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UPCI Researcher Named Outstanding Investigator by NCI, Awarded $6.3M for Studying How Food Can Lower Cancer Risks

PITTSBURGH, Aug. 6, 2015 Thomas Kensler, Ph.D., professor of pharmacology and chemical biology and co-leader for the Cancer Epidemiology and Prevention Program at the University of Pittsburgh Cancer Institute (UPCI), was awarded a $6.3 million Outstanding Investigator Award from the National Cancer Institute (NCI). This new award acknowledges experienced researchers and provides them with long-term support for their exceptional work.

Dr. Kensler’s research focuses on chemoprevention, or how food can be used to lower the risk of developing cancer caused by unavoidable environmental toxins.

“The NCI Outstanding Investigator Award addresses a problem that many cancer researchers experience:  finding a balance between focusing on their science while ensuring that they will have funds to continue their research in the future,” said Dinah Singer, Ph.D., director of NCI’s Division of Cancer Biology. “With seven years of uninterrupted funding, NCI is providing investigators the opportunity to fully develop exceptional and ambitious cancer research programs.”

The seven-year grant is one of just 60 awarded in its inaugural year.

Research has shown that controlling diet, increasing exercise and quitting smoking can decrease the risk of developing cancer; however, environmental toxins such as fossil fuel combustion products are more difficult to mitigate. Past studies by Dr. Kensler’s team in China, where environmental controls are less rigorous, have examined the bioactive molecules in broccoli and how they may help people there detoxify air pollutants.

“Pollution is a global problem and its effects are seen most often among the elderly, disabled, children and minorities. We need effective and affordable interventions, and using food-based strategies could be the ideal way to address this,” Dr. Kensler said.

He and his team will focus on a biological pathway known to play a role in detoxification, identify and validate biomarkers of its activity, and examine the molecular consequences of its chronic activation.

“It’s truly an honor for Dr. Kensler to be among the first to receive this prestigious award. He has pioneered our understanding of how chemically reactive constituents in foodstuffs can profoundly and positively impact tissue defense and repair mechanisms. We’re proud of the work he is doing to try and lessen the burden of cancer, not only in western Pennsylvania but around the globe,” said Bruce Freeman, Ph.D., UPMC-Irwin Fridovich Professor and Chair of Pharmacology and Chemical Biology.

Research reported in this publication was supported by the NCI under award number 1R35CA197222-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Cancer Researcher at Children’s Hospital of Pittsburgh of UPMC Receives Grant from St. Baldrick’s Foundation

PrintPITTSBURGH, Aug. 6, 2015 Edward V. Prochownik, M.D., Ph.D., director of oncology research at Children’s Hospital of Pittsburgh of UPMC, and the Paul C. Gaffney Professor of Pediatrics, has been awarded a research grant of $100,000 from the St. Baldrick’s Foundation, a volunteer-driven charity dedicated to raising money for childhood cancer research.

The award to Dr. Prochownik is one of 70 grants totaling more than $21.1 million nationally and internationally awarded by St. Baldrick’s in support of pediatric oncology research. These grants provide resources to institutions to conduct more research and enroll more children in ongoing clinical trials. Dr. Prochownik and his team will explore the implications of new observations of cancer cell growth.

“Cancer cells must alter their metabolism to provide the necessary energy and metabolic building blocks needed to support their rapid division,” said Dr. Prochownik, who also is professor of molecular genetics and biochemistry, University of Pittsburgh School of Medicine. “We have identified some of the key means by which the cell can control these changes. Confirming and extending these findings as we propose to do could provide novel and specific ways to interfere with this process and thus inhibit tumor growth while minimizing long-term side effects.”

Over the past year, Dr. Prochownik and his research team have developed a model of hepatoblastoma, the most common childhood liver cancer, which in advanced states is difficult to treat and requires use of drugs that can cause long-term toxicities.

“We have discovered that the mitochondria of these hepatoblastoma cells appear to be reprogrammed so as to allow them to function at maximal capacity and thus provide large amounts of energy and metabolic building blocks needed by the rapidly growing and dividing cancer cells,” explained Dr. Prochownik. “We hope that our observations at this level can be translated into new and specific ways of treating this cancer while at the same time reducing toxicity.”

This past year, three St. Baldrick’s head-shaving events were hosted in Pittsburgh, where more than 140 people “braved the shave” and raised nearly $86,000.

For more information about Dr. Prochownik, please visit www.chp.edu.

Ancient Proteins Involved in DNA Repair Could Shed Light on Tumor Development, Says Pitt Study

PITTSBURGH, July 28, 2015 – By studying the yeast used in beer- and bread-making, researchers at the University of Pittsburgh School of Medicine have uncovered the mechanism by which ancient proteins repair DNA damage and how their dysfunction could lead to the development of tumors. The findings, published online today in Nature Communications, could lead to new ways to tailor cancer therapies.

In humans, protein mutations called RAD51 paralogues have been associated with breast and ovarian tumors, said senior investigator Kara Bernstein, Ph.D., assistant professor of microbiology and molecular genetics at Pitt School of Medicine and the University of Pittsburgh Cancer Institute, partner with UPMC CancerCenter.

“These are proteins that have been present throughout evolution in many species, but very little has been known about what they do,” she said. “Our study shows for the first time the mechanism of how they are involved in the repair of damaged DNA.”

Because RAD51 paralogues are too difficult to work with in animal cells, the research team instead explored their function in yeast. They found the proteins interact with other proteins called the Shu complex to repair breaks in DNA strands, which can be caused by environmental toxins, radiation and other naturally occurring exposures.

Shu complex works synergistically with additional RAD51 paralogues to search for homologous, or complementary, DNA regions with double-strand breaks, in which both poles of the twisting DNA ladder have been broken, the researchers found. Pieces of the genetic code can be lost in such areas; the paralogues and complex repair the damage by filling in the missing pieces in a process called homologous recombination.

“Now that we understand what the proteins do, we can perhaps tailor therapies for patients who have cancer and mutations in these repair genes,” Dr. Bernstein said.

The team included Stephen K. Godin, Faiz F. Kabbinavar, and Andrew P. Van Demark, Ph.D., of Pitt; and William A. Gaines, Ph.D., Timsi Rao, Ph.D., and Patrick Sung, Ph.D., of Yale University. The project was funded by National Institutes of Health grants ES015252, ES007061, CA168635, GM088413 and GM101808.

UPCI Called ‘Outstanding’ as Comprehensive Cancer Center Grant Renewed by National Cancer Institute for $25.6M

PITTSBURGH, July 27, 2015 – The University of Pittsburgh Cancer Institute (UPCI) has been rated “outstanding” and renewed as a National Cancer Institute (NCI)-designated Comprehensive Cancer Center, an award that recognizes the world-class research that sets the center among an elite group nationwide. The five-year grant is for $25.6 million and comes as UPCI celebrates its 30th year as a leader in working to reduce the burden of cancer.

UPCI is one of just 44 NCI-designated Comprehensive Cancer Centers in the U.S.

“The NCI renewal is an incredible accomplishment that comes after an extensive application and review process. The award recognizes our strength in basic, clinical and population research, education and community outreach and reflects the dedication of everyone here who is working toward a future without cancer,” said Nancy E. Davidson, M.D., director of UPCI and UPMC CancerCenter, Hillman Professor of Oncology and Distinguished  Professor of Medicine at Pitt, and president-elect of the American Association of Cancer Research.

With 320 faculty members from 42 Pitt departments, UPCI received $68 million in annual funding from NCI in 2015 to support cancer research activities.  Since the last renewal award, UPCI program members have published nearly 5,000 articles in peer-reviewed journals and received prestigious awards, including renewal of Specialized Programs of Research Excellence (SPOREs) grants in lung cancer, head and neck cancer, and melanoma and skin cancer and a new SPORE with another center in ovarian cancer.

Among other notable accomplishments, UPCI was also selected by the NCI as a National Clinical Trials Network Lead Academic Participating Site and as an Experimental Therapeutics-Clinical Trials Network Lead Academic Organization, both of which aim to streamline research trials.  In addition, UPCI is playing a key role in an international study examining how environmental and lifestyle exposures and genetics have affected the incidence, mortality and age-related outcomes of cancer in more than 81,000 Chinese men and women, an effort funded by the NCI.

“Our faculty members are among the most sought- after cancer experts in the country, and we’re proud of the work that sets UPCI apart from other cancer research centers,” said Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of Medicine.

Known colloquially as the “core grant,” NCI’s Cancer Center Support Grant is awarded every five years. Established in 1985, UPCI first received its status as an NCI-designated Comprehensive Cancer Center in 1990 and has retained this distinction since then.

Pitt Scientists Lead Consensus Guidelines for Thyroid Cancer Molecular Tests

PITTSBURGH, July 6, 2015 University of Pittsburgh Cancer Institute (UPCI) scientists recently led a panel of experts in revising national guidelines for thyroid cancer testing to reflect newly available tests that better incorporate personalized medicine into diagnosing the condition.

Their clinical explanation for when to use and how to interpret thyroid cancer tests is published in the July issue of the scientific journal Thyroid. The American Thyroid Association is revising its 2015 Guidelines for Thyroid Nodule and Thyroid Cancer Management to direct doctors to the scientific publication.

“Minimally invasive molecular testing for thyroid cancer has improved by leaps and bounds in the last several years,” said co-author Robert L. Ferris, M.D., Ph.D., professor and chief of the Division of Head and Neck Surgery in Pitt’s School of Medicine. “But different tests perform differently and, therefore, need to be interpreted carefully to make the best decisions regarding extent of surgery for patients with thyroid nodules. Our goal with this analysis is to give clinicians a clear understanding of what each type of test can tell them and when to use them to determine the best course of treatment.”

Cancer in the thyroid, which is located just below the “Adam’s apple” area of the neck, is 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.

UPCI, partner with UPMC CancerCenter, has been a national leader in developing personalized genetic tests for thyroid cancer that have spared patients repeat or unnecessary surgeries. A low-cost test called ThyroSeq, developed by a team led by Yuri Nikiforov, M.D., Ph.D., director of Pitt’s Division of Molecular and Genomic Pathology, allows pathologists to simultaneously test for multiple genetic markers of thyroid cancer using just a few cells collected from the nodule.

This allows doctors to “rule-in” a specific cancer diagnosis with a high degree of certainty, without a biopsy to remove a large portion of the thyroid, which would then have to be followed with a second surgery if cancer is detected to remove the entire gland. As Dr. Nikiforov’s group added more genetic sequences to the ThyroSeq test to create a larger and more sensitive version of the test, it is now also performing as a “rule-out” test that can tell doctors with a high degree of certainty that a patient does not have cancer.

Other available tests use different technology to serve as accurate “rule-out” tools, but do not have the high sensitivity needed to also reliably “rule-in” cancer. And, in some cases, the accuracy of the “rule out” tests depends on the prevalence of cancer in the patients seen by each individual cancer institute. This is critical because clinicians must know this rate at their institution to correctly calculate the accuracy of “rule-out” test results for each patient.

In addition to Dr. Ferris and co-author Sally E. Carty, M.D., who is professor and chief of the Division of Endocrine Surgery in Pitt’s School of Medicine and co-director of the UPMC/UPCI Multidisciplinary Thyroid Center, the panel reviewing the tests was a multidisciplinary group from a dozen institutions in the U.S. and Canada.

“This was a very innovative and collegial initiative,” said Dr. Carty.  “Through an objective review of the existing tests and the scientific literature characterizing their performance, we are seeking to help clinicians make the best decisions for their patients.”

Dr. Ferris agrees, noting that “this is an exciting time in personalized medicine, and these tests give us the ability to not only better diagnose and treat thyroid cancer, but also significantly reduce surgeries for people who don’t have cancer.”

Additional authors on this publication are Zubair Baloch, M.D., Ph.D., University of Pennsylvania Medical Center; Victor Bernet, M.D., Mayo Clinic; Amy Chen, M.D., Emory University; Thomas J. Fahey III, M.D., New York Presbyterian Hospital; Ian Ganly, M.D., Ph.D., and Ashok Shaha, M.D., both of Memorial Sloan-Kettering Cancer Center; Steven P. Hodak, M.D., and Kepal N. Patel, M.D., both of New York University Medical Center; Electron Kebebew, M.D., National Cancer Institute; David L. Steward, M.D., University of Cincinnati Medical Center; Ralph P. Tufano, M.D., Johns Hopkins University; and Sam M. Wiseman, M.D., St. Paul’s Hospital & University of British Columbia.

Pitt’s Dr. Yuan Chang Appointed to National Cancer Advisory Board

PITTSBURGH, June 23, 2015 – President Barack Obama recently appointed a pathologist in the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, to a national board charged with identifying the most promising cancer research projects nationwide.

Yuan Chang, M.D., Distinguished Professor of Pathology in Pitt’s School of Medicine, has been Dr. Yuan Changappointed with four other scientists to serve as members of the National Cancer Advisory Board.

“I am honored that these talented individuals have decided to serve our country. They bring their years of experience and expertise to this administration, and I look forward to working with them,” President Obama said in announcing the appointments.

The National Cancer Advisory Board consists of 12 members appointed by the president to advise the National Institutes of Health’s (NIH) National Cancer Institute. The members review applications for grants and cooperative agreements for cancer research and training, and recommend approval of the projects that show the most promise of making valuable contributions to human knowledge.

“This is a great opportunity for me to professionally contribute to the directive of the National Institutes of Health,” said Dr. Chang, also UPMC Professor of Cancer Virology Research. “My goal is to bring my basic research expertise on infectious diseases and cancer to inform the administrative goals of the NIH.”

Dr. Chang joined the Pitt School of Medicine in 2002, after she and Patrick S. Moore, M.D., M.P.H., discovered Kaposi’s sarcoma-associated herpesvirus, which causes Kaposi’s sarcoma, the most common malignancy occurring in AIDS patients. The team then went on to discover Merkel cell polyomavirus, which causes a rare but deadly skin cancer.

Dr. Chang earned her Bachelor of Science degree from Stanford University and a medical doctorate from the University of Utah College of Medicine.

Prior to coming to Pitt, Dr. Chang served in several clinical and academic positions from 1993 to 2002 at the Columbia University College of Physicians and Surgery and Columbia Presbyterian Hospital. Before that she was a clinical instructor at Stanford University Medical Center.

Image credit: Joshua Franzos

Pitt Researchers Find Genetic Testing in Thyroid Cancer May Aid in Surgical Decision Making

PITTSBURGH, June 10, 2015 – A team of researchers led by Linwah Yip, MD, associate professor in the Department of Surgery, recently found that routine genetic testing to detect mutations implicated in thyroid carcinogenesis can help guide perioperative decision making.  Their research recently was presented by Dr. Yip at the annual meeting of the American Surgical Association in San Diego.

Dr. Yip and her colleagues at the University of Pittsburgh conducted a retrospective review of a consecutive series of 1,510 patients from the electronic medical record of a single institution. The patients had initial surgery for histologically confirmed thyroid cancer. All cancers in the study were tested for mutations in seven genes associated with thyroid carcinogenesis. Although risks associated with mutations are not always clear-cut, the researchers found that distant metastases were more common in thyroid cancer patients who were positive for the RET/PTC mutation, while thyroid cancer expressing BRAF V600E or RET/PTC was associated with higher-grade cancer on presentation and early recurrence.

Additional researchers on the study were Marina N. Nikiforova, MD, Jenny Yoo, MD, Kelly L. McCoy, MD, Michael T. Stang, MD, Kristina J. Nicholson, MD, Michaele J. Armstrong, PhD, Steven P. Hodak, MD, Robert L. Ferris, MD, PhD, Yuri E. Nikiforov, MD, PhD, Sally E. Carty, MD, all currently or formerly of the University of Pittsburgh.

For more information, please visit the American College of Surgeons webpage.

National Thyroid Cancer Experts Meet at UPMC to Advance Patient Care

PITTSBURGH, April 30, 2015 – Nearly 200 physicians and researchers from across the country will gather in the Herberman Conference Center at UPMC Shadyside Saturday to discuss adapting the new American Thyroid Association (ATA) guidelines into clinical practice and to find new ways of working together to improve patient care.

The Seventh Annual Multidisciplinary Thyroid Cancer Symposium, which is sponsored by UPMC, the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter and the University of Pittsburgh School of Medicine, will bring together leading experts in the field to cover a wide variety of topics, including best practices in managing patients with advanced thyroid cancer, the value in predictive molecular testing,  and the latest surgical approaches in the field.

“Our understanding of thyroid cancer has advanced significantly in recent years, and new treatment guidelines were necessary to incorporate the latest research,” said Robert Ferris, M.D., Ph.D., chief of the Division of Head and Neck Surgery at Pitt and one of the conferences co-chairs. “The predictive molecular testing, which was researched and developed at UPMC, will be part of the recommendations for evaluation of a thyroid nodule and will arise in a new consensus statement recently developed by the ATA.  We are looking forward to the discussion this meeting will generate.”

Approximately 63,000 cases of thyroid cancer will be diagnosed in 2015. Thyroid cancer commonly is diagnosed at a younger age than most other adult cancers, and the chance of being diagnosed has risen in recent years as a result of the increased use of thyroid ultrasound.

The event includes a continuing medical education credit component for physicians.

Two-Week International Diet Swap Shows Potential Effects of Diet on Colon Cancer Risk

PITTSBURGH, April 28, 2015 – African-Americans and Africans who swapped their typical diets for just two weeks similarly exchanged their respective risks of colon cancer as reflected by alterations of their gut bacteria, according to an international study led by researchers at the University of Pittsburgh School of Medicine published online today in Nature Communications.

Principal investigator Stephen O’Keefe, M.D., professor of medicine, Division of Gastroenterology, Hepatology and Nutrition, Pitt School of Medicine, observed while practicing in South Africa that his rural patients rarely had colon cancer or intestinal polyps, which can be a cancer precursor. In the Western world, colon cancer is the second-leading cause of cancer death and African-Americans carry the greatest disease burden in the United States.

“The African-American diet, which contains more animal protein and fat, and less soluble fiber than the African diet, is thought to increase colon cancer risk,” Dr. O’Keefe explained. “Other studies with Japanese migrants to Hawaii have shown that it takes only one generation of Westernization to change their low incidence of colon cancer to the high rates observed in native Hawaiians. In this project, we examined the impact of a brief diet change on the colon in a controlled setting where we didn’t have to worry about the influence of smoking and other environmental factors on cancer risk.”

After assessment of their in-home diets, 20 African-American and 20 rural South African volunteers ages 50 to 65 were housed at a University of Pittsburgh site and at an African lodging facility respectively. There they ate meals prepared by the researchers using ingredients and cooking techniques typical of the other group. The team examined fecal and colon content samples, obtained during colonoscopy, of each volunteer at baseline and after the two-week study period.

Although the diet change was brief, each group took on the other’s rates of turnover of cells of the intestinal lining, levels of fiber fermentation, and markers of bacterial metabolic activity and inflammation associated with cancer risk. In particular, African-Americans experienced an increase in butyrate production, which is thought to play a key role in anti-cancer pathways. The researchers also noted they removed intestinal polyps from nine of the African-American volunteers, but none were present in the Africans.

“We can’t definitively tell from these measurements that the change in their diet would have led to more cancer in the African group or less in the American group, but there is good evidence from other studies that the changes we observed are signs of cancer risk,” said co-author Jeremy Nicholson, Ph.D., of Imperial College London.

According to Dr. O’Keefe, increasing the amount of fiber in the diet – from approximately 10 grams to more than 50 for African-Americans in the diet swap – likely led to biomarker changes reflecting reduced cancer risk, but eating less animal fat and proteins also could be helpful.

“These findings are really very good news,” he said. “In just two weeks, a change in diet from a Westernized composition to a traditional African high-fiber, low-fat diet reduced these biomarkers of cancer risk, indicating that it is likely never too late to modify the risk of colon cancer.”

The team included other researchers from the University of Pittsburgh and Imperial College London, as well as Wageningen University in the Netherlands; University of Helsinki, Finland; University of Illinois; and the University of KwaZulu-Natal in South Africa.

Funding for the study was provided National Institutes of Health grants CA135379, RR024153 and TR000005; the National Institute for Health Research Imperial Biomedical Research Centre, UK; the Academy of Medical Sciences; the Spinoza Award of the Netherlands Organization for Scientific Research, the European Research Council and the Academy of Finland.

Inflammation-Cancer Feedback Loop Discovery is a Step Toward Better Cancer Drugs

PHILADELPHIA, April 20, 2015 – New findings hidden within the complex machinery behind the vicious cycle of chronic inflammation and cancer are presented today by researchers from the University of Pittsburgh Cancer Institute, partner with UPMC Cancer Center, at the American Association for Cancer Research (AACR) Annual Meeting in Philadelphia.

The research is funded by the National Institutes of Health (NIH) and Fondazione RiMED, of Palermo, Italy.

Inflammation is an important immune system tool that helps the body rid itself of foreign invaders, such as bacteria. However, chronic inflammation can fuel tumor growth by facilitating formation of cancer blood vessels, supplying nutrients and setting cancerous cells free to colonize other parts of the body.

The basic research into the specific mechanisms promoting cancer inflammation is a critical step in the development of drugs that could interrupt this process.

“In the last 20 years we’ve recognized that chronic inflammation and cancer are connected – long-term inflammation leads to the development of dysplasia and tumor progression,” said lead author Sandra Cascio, Ph.D., a research associate in Pitt’s Department of Immunology. “Recently, scientists have provided detailed insights into molecules and cellular pathways linking inflammation and cancer. In our study, we found a new mechanism that had previously escaped us.”

The mechanism is driven by a complex of MUC1, a molecule long studied in the laboratory of senior author and Pitt immunologist Olivera Finn, Ph.D., and p65, a molecule belonging to a protein complex family known to be activated in inflammation.

Dr. Cascio, in collaboration with Dr. Finn, looked for MUC1/p65-mediated epigenetic modifications affecting inflammatory genes. Epigenetics refers to outside factors that modify the activity of a gene, but do not cause a more obvious genetic mutation. Sure enough, the researchers discovered that this complex, which they found specifically in cancer cells, was causing DNA to be transcribed differently than expected.

“Normally MUC1 is covered in sugar molecules, like leaves cover a tree in spring,” said Dr. Cascio. “When it is made by a tumor, it lacks sugar and is more like a tree in fall. Our research shows that this form of MUC1 associates with p65 and regulates transcription of pro-inflammatory cytokine genes in tumor cells. This leads to the recruitment of inflammatory cells into the tumor site. Inflammatory cells, including macrophages, produce additional cytokines that enhance the activity of MUC1 and p65, establishing a continuous positive feedback loop, or a vicious circle, resulting in tumor progression.”

In order to pinpoint this altered pro-inflammatory mechanism in cancer cells, Dr. Cascio and her team combed through more than 20 types of epigenetic modifications and 300 factors that allow for the remodeling of chromatin, which are macromolecules in cells that control gene expression and DNA replication.

Specifically, the researchers found that MUC1 and p65 involve an enzyme called the Enhancer of Zeste homolog 2, or EzH2, known to induce epigenetic modifications, in order to prompt chromatin remodeling on cytokine gene promoters.

“Developing drugs that could keep these genes from being improperly turned on and off could interrupt this cancer-inflammation process and stop the tumor growth and spread,” said Dr. Cascio. “It’s a promising avenue for future exploration.”

Joshua Sciurba, B.S., of Pitt at the time of this research, also participated in this work.

This research was funded by Fondazione RiMED and NIH National Cancer Institute grant CA56103.

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