Skip to Navigation
University of Pittsburgh
Print This Page Print this pages

May 17, 2012

Research Notes

Carcinoma target identified

Four years after they discovered the viral roots of a rare skin cancer, researchers at the University of Pittsburgh Cancer Institute (UPCI) and the School of Medicine have identified a molecule activated by this virus that, in animal studies, could be targeted to selectively kill the tumor cells. The treatment soon will be tested in patients.

Merkel cell carcinoma (MCC), a skin cancer that is more common among seniors and those with weakened immune systems, could not be readily diagnosed at one time, and it still has a very poor prognosis, said Patrick S. Moore and Yuan Chang of UPCI’s cancer virology program and senior authors of a study that appears online in Science Translational Medicine.

Moore noted, “This research effort shows the speed at which genomics can identify molecular causes for cancer and then point the way toward a rational and targeted treatment.”

In 2008, the team first described the Merkel cell polyomavirus (MCV) in Merkel cell carcinoma. Within a year, they showed it was responsible for tumor development in most cases of the disease. At least four out of five healthy adults worldwide are infected with MCV, which usually doesn’t cause any symptoms.

Chang said, “The virus remains in the skin cells and, in most cases, no damage is done. But when mutations occur to this virus, it can cause cancer. Most of the 1,500 new MCC cases per year in the U.S. are caused by MCV infection.”

In quick succession, the team devised tests to identify virus-induced MCC and began unraveling the biochemical pathways that encourage tumor formation. In their latest project, they “knocked out” a key viral protein called T antigen and found that MCV directly elevates a cellular protein called survivin.

Survivin prevents cells from dying and supports cell division, the researchers said. They found that a drug called YM155, which turns off the survivin gene again, was an extremely potent killer of MCC cells in test tubes and was able to suppress the growth of human tumors that had been established in experimental mice.

In comparison, 1,360 other drugs — including most of the common chemotherapy drugs — were screened and failed to both kill MCC cells and prevent tumor growth at levels commonly achieved in patients.

A multicenter clinical trial of YM155 is expected to begin in the next six months to determine its effectiveness in MCC patients.

The trial will be led locally by Department of Medicine faculty members Hussein Tawbi and John Kirkwood, who also is co-leader of the UPCI melanoma program.

Typically, neither the cause of a cancer nor the target for a cancer drug is known initially, so most treatments have developed over decades through trial and error. Most therapies affect both healthy tissues and cancer cells, resulting in side effects that limit the drug dose that can safely be given.

This study, in contrast, was a “rational” drug study where the underlying cellular defect caused by the virus was discovered through genetic studies and then a drug targeting this process was tested.

Moore noted, “Scientists can now quickly come up with answers to complex problems, like cancer, using human genetics. In less than five years, we have gone from knowing very little about MCC to knowing its exact cause and are devising new, precisely targeted and less-toxic therapies.”

Moore also is a Distinguished Professor and American Cancer Society Professor in the Department of Microbiology and Molecular Genetics. Chang also is a Distinguished Professor and American Cancer Society Professor in the Department of Pathology.

Other Pitt co-authors included Reety Arora, Masahiro Shuda, Anna Guastafierro, Huichen Feng, Tuna Toptan and Yanis Tolstov of the UPCI cancer virology program; Daniel Normolle of the UPCI biostatistics facility; Laura L. Vollmer of Pitt’s Drug Discovery Institute (DDI); Andreas Vogt of DDI and Pitt’s Department of Computational and Systems Biology; Alexander Dömling of the departments of pharmaceutical sciences and chemistry, and Jeffrey L. Brodsky of the Department of Biological Sciences.

The research was funded by the National Cancer Institute and the American Cancer Society.

Kidney treatment guidelines developed

Kidney complications during hospitalization are as frequent and as dangerous to patients as heart attacks, and the medical community must implement recently developed guidelines to better detect and respond to the problem, said a critical care expert at the School of Medicine and UPMC in the online version of the Journal of the American Medical Association.

Acute kidney injury (AKI) is not well understood by doctors, and is even more unfamiliar to the public, wrote John A. Kellum, a professor and vice chair for research in the Department of Critical Care Medicine, and colleagues.

“Research shows that as many as 60 percent of patients in the intensive care unit will develop kidney problems, which can lead to long-term, life-threatening complications,” Kellum said. “Doctors, patients and families should perhaps view the dangers of and the need to avoid a ‘kidney attack’ with the same sense of urgency that heart attack provokes.”

Until recently, there were no recommendations about when to start treatments, such as a medication change, correcting fluid overload or dialysis, in response to abnormal kidney function, he said. But in March, an international panel of experts co-chaired by Kellum established clinical practice guidelines to end the confusion.

UPMC will launch an effort this month in which an alert will appear in a patient’s electronic medical record when certain kidney function lab tests are abnormal. It will cue the medical staff to seek advice about appropriate therapeutic strategies from nephrologists or, in the case of severe illness, critical care specialists.

“That’s a simple way of making sure that the patient gets assessed early by clinicians who have the most experience in managing AKI,” Kellum said. “UPMC already includes a sign of kidney attack — very low urine output — as a trigger for its rapid-response team. The idea is to address kidney attacks just as we do with cardiac arrest and other scenarios in which a patient becomes dangerously ill very quickly.”

CNV a better predictor of prostate cancer progress

Pathology researchers say that measuring certain gene abnormalities in the blood or tumor tissue of prostate cancer patients is a better indicator of the likelihood of relapse than the current PSA test, which measures blood levels of prostate-specific antigen.

The findings, published online in The American Journal of Pathology, show that the copy number variation (CNV) test also can indicate how aggressive or mild the relapse will be.

CNV measures the deletion or increased redundancy of areas of DNA within chromosomes in the tumor, neighboring tissues or blood. Senior investigator Jian-Hua Luo, a faculty member in pathology, said, “Our method will allow us to determine at the time of, or after biopsy or prostate removal, whether the cancer is likely to come back and, if so, how aggressively. It promises to more accurately predict the progression of the disease.”

The researchers analyzed the genomes of 238 samples from men whose prostate glands were surgically removed; 104 prostate tumor samples; 85 blood samples from prostate cancer patients, and 49 samples of disease-free prostate tissues near the tumors.

One-third of the samples were from patients whose cancer had recurred and whose PSA level had doubled in less than four months, which is associated with lethal prostate cancer; one-third from patients with disease recurrence with a slowly increasing PSA level that doubled in more than 15 months, and one-third with no relapse more than five years after surgery. The researchers also examined an additional 25 samples from prostate cancer patients to validate their findings.

They found that deletion and increased redundancy of DNA occurred in all chromosomes in prostate cancer samples. Some of these changes occurred with high frequency. Deletion and increased redundancy of DNA also occurred in benign neighboring tissue and blood samples of the cancer patients.

Gene-specific tumor CNV correctly predicted 73 percent of cases that had relapsed and 75 percent of cases in which PSA levels rapidly doubled. The CNV model from disease-free neighboring tissue correctly predicted 67 percent of cases for relapse and 77 percent of cases for short PSA doubling time. A specific tumor CNV from blood could predict 81 percent of relapse cases and 69 percent of the cases for short PSA doubling time.

The results suggest that CNV analysis could indicate the likelihood of recurrence reliably when a suspicious mass is biopsied, when a tumor is removed or in post-treatment blood monitoring. The test also could help doctors decide early in the disease process whether an individual’s cancer warrants additional therapy, Luo said.

Co-authors of the paper included Yan P. Yu, Baoguo Ren, William LaFramboise and George Michalopoulos of pathology; Chi Song and George Tseng of biostatistics, and Joel Nelson of urology.

The study was funded by the National Cancer Institute and the University of Pittsburgh Cancer Institute.

Marathoners’ hearts monitored

Researchers from the Department of Emergency Medicine launched a year-long research study into the cardiovascular stress that athletes experience from long-endurance events at this year’s Pittsburgh Marathon.

The researchers put heart monitors on 10 volunteer participants before, during and the day after the May 6 event, and also drew a blood sample immediately following the 26.2-mile race. The study participants, who cut across age ranges and competitive abilities, wore monitors that displayed results similar to a stress test  — findings that can be compared with training journals kept by participants for 10-12 weeks.

Emergency medicine faculty member Clifton Callaway said, “Much of the training for a marathon is, in fact, conditioning of the heart for this event. Despite this, there are very few studies about heart activity during actual races, and even fewer about the recovery the day after a race. Moreover, many previous studies have focused on elite runners who may not be representative of the large numbers of amateur runners who now participate in these races.”

Callaway and fellow emergency medicine faculty member Dave Hostler are the principal investigators of the research project, which they hope to expand to other major marathons around the United States.

The study is being funded by the Department of Emergency Medicine.

Ancient climate change examined

Pitt geologists have joined an international group of scientists to study prehistoric climate changes in the Arctic.

Their findings from an analysis of sedimentary and geochemical records of water-level changes in a lake in Canada’s Yukon Territory were published online in the April issue of Journal of Paleolimnology.

Lead author David Pompeani, a doctoral student in geology, said, “During the last 10,000 years there have been certain times in which rapid climate change events occurred. By analyzing Rantin Lake, we’ve contributed a piece of the puzzle toward mapping the timing and magnitude of these prehistoric events throughout the Arctic.”

In July 2006, the Pitt team, which included geology and planetary science faculty member Mark Abbott and former geology PhD student Byron Steinman (now a postdoctoral researcher at Penn State), collected two lake sediment cores and analyzed them for geochemical composition, sedimentary structure and fossil content.

Because droughts are reflected in a drop in lake levels and wet periods are characterized by deep waters, researchers were able to make inferences about past variations in the balance between precipitation and evaporation in the southern Yukon.

A comparison of the lake-level proxies with a previously developed fossil pollen record from the same lake found that rapid vegetation changes over the Holocene also occurred during shifts in the precipitation/evaporation balance, suggesting hydrologic conditions played an integral role in the evolution of the Yukon’s ecosystem.

The development of unique shallow-water sediment at the deep-water core site indicated that lake levels dropped significantly during a “megadrought” in the early Holocene.

“About 8,400 years ago, the lake almost dried out,” said Pompeani. “We documented the timing of this drought and studied its transition to conditions more typical of what we observed in the late Holocene.”

Pitt’s study, said Pompeani, contributes to the long-term perspective on natural climate variability that is needed to understand historically unprecedented changes now occurring in the Arctic.

Rapid changes in the Arctic climate system that occurred in the relatively recent past can be compared with climate models to improve the understanding of the processes responsible for such nonlinear changes.

The National Science Foundation provided funding.

Wheelchair breakdowns up

The rate of wheelchair breakdowns has risen significantly from an already high number, and it continues to leave more people with spinal-cord injuries in precarious situations, according to specialists at the School of Medicine and UPMC.

In findings published online in The American Journal of Physical Medicine and Rehabilitation, senior author Michael Boninger, chair of the School of Medicine’s Department of Physical Medicine and Rehabilitation, and colleagues said that wheelchair mechanical issues over six months’ time adversely impact users.

The researchers studied 723 people using wheelchairs a minimum of 40 hours per week, 2006-11. Research they conducted 2004-06 in 2,213 individuals found that one in six users reported two-three repairs in six months.

The new study found that 52.6 percent of full-time wheelchair users were affected and that minorities and power-wheelchair users experienced more problems. They also reported a higher number of consequences, including missing medical appointments, being stranded or getting injured.

More than one in three people with spinal-cord injuries reported needing two-three different repairs on their wheelchairs in a six-month period. Some 17.3 percent reported four or more repairs. In all, since the previous UPMC and Pitt research project on this subject, the average number of repairs rose nearly 40 percent —from 1.03 to 1.42 — and the total number of consequences doubled.

Users of Medicare/Medicaid-funded wheelchairs also had higher rates of consequences and breakdowns; the researchers concluded that might be related in part to recent changes in insurance reimbursement policies.

Boninger, who also is the director of the UPMC Rehabilitation Institute, said: “If another primary mode of transportation such as a car broke down so frequently, there’d be an uproar and a focused effort to address the underlying causes.”

The National Institute on Disability and Rehabilitation Research Office of Special Education and Rehabilitative Services and the U.S. Department of Education provided funding.

Leave a Reply