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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.

Coupling Head and Neck Cancer Screening and Lung Cancer Scans Could Improve Early Detection, Survival

PITTSBURGH, January 5, 2015 – Adding head and neck cancer screenings to recommended lung cancer screenings would likely improve early detection and survival, according to a multidisciplinary team led by scientists affiliated with the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter.

In an analysis published in the journal Cancer and funded by the National Institutes of Health (NIH), the team provides a rationale for a national clinical trial to assess the effectiveness of adding examination of the head and neck to lung cancer screening programs. People most at risk for lung cancer are also those most at risk for head and neck cancer.

“When caught early, the five-year survival rate for head and neck cancer is over 83 percent,” said senior author Brenda Diergaarde, Ph.D., assistant professor of epidemiology at Pitt’s Graduate School of Public Health and member of the UPCI. “However, the majority of cases are diagnosed later when survival rates generally shrink below 50 percent. There is a strong need to develop strategies that will result in identification of the cancer when it can still be successfully treated.”

Head and neck cancer is the world’s sixth-most common type of cancer. Worldwide every year, 600,000 people are diagnosed with it and about 350,000 die. Tobacco use and alcohol consumption are the major risk factors for developing the cancer.

The early symptoms are typically a lump or sore in the mouth or throat, trouble swallowing or a voice change, which are often brushed off as a cold or something that will heal. Treatment, particularly in later stages, can be disfiguring and can change the way a person talks or eats.

Dr. Diergaarde and her team analyzed the records of 3,587 people enrolled in the Pittsburgh Lung Screening Study (PLuSS), which consists of current and ex-smokers aged 50 and older, to see if they had a higher chance of developing head and neck cancer.

In the general U.S. population, fewer than 43 per 100,000 people would be expected to develop head and neck cancer annually among those 50 and older. Among the PLuSS participants, the rate was 71.4 cases annually per 100,000 people.

Recently, the U.S. Preventive Services Task Force, as well as the American Cancer Society and several other organizations, recommended annual screening for lung cancer with low-dose computed tomography in people 55 to 74 years old with a smoking history averaging at least a pack a day for a total of 30 years. The recommendation came after a national clinical trial showed that such screening reduces lung cancer mortality.

“Head and neck cancer is relatively rare, and screening the general population would be impractical,” said co-author David O. Wilson, M.D., M.P.H., associate director of UPMC’s Lung Cancer Center. “However, the patients at risk for lung cancer whom we would refer for the newly recommended annual screening are the same patients that our study shows also likely would benefit from regular head and neck cancer screenings. If such screening reduces mortality in these at-risk patients, that would be a convenient way to increase early detection and save lives.”

Dr. Diergaarde’s team is collaborating with otolaryngologists to design a national trial that would determine if regular head and neck cancer screenings for people referred for lung cancer screenings would indeed reduce mortality.

Additional researchers on this study are Ronak Dixit, Joel L. Weissfeld, M.D., M.P.H., Paula Balogh, D.N.P., F.N.P., Pamela Sufka and Jennifer R. Grandis, M.D., F.A.C.S., all of Pitt; and Jill M. Siegfried, Ph.D., of the University of Minnesota.

This research was funded by NIH grants P50 CA097190, P50 CA090440 and P30 CA047904.

Save the Date: Breast Symposium 2015

PITTSBURGH, Dec. 19, 2014 – Breast Symposium 2015: Updates in the Management of Breast Cancer/Breast Disease will be held at the Herberman Conference Center in Pittsburgh, Pa. on Friday, April 24, 2015.

This course is designed to cover the most recent advances in breast health screening and diagnosis including methods of detection, application of new technology, and benign disease and cancer management. Upon completion of the activity, participants should be able to:

  • Discuss the latest breast cancer methods of detection, treatment, surveillance, and research
  • Describe how these advances can be applied to their practice

Who Should Attend
This course is designed for physicians, nurses and other health care professionals practicing in the areas of Primary Care, Gynecology, Radiology, and General Surgery; recommended for any practitioner caring for women.

Location
UPMC Shadyside
Herberman Conference Center
5230 Centre Avenue
Pittsburgh, PA 15232

Course Co-Directors
Marguerite A. Bonaventura, MD
Associate Professor of Surgery
University of Pittsburgh School of Medicine

Gretchen M. Ahrendt, MD
Associate Professor of Surgery
University of Pittsburgh School of Medicine

This activity has been approved for AMA PRA Category 1 Credit.TM

Online registration will be available on the Upcoming Events page at the Center for Continuing Education in the Health Sciences.

Expert in Immune Responses in Stem Cell Transplantation Joins UPCI

PITTSBURGH, Dec. 17, 2014 – Warren Shlomchik, M.D., a leading expert in investigating the immunologic mechanisms underlying graft-versus-host-disease (GVHD), a common complication for some stem cell transplant patients, has been named director of stem cell transplantation and cell therapies for the University of Pittsburgh’s Division of Hematology-Oncology and University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter, and UPCI’s scientific director of hematopoietic malignancies.

Dr. Shlomchik’s appointment is effective March 1, 2015. He will also serve as a professor of medicine and immunology at the University of Pittsburgh School of Medicine. He comes to Pittsburgh from Yale Cancer Center at the Yale University School of Medicine, where he had been on the senior faculty for 16 years.

“Warren’s work has been invaluable in helping researchers understand more about the mechanisms of GVHD. His main priorities here in Pittsburgh will be to continue to conduct innovative, ground-breaking lab-based science and to oversee the translation of that science into investigator-initiated clinical trials, which will be a huge advance for our transplant and hematopoietic malignancies clinical research program,” said Edward Chu, M.D., chief of the Division of Hematology/Oncology and deputy director of UPCI.

Dr. Shlomchik is a leading expert in GVHD, a well-established complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted donor cells attack the transplant recipient’s body. At Pitt, Dr. Shlomchik will continue his research on GVHD mechanisms as well as work to develop novel immunologic-based and cell therapy approaches to circumvent and/or overcome the development of GVHD.

“We’ve been very fortunate at UPCI this year to add several renowned researchers to our ranks, including Dr. Shlomchik,” said Nancy E. Davidson, M.D., director of UPCI and UPMC CancerCenter. “The decision of these researchers to come here shows that we are serious about the work we are doing to unravel the mysteries of cancer and take those findings directly to our patients.”

Dr. Shlomchik earned his bachelor of arts at Harvard University and his medical degree at the University of Pennsylvania. He completed his residency in internal medicine at New York Hospital/Cornell Medical Center and was a fellow at the University of Pennsylvania in hematology-oncology.

Newly-Identified Gene Mutation Could Help Explain How Breast Cancer Spreads

SAN ANTONIO, Dec. 9, 2014 – A newly-identified genetic mutation could increase our understanding of how breast cancer spreads and potentially guide treatment options for women with the disease, according to a study from Magee-Womens Research Institute (MWRI) and the University of Pittsburgh Cancer Institute (UPCI) presented today at the 2014 San Antonio Breast Cancer Symposium.

This research represents the most comprehensive analysis to date of genomic changes that occur in breast cancer progression and indicate the extensive changes that happen during the spread of the disease.

Researchers from MWRI and UPCI sequenced frozen breast tumor samples from six patients, beginning with the primary tumor when the cancer was first diagnosed through the progression of metastatic disease.  Using multiple sequencing techniques, the team identified a new gene created by two separate genes that fused together as a result of unstable DNA.  This fusion gene was identified in a metastatic tumor sample and is believed to play a part in the spread of the original breast cancer.

“We applied all of our sequencing technologies to the tumors in order to understand the changes that occur between the first breast cancer occurrence and late-stage disease,” said Ryan Hartmaier, a research instructor at the University of Pittsburgh and lead author of the study.

Since several types of breast cancer are fueled by the hormone estrogen, estrogen blocking treatment is often recommended to prevent the disease from spreading. However, the fusion gene identified did not  respond to estrogen blocking treatment, contributing to the breast cancer’s spread.

“This research helps us further understand the genomic landscape of metastatic breast cancer,” said Adrian Lee, Ph.D., the study’s senior author, director of the Women’s Cancer Research Center and professor of pharmacology, chemical biology and human genetics Pitt. “The new class of genetic changes identified take us another step further in personalized medicine and could change the way we treat certain patients if we are able to identify who will develop this genetic mutation.”

New Drug Therapy A Safe, Effective Option for Elderly Patients with Acute Myeloid Leukemia

PITTSBURGH, Dec. 8, 2014 – Seventy percent of elderly patients with acute myeloid leukemia (AML) who were treated with a combination of drugs aimed to make chemotherapy treatments effective and less toxic achieved remission or a slowing of disease progression, according to research at the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter. The findings were presented Sunday at the 56th American Society of Hematology Annual Meeting in San Francisco.

The research is important because most elderly patients diagnosed with AML can’t tolerate the aggressive chemotherapy needed and tend to have more aggressive disease than younger patients, making prognosis poor. So researchers, led by UPCI’s Annie Im, M.D., an assistant professor of medicine in Pitt’s Division of Hematology/Oncology, examined whether an epigenetic strategy using the drugs decitabine followed by cytarabine would help make other treatments more tolerable by reactivating genes that had previously been silenced by the malignancy.

“Outcomes are really poor in elderly patients who have AML because the only therapies we have are often too toxic to offer as treatment options, and the unmet need for novel therapies is dire,” Dr. Im said. “But we have shown that using this therapy in this patient population is safe and effective.”

In the study, 23 patients were evaluated after receiving what’s called an induction therapy of decitabine intravenously for five days followed by a standard dose of cytarabine intravenously for five days. Fourteen patients had complete remission and five patients had a complete remission with delayed bone marrow recovery. All patients except for two received two cycles of induction.

Researchers believe the drugs work because they help reactivate genes that had been silenced by the malignancy. In addition, evidence suggests that epigenetic priming by decitabine enhances the efficacy of cytarabine. The next phase of the trial will examine overall survival and the rate of adverse events, and include epigenetic correlative studies.

NSAIDs Prevent Colon Cancer by Inducing Death of Intestinal Stem Cells That Have Gene Mutation

PITTSBURGH, Nov. 3, 2014 – Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against the development of colorectal cancer by inducing cell suicide pathways in intestinal stem cells that carry a certain mutated and dysfunctional gene, according to a new study led by researchers at the University of Pittsburgh Cancer Institute (UPCI) and the School of Medicine. The findings were published online today in the Proceedings of the National Academy of Sciences.

Scientists have long known from animal studies and clinical trials that use of NSAIDs, such as aspirin and ibuprofen, lowers the risk of developing intestinal polyps, which can transform into colon cancer. But they have not known why, said senior investigator Lin Zhang, Ph.D., associate professor, Department of Pharmacology and Chemical Biology, Pitt School of Medicine, and UPCI, a partner with UPMC CancerCenter.

“Our study identifies a biochemical mechanism that could explain how this preventive effect occurs,” he said. “These findings could help us design new drugs to prevent colorectal cancer, which is the third leading cause of cancer-related deaths in the country.”

The research team performed experiments in animal models and examined tumor samples from patients who had taken NSAIDs and those who hadn’t. They found that NSAIDs activate the so-called death receptor pathway, which selectively triggers a suicide program in intestinal stem cells that have a mutation in the APC gene that renders the cells dysfunctional. Healthy cells lack the mutation, so NSAIDs cause them no harm. In that manner, the drugs instigate the early auto-destruction of cells that could lead to precancerous polyps and tumors.

“We want to use our new understanding of this mechanism as a starting point to design better drugs and effective cancer prevention strategies for those at high risk of colon cancer,” Dr. Zhang said. “Ideally, we could harness the tumor-killing traits of NSAIDs and avoid possible side effects that can occur with their chronic use, such as gastrointestinal bleeding and ulcers.”

The research team included lead author Brian Leibowitz, Ph.D., and Jian Yu, Ph.D., of UPCI and the Pitt’s Department of Pathology, as well as others from UPCI and Pitt School of Medicine; Sichuan University, China; INCELL Corp, San Antonio, Texas; and Indiana University School of Medicine.

The project was funded by National Institutes of Health grants CA106348, CA121105, CA172136, CA129829 and DK085570, and the American Cancer Society.

Never Giving Up: UPMC, Pitt Researchers Receive Grants Totaling $800,000 from V Foundation

PITTSBURGH, Oct. 21, 2014 – Researchers from the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, have been awarded a grant from the V Foundation for Cancer Research to study gene mutations in patients whose head and neck cancer was caused by human papillomavirus (HPV) in hopes of finding a more effective, less toxic therapy for this often painful, disfiguring disease.

The three-year, $600,000 grant was awarded to principal investigator Julie Bauman, M.D., M.P.H., associate professor of medicine and director of the Head and Neck Cancer Section in the Division of Hematology-Oncology at the University of Pittsburgh School of Medicine and co-director of the UPMC Head and Neck Cancer Center of Excellence. The V Foundation, formed by ESPN and former college basketball coach Jim Valvano who is known for challenging people to never give up, also recognized Pitt’s Kara Bernstein, Ph.D., with a V Scholar award, worth $200,000 over two years.

“Coach Valvano established the V Foundation in 1993, the same year he lost his own battle with cancer. His dream was to find a cure for cancer, and we share in that dream here at the University of Pittsburgh Cancer Institute,” said Nancy E. Davidson, M.D., director UPCI and UPMC CancerCenter. “These are highly competitive grants, and we are so pleased that Pitt investigators were recognized.”

Dr. Bauman said the grant will help researchers build on existing scientific knowledge and pioneer new treatments for head and neck cancer, which affects more than 50,000 people in the U.S. and 600,000 people worldwide each year. The primary cause of head and neck cancer in North America and Europe is becoming oral infection with HPV. Although HPV-related cancer responds well to intensive treatment, combinations of surgery, radiation and chemotherapy can result in permanent changes to uniquely human functions: facial expression, speech and swallowing.

“We’ve already learned that half of HPV-related head and neck cancers demonstrate abnormalities in a gene known as PIK3CA,” Dr. Bauman said. “We’re now learning how alterations in this gene cooperate with the virus to transform benign HPV infections into cancer. In addition, we are conducting a clinical trial to see whether a new drug that targets PIK3CA improves response in patients with HPV-related cancer. Ultimately, we aim to identify more effective and less toxic treatments, and even to prevent the transformation of HPV infection into cancer.”

Dr. Bauman is collaborating on the study with Jennifer Grandis, M.D., F.A.C.S., Pitt’s vice chair for research, professor of otolaryngology and pharmacology, and program leader for UPCI’s Head & Neck Cancer Program; Michelle Ozbun, Ph.D., the Maralyn S. Budke Endowed Professor of Viral Oncology at the University of New Mexico Cancer Center; Uma Duvvuri, M.D., Ph.D., Pitt assistant professor of otolaryngology; Andrew Cowan, M.D., Ph.D., assistant professor of surgery, Division of Otolaryngology, University of New Mexico Cancer Center; and Simion Chiosea, M.D., of the UPMC Anatomic Pathology Department.

The V Foundation has awarded more than $100 million for cancer research to more than 100 facilities nationwide since its inception. The translational research grants are designed to accelerate laboratory findings with the goal of benefiting patients more quickly. The V Scholar grants are designed to help early career cancer investigators develop into promising future research talents.

As a V Scholar, Dr. Bernstein will use her award to investigate why people who have mutations in proteins known as RAD51 paralogues are more susceptible to getting cancer – particularly breast and ovarian – and to identify methods for treating their specific cancers.

“Our goal is to uncover individualized cancer treatment for these particular tumors so these patients will have the best outcomes possible,” Dr. Bernstein said.

Pitt/McGowan Institute Team Discovers Stem Cells in the Esophagus

PITTSBURGH, Oct. 16, 2014 – Despite previous indications to the contrary, the esophagus does have its own pool of stem cells, said researchers from the University of Pittsburgh School of Medicine in an animal study published online today in Cell Reports. The findings could lead to new insights into the development and treatment of esophageal cancer and the precancerous condition known as Barrett’s esophagus.

According to the American Cancer Society, more than 18,000 people will be diagnosed with esophageal cancer in the U.S. in 2014 and almost 15,500 people will die from it. In Barrett’s esophagus, the lining of the esophagus changes for unknown reasons to resemble that of the intestine, though gastro-esophageal reflux disease or GERD is a risk factor for its development.

“The esophageal lining must renew regularly as cells slough off into the gastrointestinal tract,” said senior investigator Eric Lagasse, Pharm.D., Ph.D., associate professor of pathology, Pitt School of Medicine, and director of the Cancer Stem Cell Center at the McGowan Institute for Regenerative Medicine. “To do that, cells in the deeper layers of the esophagus divide about twice a week to produce daughter cells that become the specialized cells of the lining. Until now, we haven’t been able to determine whether all the cells in the deeper layers are the same or if there is a subpopulation of stem cells there.”

The research team grew pieces or “organoids” of esophageal tissue from mouse samples, and then conducted experiments to identify and track the different cells in the basal layer of the tissue. They found a small population of cells that divide more slowly, are more primitive, can generate specialized or differentiated cells, and have the ability to self-renew, which is a defining trait of stem cells.

“It was thought that there were no stem cells in the esophagus because all the cells were dividing rather than resting or quiescent, which is more typical of stem cells,” Dr. Lagasse noted. “Our findings reveal that there indeed are esophageal stem cells, and rather than being quiescent, they divide slowly compared to the rest of the deeper layer cells.”

In future work, the researchers will examine human esophageal tissues for evidence of stem cell dysfunction in Barrett’s esophagus disease.

“Some scientists have speculated that abnormalities of esophageal stem cells could be the origin of the tissue changes that occur in Barrett’s disease,” Dr. Lagasse said. “Our current and future studies could make it possible to test this long-standing hypothesis.”

The project’s co-investigators are Aaron DeWard, Ph.D., and Julie Cramer, Ph.D., both of Pitt’s Department of Pathology and the McGowan Institute.

The research was funded by grants from the Commonwealth of Pennsylvania, National Institutes of Health grant DK08571, the McGowan Institute and the University of Pittsburgh Department of Pathology Postdoctoral Research Training Program.

UPMC Partners with GK Klinika to Develop and Co-Manage Cancer Hospital in Lithuania

 PITTSBURGH, Oct. 7, 2014 GK Klinika Group, a private health care company in the Baltic region, is partnering with UPMC for its help in developing and co-managing a new, 100-bed cancer hospital in Vilnius, Lithuania.

Scheduled to open in 2017 and funded by GK Klinika, the hospital is expected to care for patients covered by both private and public insurance to enhance the quality of oncology care throughout the Baltic region. Under the 15-year agreement, UPMC will assist with project planning, construction and training, and will co-manage all clinical and administrative activities after the facility opens.

The prime minister of Lithuania, Algirdas Butkevicius, will participate in a signing ceremony at UPMC’s headquarters today. The Lithuanian government is actively working to encourage foreign business expansion in that country, particularly in its highly advanced life sciences sector, and expects that this partnership with UPMC will foster U.S.-Lithuania relations and geopolitical stability in the region. 

“As an international leader in health care and medical research — and one that has proven that its model of care can be adapted to other countries and cultures — UPMC was the logical choice to be our partner in creating a world-class cancer facility,” said Karapet Babaian, M.D., chief executive officer of GK Klinika and of Baltijos Medicinos Tyrimu Institutas (BMTI), the unit that is working with UPMC. “The scope and length of this agreement is a testament to our faith in this new partnership.”

GK Klinika is one of the leading private clinics in the Baltic region, with more than 15 years of experience and a reputation for promoting innovative medical technology to achieve better patient outcomes. 

“GK Klinika and UPMC share the same vision: to give patients access to the best cancer care in the world close to home. We look forward to working with our partner to make that dream a reality in Lithuania,” said Charles Bogosta, president of UPMC’s International and Commercial Services Division.

UPMC’s wide-ranging assistance to GK Klinika will include hiring and training of staff in Pittsburgh and Vilnius, information technology planning, developing early cancer detection programs, conducting a genomics-testing pilot project and providing disease-specific treatment algorithms. UPMC physicians also will periodically provide consults related to advanced surgeries performed at the new hospital and second opinions via telemedicine.

The chief executive officer of the new hospital will be appointed by mutual agreement of both partners. 

Starting with its partnership to create a transplant center in Italy 18 years ago, UPMC has expanded its international footprint to include operations or services in countries that now include Ireland, India, China, Singapore, Japan and Kazakhstan. Through its international growth and commercialization efforts with industry partners, UPMC is diversifying its sources of revenue, fueling economic development in its local communities, and strengthening its ability to recruit and retain the best clinicians to improve health care outcomes globally.

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