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Adding Chemotherapy to Radiation Treatment Not Effective in Treating Vulvar Cancer, UPMC Study Shows

SAN FRANCISCO, Sept. 18 - The addition of chemotherapy to post-surgical radiation treatment is not effective in treating vulvar cancer, according to Magee-Womens Hospital of UPMC research presented this week in San Francisco at the 56th annual meeting of the American Society for Radiation Oncology (ASTRO).

Vulvar cancer is extremely rare, accounting for just 4 percent of gynecologic cancers and 0.6 percent of cancers women face in the U.S. each year. Led by Sushil Beriwal, M.D., associate professor with the department of radiation oncology at the University of Pittsburgh School of Medicine and radiation oncologist at Magee, this study identified patients diagnosed with vulvar cancer between 1998 and 2011 who had undergone surgery to remove the cancer and required adjuvant radiation therapy because the disease had spread to their lymph nodes.

The study utilized the National Cancer Database, a nationwide oncology outcomes database, to identify 1,087 patients who underwent chemotherapy treatment in addition to radiation therapy after their initial surgery to remove the cancer. The study took into account factors including age, race, insurance coverage, tumor size and spread of the disease.

“Our study found that overall, the addition of chemotherapy to adjuvant radiation therapy did not improve patient survival,” said Dr. Beriwal. “While retrospective studies do impose some limits on our conclusion, we found that at the very least, use of concurrent chemotherapy should be carefully evaluated on an individual basis.”

While the study didn’t confirm a benefit of the addition of adjuvant chemotherapy to treatment, Dr. Beriwal said it is important to share the findings because they move researchers one step closer to understanding how to most effectively treat vulvar cancer.

 

Genetic Discovery Yields Prostate Cancer Test, Promise of Future Therapy

PITTSBURGH, Sept. 15, 2014 – A genetic discovery out of the University of Pittsburgh School of Medicine is leading to a highly accurate test for aggressive prostate cancer and identifies new avenues for treatment.

The analysis, published today in the American Journal of Pathology, found that prostate cancer patients who carry certain genetic mutations have a 91 percent chance of their cancer recurring. This research was funded by the National Institutes of Health (NIH), American Cancer Society and University of Pittsburgh Cancer Institute (UPCI).

“Being able to say, with such certainty, that a patient is nearly guaranteed to see a recurrence of his prostate cancer means that doctors and patients can elect to be more aggressive in treating the cancer, knowing that the benefits likely outweigh the risks,” said Jian-Hua Luo, M.D., Ph.D., professor of pathology, Pitt School of Medicine and member of UPCI. “Eventually, this could lead to a cure for prostate cancer through genetic therapy. With this discovery, we’re at the tip of the iceberg in terms of possibilities for improving patient outcomes.”

Prostate cancer is the second most common cancer among men (behind skin cancer), with one in seven men diagnosed with prostate cancer in their lifetime. The American Cancer Society estimates that this year in the U.S., about 233,000 new cases of prostate cancer will be diagnosed, and 29,480 men will die of prostate cancer.

Despite the high incidence rate, only a fraction of men diagnosed with prostate cancer develop metastases, and even fewer die from the disease.

“In some cases, this can make the treatment more dangerous than the disease, so doctors need more accurate tests to tell them which patients would most benefit from aggressive therapies, such as surgery, radiation and chemotherapy,” said Dr. Luo.

Dr. Luo and his team sequenced the entire genome of prostate tissue samples from five prostate cancer patients who experienced aggressive recurrence of their cancer and compared them to normal tissue samples from men without cancer.

In the patients with prostate cancer recurrence, they identified 76 genetic fusion transcripts, which are hybrid genes formed from two previously separate genes and often are associated with cancer. After further testing, eight of the genetic fusion transcripts were found to be strongly associated with prostate cancer.

The researchers then screened for the eight fusion transcripts in 127 samples from patients with aggressive prostate cancer recurrence, 106 samples from prostate cancer patients with no recurrence at least five years after surgery, and 46 samples from prostate cancer patients with no recurrence less than five years after surgery. The samples came from UPMC, Stanford University Medical Center and University of Wisconsin Madison Medical Center.

In those samples, 91 percent with aggressive recurrence of their prostate cancer were positive for at least one of the fusion transcripts. Two of the fusion transcripts in particular were strongly associated with poor outcomes — none of the patients whose samples contained them survived to five years.

In contrast, 68 percent of patients whose samples did not contain at least one of the transcripts remained cancer-free.

Dr. Luo said if continued clinical trials of the test do well, it could be available to all prostate cancer patients in a few years.

In addition, studies are being developed to further investigate the genetic fusion transcripts most strongly associated with aggressive prostate cancer. Drugs and therapies could be developed to correct or stop the mutations, thereby halting the cancer progression, Dr. Luo explained.

Additional researchers on this study are Yan P. Yu, M.D., Ph.D., Ying Ding, Ph.D., Zhanghui Chen, Ph.D., Silvia Liu, B.S., Amantha Michalopoulos, B.S., Riu Chen, B.S., Kathleen Cieply, M.S., Alyssa Luvison, B.S., Bao-Guo Ren, M.D., Joel B. Nelson, M.D., George Michalopoulos, M.D., Ph.D., and George C. Tseng, Sc.D., all of Pitt; Zulfiqar G. Gulzar, Ph.D., and James D. Brooks, M.D., both of Stanford; and Bing Yang, Ph.D., and David Jarrard, M.D., both of the University of Wisconsin.

This research was supported by the NIH grants RO1 CA098249 and 1U01CA152737-01, American Cancer Society grant RSG-08-137-01-CNE and UPCI.

Internationally Acclaimed Scientist Named Co-Leader of UPCI Lung Cancer Program

PITTSBURGH, September 9, 2014 – An international leader in the field of epigenetics whose work has led to important discoveries into how cancer develops and progresses has been named the co-leader of the Lung Cancer Program at the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter. James Herman, M.D., comes to Pittsburgh from Johns Hopkins School of Medicine, where he joined the faculty in 1996. 

At Pitt’s School of Medicine, Dr. Herman will be a visiting professor of medicine in the Division of Hematology/Oncology. His appointment is effective Nov. 1. 

“Jim is a senior scientist who brings extensive experience to UPCI. He will assume leadership of the UPCI Lung Cancer SPORE grant and work closely with Dr. Mark Socinski in our Lung Cancer Program, strengthening an already impressive team,” said Nancy E. Davidson, M.D., director of UPCI and the UPMC CancerCenter. The National Cancer Institute’s prestigious SPORE, or Specialized Program of Research Excellence, is one of four such specialized research grants held at UPCI.

In addition to his work as a researcher, Dr. Herman is expected to have an appointment at the Veterans Affairs Hospital in Pittsburgh, where he will work to promote clinical care, education and clinical trials in thoracic malignancies. He will also serve as a co-director of the medical oncology fellowship program to promote training in basic and translational research.

“Our fellows are very lucky to have the opportunity to work with and learn from Dr. Herman. He has a vast knowledge of cancer research, and we can all benefit from having someone of his caliber on our team,” said Edward Chu, M.D., deputy director of UPCI and chief of the Division of Hematology-Oncology.

The author of more than 250 papers, chapters and editorials, Dr. Herman and his team are especially well-known for their development of the methylation-specific PCR assay (MSP), which is widely used to characterize DNA methylation patterns. His work has been supported by a variety of sources, including a V Scholar Award, multiple grants from the National Institutes of Health (including service as a project co-leader on the Hopkins Lung Cancer SPORE), and most recently a Department of Defense grant, all in the general area of epigenetics of cancer. He has served as a member of the editorial board for a number of journals, including Clinical Cancer Research and Journal of Clinical Oncology.

Dr. Herman received his medical degree from Johns Hopkins in 1989, where he was elected to Alpha Omega Alpha.  After completing a residency in internal medicine at Duke, he returned to Hopkins to undertake a fellowship in medical oncology. He joined the Hopkins faculty in 1996, and rose through the ranks to serve as professor of oncology starting in 2009.

UPMC-Developed Test Increases Odds of Correct Surgery for Thyroid Cancer Patients

PITTSBURGH, July 24, 2014 – The routine use of a molecular testing panel developed at UPMC greatly increases the likelihood of performing the correct initial surgery for patients with thyroid nodules and cancer, report researchers from the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter.

The test, available at the UPMC/UPCI Multidisciplinary Thyroid Center and other diagnostic testing agencies, improved the chances of patients getting the correct initial surgery by 30 percent, according to the study published this month in the Annals of Surgery.

“Before this test, about one in five potential thyroid cancer cases couldn’t be diagnosed without an operation to remove a portion of the thyroid,” said lead author Linwah Yip, M.D., assistant professor of surgery in Pitt’s School of Medicine and UPMC surgical oncologist.  Previously, “if the portion removed during the first surgery came back positive for cancer, a second surgery was needed to remove the rest of the thyroid. The molecular testing panel now bypasses that initial surgery, allowing us to go right to fully removing the cancer with one initial surgery. This reduces risk and stress to the patient, as well as recovery time and costs.”

Cancer in the thyroid, which is located in the “Adam’s apple” area of the neck, is now the fifth most common cancer diagnosed in women.  Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.

Previously, the most accurate form of testing for thyroid cancer was a fine-needle aspiration biopsy, where a doctor guides a thin needle to the thyroid and removes a small tissue sample for testing. However, in 20 percent of these biopsies, cancer cannot be ruled out. A lobectomy, which is a surgical operation to remove half of the thyroid, is then needed to diagnose or rule-out thyroid cancer. In the case of a postoperative cancer diagnosis, a second surgery is required to remove the rest of the thyroid.

Researchers have identified certain gene mutations that are indicative of an increased likelihood of thyroid cancer, and the molecular testing panel developed at UPMC can be run using the sample collected through the initial, minimally invasive biopsy, rather than a lobectomy. When the panel shows these mutations, a total thyroidectomy is advised.

Dr. Yip and her colleagues followed 671 UPMC patients with suspicious thyroid nodes who received biopsies. Approximately half the biopsy samples were run through the panel, and the other half were not. Patients whose tissue samples were not tested with the panel had a 2.5-fold higher statistically significant likelihood of having an initial lobectomy and then requiring a second operation.

“We’re currently refining the panel by adding tests for more genetic mutations, thereby making it even more accurate,” said co-author Yuri Nikiforov, M.D., Ph.D., professor in the Department of Pathology at Pitt and director of thyroid molecular diagnostics at the UPMC/UPCI Multidisciplinary Thyroid Center. “Thyroid cancer is usually very curable, and we are getting closer to quickly and efficiently identifying and treating all cases of thyroid cancer.”

In 2009, the American Thyroid Association (ATA) revised its guidelines to add that doctors may consider the use of molecular markers when the initial biopsy is inconclusive.

“The ATA is currently revising those guidelines to take into account the latest research, including our findings,” said senior author Sally Carty, M.D., Pitt professor of surgery, co-director of the UPMC/UPCI Multidisciplinary Thyroid Center and recent president of the American Association of Endocrine Surgeons. “The molecular testing panel holds promise for streamlining and eliminating unnecessary surgery not just here but nationwide.”

A previous study led by Dr. Yip showed the panel to be cost-saving when used to help in the diagnosis of thyroid cancer.

Each year, approximately half of the 25,000 patients assessed at UPMC’s Multidisciplinary Thyroid Center are found to have thyroid conditions, and more than 900 thyroid operations are performed by the center’s surgeons. The center aims to provide patients with one-stop evaluation from thyroid experts in a variety of fields, including surgery and endocrinology.

Additional researchers on this study are Laura I. Wharry, M.D., Michaele J. Armstrong, Ph.D., Ari Silbermann, B.S., Kelly L. McCoy, M.D., and Michael T. Stang, M.D., all of the Pitt Department of Surgery; Nobuyuki P. Ohori, M.D., and Marina N. Nikiforov, M.D., all of the Pitt Department of Pathology; Shane O. LeBeau, M.D., Christopher Coyne, M.D., and Steven P. Hodak, M.D., all of the Pitt Department of Endocrinology; Julie E. Bauman, M.D., of the PItt Department of Hematology/Oncology; Jonas T. Johnson, M.D., of the Pitt Department of Otolaryngology; and Mitch E. Tublin, M.D., of the Pitt Department of Radiology.

This study was funded by a grant from UPMC.

Viral Infections, Including Flu, Could Be Inhibited by Naturally Occurring Protein, UPCI Finds

PITTSBURGH, June 12, 2014 – By boosting a protein that naturally exists in our cells, an international team of researchers led by the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, has found a potential way to enhance our ability to sense and inhibit viral infections.The laboratory-based discovery, which could lead to more effective treatments for viruses ranging from hepatitis C to the flu, appears in the June 19 issue of the journal Immunity. The research is supported by the National Institutes of Health.

“Despite remarkable advances in vaccination and treatment, diseases caused by viral infections remain among the leading causes of death worldwide,” said senior author Saumendra N. Sarkar, Ph.D., assistant professor of microbiology and molecular genetics at UPCI. “We need new defenses against viral infections, and our discovery is proving to be a promising avenue for further exploration.”

Dr. Sarkar and his team made the discovery while investigating a protein called oligoadenylate synthetases-like, or OASL, which appears in increased quantities in people with liver cancer caused by the hepatitis C virus.

Hepatitis C, influenza, the childhood respiratory illness RSV, and many other viruses are known as ribonucleic acid (RNA) viruses, which use RNA as their genetic material when they replicate. The OASL protein enhances cells’ ability to detect virus RNA, activating the immune system to sense the virus and inhibit replication.

In laboratory tests, boosting this protein in human cells effectively inhibits viral replication. Conversely, mice that do not have OASL were found to be much more susceptible to viral infections.

The finding is especially notable because it may offer an alternative to interferons, another kind of protein that is made and released by cells in response to viruses. Interferons are used in therapy against some viral infections, including hepatitis C, but are not effective for other RNA viruses, such as influenza. Interferon therapy also has major side effects, and not all patients respond well to treatment.

Dr. Sarkar and his team plan to determine the most efficient way to boost the OASL pathway in patients and are working with pulmonologists to develop and identify funding for a study to evaluate the effect of boosting OASL in people with lung infections.

“The respiratory system is a much easier target to deliver this type of therapy, compared to an organ, such as the liver, so we’ll be starting with infections like RSV,” said Dr. Sarkar. “From there we could branch out to other RNA viruses and perhaps find effective ways to boost our inherent immunity against a broad range of viral infections.”

Additional authors on this study are Jianzhong Zhu, Ph.D., Yugen Zhang, Ph.D., Arundhati Ghosh, Ph.D., Rolanodo A. Cuevas, M.S., Adriana Forero, Ph.D., Madhavi K. Ganapathiraju, Ph.D., Carolyn B. Coyne, Ph.D., all of Pitt; Jayeeta Dhar, Ph.D., and Sailen Barik, Ph.D., both of Cleveland State University; Mikkel Søes Ibsen, M.S., and Rune Hartmann, Ph.D., both of Aarhus University in Denmark; Jonathan Leo Schmid-Burgk, M.S., Tobias Schmidt, M.S., and Veit Hornung, Ph.D., all of the University of Bonn in Germany; and Takashi Fujita, Ph.D., of Kyoto University in Japan.

This research was supported by National Institute of Allergy and Infectious Diseases grant no. AI082673 and UPCI.

Potential Breast Cancer Drug Performs Well in Early Clinical Trials

CHICAGO, June 1, 2014 – A drug previously studied to improve chemotherapy may be effective in treating patients with cancers related to the BRCA 1 or 2 genetic mutations, as well as patients with BRCA-like breast cancers, according to a University of Pittsburgh Cancer Institute (UPCI) clinical trial.

The results of the phase I study were presented today at the 50th annual American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

The drug, veliparib (ABT-888), is a PARP inhibitor, which means it lowers the resistance of cancer cells to treatment by targeting the polymerase (PARP) family of enzymes responsible for a wide variety of cellular processes in cancer cells, particularly DNA repair.

“Cancer cells have increased levels of PARP, which we believe may, in part, lead to resistance to chemotherapies and other cancer treatments,” said Shannon Puhalla, M.D., assistant professor of medicine, University of Pittsburgh School of Medicine, and breast oncologist with UPMC CancerCenter at Magee-Womens Hospital of UPMC. “Tumor cells in patients with BRCA mutations are particularly sensitive to the effects of PARP inhibitors due to underlying DNA repair abnormalities caused by the BRCA mutation. Veliparib can act as personalized medicine for patients with tumors caused by an inherited BRCA mutation, due to this particular sensitivity.”

The study enrolled 60 patients with a BRCA genetic mutation and 28 patients without a mutation. The objectives of the trial included determining how veliparib affected cancer cells and observing how patients responded to the drug.

“We found that veliparib is well-tolerated by patients, with fewer side effects than what can be seen with chemotherapies. In addition, anti-tumor activity was detected in both our BRCA-positive and our BRCA-negative patients,” said Dr. Puhalla.

Dr. Puhalla and a research team at UPCI have been investigating ABT-888 for five years. Their research began in the laboratory and progressed to human clinical trials. Dr. Puhalla currently is leading a phase II clinical trial with ABT-888.

“Many cancer patients with BRCA mutations end up exhausting their treatment options. Veliparib may give them another option.” Dr. Puhalla said.

The study was funded in part by an ASCO career development award Dr. Puhalla received in 2010 and an ASCO translational research professorship received by the late Merrill Egorin, M.D., who co-directed the Molecular Therapeutics and Drug Discovery program at UPCI. This study also is supported by the Pittsburgh-based Frieda G. and Saul F. Shapira BRCA Cancer Research Program and Cancer Fighting Princess.

Pennsylvania Recognizes May as Bladder Cancer Awareness Month

PITTSBURGH, May 20, 2014 The month of May has been officially recognized as Bladder Cancer Awareness Month by the State of Pennsylvania. Resolution #699 was sponsored by Representative Robert Freeman, and overwhelmingly passed by the PA House of Representatives. This recognition by the state of PA aligns with the national efforts of the Bladder Cancer Advocacy Network (BCAN). Marge Coffin, the Lehigh Valley-Central PA Chapter President of the BCAN, worked with Representative Freeman’s office to make the recognition official.

“I believe that Resolution #699 is a positive step forward in our efforts to raise awareness and understanding of this disease,” Coffin says.

In the United States, bladder cancer is the sixth most commonly diagnosed form of cancer and approximately 75,000 will be diagnosed this year. There is little public awareness of the disease, despite the fact that more than 500,000 people are currently living it. The signs and symptoms of bladder cancer can be similar to those of other conditions, which has often led to later diagnoses and poor outcomes. Throughout the month, the BCAN will provide educational materials, host events, and will focus on women and bladder cancer.

For more information about Bladder Cancer Awareness Month, please visit BCAN.org.

Jeffrey Gingrich, MD, from the Department of Urology at UPMC discusses the management and treatment of  bladder cancer in the following video: Neoadjuvant Chemotherapy in the Management of Bladder Cancer.

Maryland Patients Can Now Access UPMC CancerCenter Resources Under New Affiliation with Meritus Health’s John R. Marsh Cancer Center in Hagerstown

PITTSBURGH, May 20, 2014 – Cancer patients in Hagerstown, Md., now have access to UPMC CancerCenter’s world-class clinical care and the latest research under a new affiliation agreement with Meritus Health’s John R. Marsh Cancer Center.

The agreement, effective May 1, allows patients to access the vast resources of the UPMC CancerCenter, including its treatment protocols, clinical trials, provider-to-provider consultations, genetic counseling support services and collaboration in research and survivorship programs.

“We are excited to be able to work with Meritus Health’s John R. Marsh Cancer Center and to offer patients in Maryland access to our vast cancer network. We are proud to be able to offer patients the best in care right in their own communities and this affiliation affirms our commitment to do just that,” said Stanley Marks, M.D., chairman of UPMC CancerCenter, partner with the University of Pittsburgh Cancer Institute.

Clinical and professional staff at Meritus Health’s John R. Marsh Cancer Center also can participate in training and education programs offered through UPMC CancerCenter, the only National Cancer Institute-designated comprehensive cancer center in western Pennsylvania.

“Meritus Health is proud of our John R. Marsh Cancer Center’s affiliation with the UPMC CancerCenter network. Access to UPMC’s international experts and resources affords us the opportunity to offer our patients enhanced cancer care services close to home,” said Joseph P. Ross, Meritus Health’s president and CEO. “Service improvements, access to research studies, genetic counseling, support programs and educational resources are valuable assets for our patients, providers and staff.”

UPCI Awarded Nearly $10 Million in Prestigious NCI Grants to Foster Cancer Research

PITTSBURGH, April 24, 2014 – The University of Pittsburgh Cancer Institute (UPCI) has been awarded two highly sought-after grants from the National Cancer Institute (NCI), totaling nearly $10 million, that will aid in bringing the latest research developments from bench to bedside and accelerate research into such things as rare tumors. UPCI is one of only 12 centers in the country to receive the NCI Experimental Therapeutics-Clinical Trials Network with Phase I Emphasis grant and the only center in Pennsylvania to receive a Lead Academic Participating Site (LAPS) grant under the NCI’s new clinical trials network.

That’s good news to patients like Patrick Jackson, who was diagnosed with a rare cancer known as grade I myxopapillary-ependymomas a few years ago. Jackson was referred to UPMC, where doctors treat just a couple of cases like his each year. He said any developments that can speed research and help cancer patients is a good thing.

“I am so fortunate that my ependymoma is low grade and has responded so well to treatment,” Jackson said. “I would just want people to know that there is hope, and there is nothing more comforting than having doctors familiar with your disease.”

The awards are further evidence of UPCI’s place as one of the premier academic cancer research centers in the country. UPCI is the only NCI-designated comprehensive cancer center in western Pennsylvania and through the network of its clinical partner, UPMC CancerCenter, enables several thousand patients to participate in clinical trials each year.

“Participating in a clinical trial is the optimal form of therapy for patients who are willing and able and allows us to learn something for the future along the way. We are grateful for the support of our patients and providers who have been an integral part of our success and helped us attain these two very important awards,” said Nancy E. Davidson, M.D., director of UPCI and the UPMC CancerCenter.

The NCI Experimental Therapeutics-Clinical Trials Network with Phase I Emphasis grant is led by UPCI Deputy Director Edward Chu, M.D. The $4.25 million, five-year grant funds complex research into new drug therapies.

“Our focus is on developing completely novel agents and combination regimens. We also are trying to understand how some of these new targeted therapies work and how we can apply science to individually tailor these new treatments to specific cancers,” Dr. Chu said.

UPCI is uniquely qualified to lead efforts in drug development because of the team approach that goes into the research, he noted, with expertise in pharmacokinetics, pharmacodynamics and basic science.

“We have a large patient base that allows us to do these novel first-in-man studies. The large majority of the patients who are referred to us have failed standard-of-care therapies, and they are looking for new treatments. There is only a small handful of cancer centers across the country that can offer the types of phase I clinical studies available to our patients here in Pittsburgh and the western Pennsylvania region,” Dr. Chu said.

The LAPS grant is part of the new National Clinical Trials Network (NCTN), designed to speed up the time it takes research to get from the lab to patients through technological advances and enhanced cooperation. The nearly $5 million award is led by Adam Brufsky, M.D., Ph.D., UPCI’s associate director for clinical investigation. The grant will fund the costs of maintaining a clinical trials infrastructure that permits patients to enroll in national trials led by the NCTN at more than a dozen sites across the UPMC CancerCenter network.

“This grant is tremendous validation from the NCI about the important and cutting-edge work that we are doing here at UPCI and our ability to shape what’s happening in cancer research across the country. We’re excited to play a vital role in this new system and expand access to trials all over western Pennsylvania,” Dr. Brufsky said.

As part of the award, Dr. Brufsky will lead a group at UPCI that includes Dwight E. Heron, M.D., Mark Socinski, M.D.; John Kirkwood, M.D., and Robert P. Edwards, M.D.

The NCTN replaces the cooperative networks that existed previously and were based on a model developed more than half a century ago. NCI officials hope to speed research through improvements in data management infrastructure, the development of a standardized process for prioritization of new studies, consolidation of its component research groups to improve efficiency, and the implementation of a unified system of research subject protection at over 3,000 clinical trials sites.

One important outcome of this new network will be the ability to facilitate the conduct of trials in rare tumors where patient accrual has always been very difficult. The availability of a national network of clinical trials sites to locate and enroll patients with unusual cancers should enhance the feasibility of conducting such studies. Also, as more cancers are molecularly defined and classified into smaller subsets, the new network structure will support the molecular screening studies needed to define and locate the smaller groups of patients who might be eligible for such studies.

“It has always been our mission at UPMC CancerCenter to provide the best care possible to patients in their own communities, and this grant enhances our ability to do that,” Dr. Davidson said.

Malfunction in Molecular ‘Proofreader’ Prevents Repair of UV-Induced DNA Damage

PITTSBURGH, April 21, 2014 – Malfunctions in the molecular “proofreading” machinery, which repairs structural errors in DNA caused by ultraviolet (UV) light damage, help explain why people who have the disease xeroderma pigmentosum (XP) are at an extremely high risk for developing skin cancer, according to researchers at the University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute (UPCI). Their findings will be published this week in the early online version of the Proceedings of the National Academy of Sciences.

Previous research has shown that a DNA-repair protein called human UV-damaged DNA-binding protein, or UV-DDB, signals for a repair when two UV-DDB molecules bind to the site of the problem, said senior investigator Bennett Van Houten, Ph.D., the Richard M. Cyert Professor of Molecular Oncology, Pitt School of Medicine, and co-leader of UPCI’s Molecular and Cell Biology Program.

“Our new study shows UV-DDB makes stops along the DNA strand and transiently attaches to it, causing a proofreading change in the protein’s conformation, or shape. If the DNA is damaged the protein stays, if the DNA is not damaged the protein leaves,” Dr. Van Houten said. “When it comes to a spot that has been damaged by UV radiation, two molecules of UV-DDB converge and stay tightly bound to the site, essentially flagging it for the attention of repair machinery.”

The researchers followed the trail of single molecules of UV-DDB by tagging them with light-emitting quantum dots, enabling them to watch the molecules jump from place to place in real time on both normal and UV-exposed DNA strands.

They also tracked a mutant UV-DDB protein associated with XP, an inherited, incurable disease of light sensitivity that affects about 1 in 250,000 people. They found that the mutant UV-DDB molecules are still capable of binding to DNA, but continued to slide along the DNA rather than staying put to signal where the fix was needed.

“Without this important damage control, UV-induced errors could accumulate to cause cell alterations that foster cancer development,” Dr. Van Houten said. “Like a bus with no brakes, the XP-associated UV-DDB complex stays on the road and sees possible passengers, but keeps going past the stop.”

Co-investigators include Harshad Ghodke, Ph.D., Ching L. Hsieh, Selamawit Woldemeskel, Simon C. Watkins, Ph.D., and Vesna Rapic-Otrin, Ph.D., all of the University of Pittsburgh School of Medicine; and Hong Wang, Ph.D., of North Carolina State University.

The project was funded by the University of Pittsburgh Cancer Institute Cancer Center Support grant CA 047904 and National Institutes of Health grant ES019566.

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