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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.

Magee, UPCI Researchers Seek New Targets for Ovarian Cancer Treatment

PHILADEPHIA, April 19, 2015 – Identifying molecular changes that occur in tissue after chemotherapy could be crucial in advancing treatments for ovarian cancer, according to research from Magee-Womens Research Institute and Foundation (MWRIF) and the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, presented today at the American Association for Cancer Research (AACR) Annual Meeting 2015.

For years now, intraperitoneal chemotherapy, a treatment which involves filling the abdominal cavity with chemotherapy drugs after surgery, has been considered the standard of care for ovarian cancer. According to Shannon Grabosch, M.D., a gynecologic oncology fellow at Magee-Womens Hospital of UPMC and the study’s lead investigator, treatment advances for this disease haven’t moved forward as quickly as they have for other cancers.

“The addition of intraperitoneal chemotherapy for women with ovarian cancer was one of the biggest achievements in improving survival outcomes, but unfortunately, we still don’t understand the biological mechanisms by which this works,” said Dr. Grabosch. “We wanted to understand what changes occurred to the local tumor environment after chemotherapy was administered, with the idea that these changes could eventually be targets for new, personalized ovarian cancer treatments.”

Dr. Grabosch and her team examined peritoneal cavity fluid and peripheral blood samples of 13 patients. The samples were obtained prior to intraperitoneal treatment and after the first and second rounds of chemotherapy. Using multiple sequencing techniques, Dr. Grabosch and her team identified chemotherapy-induced molecular changes.

“We were able to identify changes in both miRNA and genes which appear to be related to chemotherapy. Furthermore, we identified different, significant changes between the peritoneal cavity and blood samples, proving that the local tumor environment is an underutilized wealth of information,” said Dr. Grabosch. “Now we need larger studies to determine whether the changes that occur in the tumor microenvironment after chemotherapy could be potential targets for new, more personalized drugs and to further understand the mechanisms of intraperitoneal chemotherapy.”

Additional authors on this research, which was funded by the Magee-Womens Research Institute and Foundation and the Gynecologic Oncology Group, are Anda M. Vlad, M.D., Ph.D., Tianzhou Ma, M.S., Jyothi Mony, Ph.D., Mary Strange, M.S., Joan Brozick, M.H.A., Julia Thaller, M.B.A., George Tseng, Ph.D., Xin Huan, Ph.D., Katie Moore, M.D., Kunle Odunsi, M.D., Ph.D., and Robert P. Edwards, M.D., all with MWRIF and UPCI.

Broccoli Sprout Extract Promising for Head and Neck Cancer Prevention

PHILADELPHIA, April 19, 2015 – Broccoli sprout extract protects against oral cancer in mice and proved tolerable in a small group of healthy human volunteers, the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, announced today at the American Association for Cancer Research (AACR) Annual Meeting in Philadelphia.

The promising results will be further explored in a human clinical trial, which will recruit participants at high risk for head and neck cancer recurrence later this year. This research is funded through Pitt’s Specialized Program of Research Excellence grant in head and neck cancer from the National Cancer Institute.

“People who are cured of head and neck cancer are still at very high risk for a second cancer in their mouth or throat, and, unfortunately, these second cancers are commonly fatal,” said lead author Julie Bauman, M.D., M.P.H., co-director of the UPMC Head and Neck Cancer Center of Excellence. “So we’re developing a safe, natural molecule found in cruciferous vegetables to protect the oral lining where these cancers form.”

Previous studies, including large-scale trials in China, have shown that cruciferous vegetables that have a high concentration of sulforaphane – such as broccoli, cabbage and garden cress – help mitigate the effects of environmental carcinogens.

Dr. Bauman collaborated with Daniel E. Johnson, Ph.D., professor of medicine at Pitt and a senior scientist in the UPCI Head and Neck Cancer Program, to test sulforaphane in the laboratory. For several months, Dr. Johnson and his team gave sulforaphane to mice predisposed to oral cancer and found that it significantly reduced the incidence and number of tumors.

“The clear benefit of sulforaphane in preventing oral cancer in mice raises hope that this well-tolerated compound also may act to prevent oral cancer in humans who face chronic exposure to environmental pollutants and carcinogens,” said Dr. Johnson.

Dr. Bauman treated 10 healthy volunteers with fruit juice mixed with sulforaphane-rich broccoli sprout extract. The volunteers had no ill-effects from the extract and protective changes were detectable in the lining of their mouths, meaning it was absorbed and directed to at-risk tissue.

These findings were enough to prompt a clinical trial that will recruit 40 volunteers who have been curatively treated for head and neck cancer. The participants will regularly take capsules containing broccoli seed powder to determine if they can tolerate the regimen and whether it has enough of an impact on their oral lining to prevent cancer. From there, larger clinical trials could be warranted.

“We call this ‘green chemoprevention,’ where simple seed preparations or plant extracts are used to prevent disease,” said Dr. Bauman, also an associate professor in Pitt’s School of Medicine. “Green chemoprevention requires less money and fewer resources than a traditional pharmaceutical study, and could be more easily disseminated in developing countries where head and neck cancer is a significant problem.”

Additional authors on this research are Yan Zhang, Ph.D., Malabika Sen, Ph.D., Daniel P. Normolle, Ph.D., Thomas W. Kensler, Ph.D., Sumita Trivedi, M.B.B.S., and Siddharth H. Sheth, D.O., M.P.H., all of Pitt; Jennifer R. Grandis, M.D., F.A.C.S., of Pitt at the time the research was conducted; and Patricia A. Egner, M.S., of Johns Hopkins University.

Pitt Cancer Virology Team Reveals New Pathway that Controls How Cells Make Proteins

PITTSBURGH, April, 13, 2015 – A serendipitous combination of technology and scientific discovery, coupled with a hunch, allowed University of Pittsburgh Cancer Institute (UPCI) researchers to reveal a previously invisible biological process that may be implicated in the rapid growth of some cancers.

The project, funded by the National Institutes of Health (NIH), is described in today’s issue of the Proceedings of the National Academy of Sciences (PNAS).

“I was so amazed by what I was seeing,” said lead author Masahiro Shuda, Ph.D., research assistant professor in Pitt’s Department of Microbiology & Molecular Genetics. “We repeated and repeated our work to prove that the standard scientific dogma wasn’t the complete story.”

Dr. Shuda and his colleagues showed that a well-known cancer protein called mTOR, previously thought to be solely responsible for controlling a form of protein production important in cancer cells, called cap-dependent translation, can actually hand its work off to a different protein, CDK1, when cells are dividing. They observed the process while examining a viral oncoprotein that allows a common and usually harmless virus to transform healthy cells into cancer cells.

Merkel cell polyomavirus (MCV) was discovered in 2008 by co-authors Yuan Chang, M.D., and Patrick S. Moore, M.D., M.P.H., in the Cancer Virology Program at UPCI, partner with UPMC CancerCenter. It causes a rare but deadly skin cancer called Merkel cell carcinoma. They later found a viral protein called “small tumor protein,” or sT. It may start a chain reaction that enables tumor growth resistant to cancer drugs that inhibit the protein mTOR.

In studies dating back to the 1960s, scientists had assumed that cap-dependent protein synthesis was turned off during cell division. The new study reveals that this is not necessarily so and that CDK1 can substitute for mTOR. Both mTOR and CDK1 work by inhibiting a gatekeeper protein, called 4E-BP1, that shuts off cap-dependent protein synthesis.

Less than 1 percent of cells are in the active division cycle called mitosis, even in very aggressive cancers, which makes studying cells in mitosis difficult. In addition, a drug traditionally used to arrest the cells during division inhibits protein production by CDK1. This is likely why previous research did not identify the important role that CDK1 appears to play.

Dr. Shuda used a technology called flow cytometry to identify cells undergoing division. With special fluorescent tags, he was able to see mitotic cells produce fully inactivated 4E-BP1 by CDK1. He also directly measured proteins being made during mitosis.

Sure enough, even when mTOR was knocked out, CDK1 was still present and able to allow protein synthesis needed for cell division to progress.

“Now, we still can’t say that this process involving CDK1 contributes to cancer – that’s something we’ll tackle with future research,” said Dr. Moore, senior author and professor of molecular genetics and biochemistry at Pitt. “But it does point toward a fundamental control mechanism in cell biology and leads to the interesting possibility that creating or combining cancer drugs, so that they inhibit both mTOR- and CDK1-related protein synthesis, could be a very useful therapy to pursue.”

Additional researchers on this work are Celestino Velásquez, B.S., Erdong Cheng, Ph.D., Daniel G. Cordek, Ph.D., and Hyun Jin Kwun, Ph.D., all of Pitt. Drs. Moore and Chang jointly run their laboratory at UPCI.

This research was supported by NIH National Cancer Institute grants R01CA136806, CA136363 and CA170354. The flow cytometry was performed using a facility supported in part by NIH grant P30CA47904.

Under Our Nose: Supplemental Oxygen Can Make Tumors Shrink, Says New Study

PITTSBURGH, March 4, 2015 – A method of profoundly enhancing some cancer treatments could be right under our noses. A study co-authored by a University of Pittsburgh researcher has shown in an animal model that breathing air with a higher than usual concentration of oxygen can alter certain metabolic pathways to allow chemotherapy and immunotherapy to shrink tumors more effectively.

The blood supply of a tumor often does not match the pace of the cancer’s growth, which leads to areas that are ischemic, or oxygen deprived, explained Edwin Jackson, Ph.D., professor of pharmacology and chemical biology, Pitt School of Medicine, and a co-author of a paper published online today in Science Translational Medicine. That causes the tumor cells to make adenosine, a molecule that not only promotes blood flow, but also binds to a receptor on killer T-cells and essentially puts them to sleep. In effect, adenosine acts as a shield against immune system cells that would otherwise attack the cancer.

“We realized if we could find a way to block the increase in adenosine, we might be able to help the immune system respond to the tumor to make anti-cancer therapies more effective,” Dr. Jackson said. “This study shows that simply breathing more oxygen can accomplish that aim, which could lead to an amazing breakthrough in cancer treatment.”

The study team, led by Michail Sitkovsky, Ph.D., director of the New England Inflammation and Tissue Protection Institute at Northeastern University, exposed mice with lung tumors to respiratory hyperoxia at levels of 40 to 60 percent oxygen, comparable to what patients might receive in the hospital. Another group of mice breathed air, which is approximately 21 percent oxygen. Tumors in mice that received supplemental oxygen shrank – some regressed completely – and the animals were more likely to survive than those on room air.

“Supplemental oxygen prevented the tumor from making extra adenosine, so the immune cells could do their job and attack the cancer cells,” Dr. Sitkovsky explained. “But if anti-tumor immune cells aren’t present, oxygen has no effect. We hope we will soon see clinical trials of respiratory hyperoxia in combination with immunotherapies to see whether it can help cancer patients.”

He noted also the effects might be stronger in combination with an agent that he calls “super-caffeine,” which blocks the receptor where adenosine binds to inhibit the immune cells.

For Dr. Jackson, whose lab is thought to be the world’s best in the measurement of adenosine and its metabolites, the breakthrough research is personally deeply rewarding. Fourteen years ago, his older brother, James F. Jackson, died at 57 of renal cell carcinoma. In 1986, Mr. Jackson received the National Science Foundation Presidential Award for Excellence in Science Teaching from Vice President George H.W. Bush.

“Jim was my childhood mentor and the reason I am a scientist today. His three years of treatment was an emotional and frustrating time for me because we didn’t have the right tools to help him,” Dr. Jackson said. “I started doing cancer research because of that experience, and I hope these results will one day prevent suffering and loss by countless other families.”

Other study investigators included researchers from the Dana Farber Cancer Institute, Harvard Medical School and the University of Miami. The project was funded by National Institutes of Health grants CA 112561, CA 111985, AT 002788, and AI 091693; National Cancer Institute grant 5PO1CA109094-03; and Northeastern University.

UPMC CancerCenter First in World to Treat Patient with New Cyberknife MLC that Shapes Radiation to Tumor, Decreases Treatment Time

PITTSBURGH, March 2, 2015UPMC CancerCenter last week became the first center in the world to treat a patient with the CyberKnife® M6™ System’s new multileaf collimator, which enables precise shaping of radiation beams to any irregularly shaped tumor, sparing healthy surrounding tissues and reducing the time patients must undergo treatments.

The CyberKnife® M6™ System with the InCise™ Multileaf Collimator (MLC) was used for the first time on Feb. 26 on a 56-year-old western Pennsylvania woman being treated for a benign brain tumor. UPMC CancerCenter was one of the InCise MLC evaluation sites working in collaboration with Accuray, the device’s manufacturer. The patient’s treatment lasted 22 minutes, about half of the time treatment would have taken without the use of advanced software and novel technologies, said Dwight E. Heron, M.D., FACRO, FACR, director of Radiation Services at UPMC CancerCenter, a partner with the University of Pittsburgh Cancer Institute.

This new technology will be especially useful for tumors in the body that are hard to reach or tend to move, he said. The treatment was administered as a multidisciplinary effort between Steven Burton, M.D., from the department of Radiation Oncology and Johnathan Engh, M.D., from the department of Neurosurgery.

“Our patient was diagnosed with a brain meningioma and was a good candidate for the highly-focused treatment that can be delivered by the CyberKnife,” said Dr. Heron, who oversees the largest system in the U.S. accredited by the American College of Radiation Oncology. “With the addition of the MLC, we were able to precisely target the tumor and spare healthy tissue, and it took us significantly less time to do it. This real-world case is consistent with our InCise MLC technical evaluation experience and exceeded our expectations in its efficiency.”

The M6 Series delivers radiosurgery and stereotactic body radiation therapy, enabling precise, high-quality dose distributions to be administered to patients with extreme accuracy over a minimum number of treatments, reducing side effects and preserving patients’ quality of life. The system is able to adjust and automatically stay on target in real-time, accounting for patient and tumor motion. CyberKnife is the only robotic radiosurgery system available today that delivers such high-precision treatments throughout the body.

“We congratulate Dr. Heron, Dr. Saiful Huq and their team on treating the first patient using the CyberKnife M6 System and InCise MLC,” said Joshua H. Levine, president and chief executive officer of Accuray. “With the addition of the MLC, clinicians can deliver the same precise radiosurgery treatments they have come to expect with the CyberKnife System for a wider range of tumor types, including larger and different kinds of tumors than were previously treated.”

UPMC Whitfield Cancer Centre Receives Joint Commission International Accreditation for 3rd Time; Meets Highest Standards of Safety and Quality

PITTSBURGH, Feb. 19, 2015 – For the third time since 2008, the UPMC Whitfield Cancer Centre, operated by UPMC in Waterford, Ireland, has successfully achieved accreditation from the Joint Commission International (JCI). This recognition is based on an extensive review of the center’s patient safety and quality standards and processes.

The JCI is the recognized leader in international health care accreditation and is considered the gold standard in global health care. Its accreditation process focuses on determining whether a health care facility has the right systems and processes in place to support high-quality and safe patient care, and has the culture and capacity to continuously improve care. JCI’s surveyors examine crucial issues such as patient and family education, access to care and medication management. The process requires hospitals to demonstrate a track record of standards compliance and relies on candid interviews with patients, nurses and physicians about care practices.

“The success of this, our third, accreditation survey reflects the ongoing efforts of the whole Cancer Centre team and their dedication to continuing to provide a quality service to all cancer patients in the southeast region,” said Catriona McDonald, director of operations and radiotherapy services manager.

“Demonstrating compliance with JCI standards serves as validation of an organization’s commitment to an internationally recognized, time-tested and comprehensive level of quality,” explained Cheryl Brill, UPMC’s vice president of international clinical operations and quality. “This outstanding result is a testament to the UPMC Whitfield Cancer Centre staff and to their commitment to excellence in the treatment of patients.”

UPMC Whitfield Cancer Centre offers the most advanced radiation therapy, including intensity-modulated radiation therapy and image-guided radiation therapy, to residents of the southeast region of Ireland. One of only four ambulatory care centers to be JCI-accredited in Ireland, the center is committed to delivering the highest standard of radiation therapy and supportive care for patients with all types of cancer.

Established to respond to a growing demand around the world for standards-based evaluation of quality in health care, JCI today accredits or certifies more than 700 health care organizations and clinical care programs in over 100 countries. JCI is the international arm of the Joint Commission, which has worked for more than 50 years to improve the quality and safety of health care services. As the largest accreditor of health care organizations in the United States, the Joint Commission accredits and certifies more than 20,500 health care organizations through a voluntary process and is recognized as a leader in all aspects of safe, high-quality care.

Statins Inhibit Spread of Some Cancers in Laboratory Tests

PITTSBURGH, January 15, 2015 – Cholesterol-lowering drugs appear to be a promising, cost-effective way to reduce the risk of metastases in some cancers, according to laboratory research led by the University of Pittsburgh School of Medicine. Metastases, rather than the original tumor, are what usually kill people with cancer.

The discovery, published in the open-access journal Scientific Reports, part of the Nature Publishing Group, reveals the mechanism by which statins may impede the process that cancerous tumor cells need in order to split off from the primary tumor and cause cancer elsewhere in the body.

“We didn’t plan to discover this – we were actually modeling metabolism of tumor cells and looking at the response of various tumor cells to existing drugs, including statins,” said senior author Zoltán Oltvai, M.D., associate professor of pathology at Pitt. “But, sure enough, we were able to show that these cholesterol-lowering drugs interrupt the growth of some cancer cell lines that are very similar to those cancer cells that leave the primary tumor and eventually colonize other organs.”

When a tumor metastasizes, it spreads cancer cells through the body using the blood stream. The cells then come to rest at another site in the body, eventually forming new tumors. Sometimes these cells lie dormant, and a person can appear cancer-free after the primary tumor is removed, only to have his or her cancer reappear years later in another organ.

Scientists have known for several years that statins sometimes seem to fight cancer; however, the mechanism wasn’t clear, and previous clinical trials have yielded mixed results regarding statins as anti-cancer drugs.

Cancer cells require the synthesis of cholesterol and cholesterol precursor molecules to reprogram themselves from an adherent, or “epithelial” state, to a mobile, or “mesenchymal” state, in order to leave or “shed” from the primary tumor and recolonize elsewhere in the body. Statins, which are routinely used to lower lipid levels, could potentially block cancer cell spread by inhibiting an enzyme that catalyzes a key step in the cholesterol synthesis process, Dr. Oltvai said.

His team found that slower-growing, mesenchymal-like cancer cell lines that contain the protein vimentin inside the cell, but do not display the protein E-cadherin on their surface, are particularly sensitive to statins. Knowing this, doctors eventually may be able to test biopsies from cancerous tumors for these markers to determine if statins may be effective.

“While statins probably aren’t going to be effective against a patient’s primary tumor, they could work to block the tumor’s ability to metastasize,” said Dr. Oltvai. “And that is very important because most cancer patients die because of the metastases.”

Dr. Oltvai noted that coupling treatment of the primary tumor – which can involve chemotherapy, surgical removal of the tumor and radiation – with statins might be a way to prevent the primary tumor from shedding cells, and also prevent those cells from surviving their journey through the body or reactivating elsewhere in the body later on.

These are preliminary results, and people should not start taking statins as an anti-cancer drug, Dr. Oltvai stressed. His team tested the cancer cells’ reaction to statins in the laboratory, and the process could be different in the human body. The researchers are pursuing funding for additional studies on how exactly statins can interfere with the process that leads to metastases and whether combining statins with other drugs may be even more potent than using statins alone.

Additional researchers on this study are Katsuhiko Warita, Ph.D., Tomoko Warita, Ph.D., Colin Beckwitt, B.S., Mark Schurdak, Ph.D., and Alan Wells, M.D., D.M.S., all of Pitt; and Alexei Vazquez, Ph.D., of Rutgers Cancer Institute of New Jersey. Dr. Wells is also part of the Pittsburgh VA Health System, and Drs. Wells and Schurdak also are affiliated with the University of Pittsburgh Cancer Institute.

This research was supported by a U.S. Department of Veterans Affairs Merit grant, a National Center for Advancing Translational Sciences grant and a grant from the National Science Foundation.

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