integrative and Comparative Physiology, is the first tolink fructose and leptin resistance.UF researchers found that rats became resistantALEXANDRA SHAPIRO, Ph.D. (LEFT)AND PHILIP J. SCARPACE, Ph.D.to leptin after being fed a diet high in fructose forsix months. Although there were no visible signsthis change was occurring, the fructose-fed rats gained considerably more weight than ratsthat never ate fructose when both groups were switched to a high-fat diet.“Leptin resistance is a condition that leads to obesity in rats when coupled with a high-fatdiet. The surprising finding here was that increasing the amount of fructose in the dietwithout increasing the amount of calories led to leptin resistance and later exacerbatedobesity when paired with a high-fat diet,” said Philip J. Scarpace, Ph.D., a professor ofpharmacology and therapeutics in the UF College of Medicine and the senior author of thestudy.According to this study’s findings, fructose itself does not cause obesity, but alters the wayleptin works.“It blocks leptin action most likely by blocking leptin entry into the brain,” saidAlexandra Shapiro, Ph.D., an assistant scientist in the department of pharmacology andtherapeutics and the lead author of the study.Typically, leptin resistance develops with obesity, but this study showed that high dietaryfructose causes a “silent” leptin resistance, Shapiro said. It develops undetected, but whenthe high-fat diet is introduced it causes greater than expected obesity.“Fructose sets you up,” Scarpace said. “If these findings are applicable to humans, thenthere could be consequences of eating a diet high in fructose, but only if you also consumean excessive amount of calories.” PA welcomewarningUF researchers fi nd biomarkerlinked to kidney damage afterheart surgeryBy Jennifer BrindiseHeart surgeons may soon beable to identify within anhour of surgery whichpatients are at high risk for kidneyinjury, UF College of Medicineresearchers said Oct. 14 at the 2008Clinical Congress of the AmericanCollege of Surgeons in SanFrancisco.Among medical concernsassociated with complex heartsurgery, kidney damage ranks onlyTHOMAS BEAVER, M.D.behind death, heart attack andstroke. Current blood tests warn of potential kidney problemswithin one or two days after heart surgery. UF surgeons believedeveloping a test that identifies at-risk patients while they are stillin the operating room could lead to treatments that prevent kidneyinjury altogether.In a study of patients who had complex heart surgery, UFresearchers found a correlation between postsurgery kidneydamage and the early presence of a protein called neutrophilgelatinase-associated-lipocalin,or NGAL, in the blood. NGALand other inflammatory biomarkers were detected as soon as onehour after completion of surgery, compared with the current testof serum creatinine, which does not show injury until one to twodays later.“The problem with kidney injury is that the markers wecommonly use, like measuring the serum creatinine, often changewhen it is already too late in the game,” said presenter Tad Kim,M.D., a UF surgical resident who is spending two years in thelaboratory as part of his training. “The damage is already doneand you can try to help rescue the kidneys, but you haven’t reallycaught it early enough. It would be nice if we could see somethingvia a simple blood or urine test that tells us earlier in the processthat the kidneys are undergoing injury so we can intervene insteadof waiting.”The study’s principal investigator, Thomas Beaver, M.D., anassociate professor of thoracic and cardiovascular surgery, said 10percent to 40 percent of patients undergoing heart surgery are atrisk for some level of kidney injury.“The kidneys are sensitive and highly dependent on their bloodsupply, which can be impaired during and after surgery,” Beaversaid. “They get 20 percent of the body’s blood flow, so any debristhat is in the bloodstream at the time of surgery is at risk ofreaching the kidneys.” PVisit us online @ http://news.health.ufl.edu for the latest news and HSC events. 11•08POST9
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