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HOUSTON – By sticking a chemical group to it at a specific site, a protein arrests an enzyme that may worsen and spread cancer, an international research team led by scientists at The University of Texas MD Anderson Cancer Center reports in the January issue of Nature Cell Biology.
In addition to highlighting a novel anti-cancer pathway, the team found that the same deactivation of the enzyme called EZH2 is necessary for the formation of bone-forming cells from the stem cells that make them and other tissues.
“EZH2 is overexpressed in aggressive solid tumors and tied to cancer progression and metastasis,” said the paper’s senior author, Mien-Chie Hung, Ph.D., professor and chair of MD Anderson’s Department of Molecular and Cellular Oncology. “We have found that another protein, CDK1, deactivates EZH2.”
The team’s basic research findings provide a rationale for developing an EZH2 inhibitor or a drug that mimics the protein that deactivates it as new cancer drugs. “You have to understand the molecular details of cancer formation and progression to develop new therapies that improve treatment and prevention,” Hung said.
In a series of experiments, the team demonstrated how CDK1 interferes with EZH2, reducing cell migration and invasion in breast cancer cell lines.
EZH2 silences gene expression by attaching a methyl group, which consists of one carbon and three hydrogen atoms, to a histone protein that is intertwined with DNA and other proteins to compose chromosomes. Genes suppressed by this methylation include tumor suppressors that would otherwise prevent cancer growth and spread.
The team showed that CDK1 short-circuits EZH2-mediated methylation by attaching a different chemical group consisting of one phosphate and three oxygen atoms to EZH2, a process called phosphorylation. And that phosphorylation has to occur at a specific amino acid on EZH2 to have this effect.
It’s a matter of phosphorylation trumping methylation, Hung said. The phosphorylated version of EZH2 cannot methylate the target histone protein, so repressed genes are awakened.
Cancer cells with EZH2 that had a mutant version of the location where the phosphate group connects, preventing phosphorylation, had double the cell migration and invasion of cancer cells with the regular, unmutated version of EZH2.
Same process vital to bone formation
EZH2 plays an important normal role in a variety of biological processes. “EZH2 is crucial to embryonic development because it turns genes off and on to guide the differentiation of embryonic stem cells into tissues and organs,” Hung said. Embryonic stem cells can turn into any type of cell.
In a separate set of experiments, the researchers demonstrated that phosphorylation of EZH2 is necessary to the production of bone cells (osteoblasts).
Mesenchymal stem cells can differentiate into bone, cartilage or fat cells. The team showed only those cells with EZH2 phosphorylated by CDK1 differentiated into bone cells. Genes crucial to bone formation were silenced by methlyation but awakened when CDK1 altered EZH2.
A genomewide screen to identify genes targeted by EZH2 in mesenchymal stem cells was conducted before and after the cells differentiated into bone cells. Before, more than 4,000 genes were found to bind to EZH2. After differentiation to bone cells, 30 or fewer genes bound to the protein.
“This and other recently reported studies open up drug development possibilities by either inhibiting the methyltransferase activity of EZH2 or regulating phosphorylation to indirectly regulate EZH2′s activity,” Hung said.
“This study also suggests a possible way to induce mesenchymal stem cell differentiation into bone cells, which may have long-term implications for regenerative medicine for bone disease,” Hung said.
This project was a result of the MD Anderson/China Medical University Hospital Sister institution collaboration.
Research was supported by grants from the National Cancer Institute, Kadoorie Charitable Foundations, National Breast Cancer Foundation, Inc., and the MD Anderson/China Medical University and Hospital Sister Foundation Funds and Cancer Center of Research Excellence from Taiwan.
Co-authors with Hung and first author Yongkun Wei, Ph.D., are Jingyu Lang, Ph.D., Bin Shi, Ph.D., Cheng-Chieh Yang, D.D.S., Ph.D., and Jer-Yen Yang Ph.D., all of MD Anderson’s Department of Molecular and Cellular Biology; Ya-Huey Chen, Ph.D., Long-Yuan Li, Ph.D., and Chun-Yi Lin, all of Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan; Su-Peng Yeh, M.D., Division of Hematology and Oncology, China Medical University and Hospital, and Chien-Chen Lai, Ph.D., Graduate Institute of Chinese Medical Science, China Medical Universiy and Hospital and the Institute of Molecular Biology, National Chung Hsing University, Taiwan. Hung also is affiliated with China Medical University and Hospital and with The University of Texas Graduate School of Biomedical Sciences at Houston.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For seven of the past nine years, including 2010, MD Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.
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The Program in Women’s Oncology and Breast Health Center at Women & Infants Hospital of Rhode Island was recently awarded a three-year full accreditation, with commendation, by the National Accreditation Program for Breast Standards.
The accreditation was awarded after a one-day visit in late September, in which a physician reviewed the Breast Health Center’s clinical facilities, patient charts and the minutes of the quarterly Cancer Committee meetings, according to Margaret M. Steinhoff, MD, chair of the Cancer Committee. The Committee also submitted data to document the Center’s compliance with the 36 standards required by the American College of Surgeons Commission on Cancer, and what had been accomplished since the most recent accreditation visit, in 2007.
In the accreditation, the surveyor commented, “This program is a true gem. Highlighted strengths include the experienced staff and leadership, support teams, interdisciplinary conference, integrative care, social work and breast navigation teams.
“I am greatly impressed by the well-focused, multiple-campus, multidisciplinary breast conference and the case complexity, discussions and care plan integration,” the surveyor added, referring to the weekly Tumor Board sessions held at the Program in Women’s Oncology in which experts from various disciplines gather to discuss the care of each patient.
In issuing the accreditation, the Breast Health Center was also given eight commendations for:
Outcomes analysis – publishing an annual report that includes an outcomes study
Abstracting timeframe ? being 100% compliant per surveyor case review
Submission of quality criteria to the national database ? all data was submitted without error
Compliance with College of American Pathology guidelines ? being 100% compliant with protocols per surveyor review
Clinical trial accrual ? accrual to clinical trials that is well in excess of the amount needed for commendation
Prevention and early detection ? offering three or more prevention or early detection programs each year
Cancer education for cancer registry staff ? the cancer registry staff who are certified tumor registrars attend a national cancer-related educational activity once during the survey cycle
Cancer-related quality improvements ? implementing more than two improvements a year that directly affect cancer patient care
“Surgical, medical oncology, radiation oncology, pathologic and radiologic expertise is well documented in patient care plans and closely adhere to National Comprehensive Cancer Network guidelines,” the surveyor noted. “The team easily meets criteria for compliance including breast conservation rates, sentinel node biopsy rates, pathology reports, hormonal therapy, benign breast disease management and clinical trials enrollment.
“Overall, the Breast Health Center is a phenomenal program that is an asset to the medical and patient community.”
In addition to Dr. Steinhoff, the Cancer Committee includes the following staff: Anna Bailey, RN, BSN, OCN, oncology nurse manager; AnneMarie Bradley, RN, MS, OCN, oncology nurse manager; Don Dizon, MD, medical oncology; Linda Donegan, MD, diagnostic imaging; David Edmonson, MD, general surgery; Heidi Fogarty, CTR, cancer registry; Wendy Fox, PT, DPT, GCS, WCS, physical therapy; Jennifer Gass, MD, assistant director of the Breast Health Center and surgeon-in-chief at Women & Infants; Amanda Goldstein Collins, RN, MS, OCN, oncology administration; Cornelius “Skip” Granai, MD, director of the Program in Women’s Oncology; Ellen Healy, MA, LMHC, social work; Susan LaSalle, quality management; Donna Loranger, RD, LDN, CNSD, nutrition; Janet Mari, RN, research; Carol Opiekun, RN, MS, hospital administration; Caroline Patterson, MDiv, chaplain; Maureen Pearlman, RN, MS, health education; Leslie Pires, MS, PharD, pharmacy; Mohamed Puthawala, MD, radiation oncology; Debborah Smith, American Cancer Society; Rina Stamas, CTR, cancer registry; Lisa Stors, LSW, American Cancer Society; Suzanne Trabucco, cancer conference; and Mary Warburton, RTR, Med, patient management.
In addition to this most recent announcement, the Breast Health Center at Women & Infants Hospital enjoys national acclaim for the following reasons:
Earning a five-year accreditation from the Society of Surgical Oncology for the Breast Fellowship Program, the longest possible duration of certification from the society
Offering the nation’s first joint breast fellowship for gynecologic oncologists, as developed by the Society of Gynecologic Oncologists and the American College of Obstetricians and Gynecologists
Earning a three-year accreditation as a Breast Center of Excellence from the American College of Radiology
About Women & Infants Hospital
Women & Infants Hospital of Rhode Island, a Care New England hospital, is one of the nation’s leading specialty hospitals for women and newborns and a U.S.News Best Hospital in Gynecology. The primary teaching affiliate of The Warren Alpert Medical School of Brown University for obstetrics, gynecology and newborn pediatrics, as well as a number of specialized programs in women’s medicine, Women & Infants is the seventh largest obstetrical service in the country with more than 9,000 deliveries per year. In 2009, Women & Infants opened the country’s largest, single-family room neonatal intensive care unit.
New England’s premier hospital for women and newborns, Women & Infants and Brown offer fellowship programs in gynecologic oncology, maternal-fetal medicine, urogynecology and reconstructive pelvic surgery, neonatal-perinatal medicine, pediatric and perinatal pathology, gynecologic pathology and cytopathology, and reproductive endocrinology and infertility, as well as the nation’s only fellowship program in obstetric medicine.
Women & Infants has been designated as a Breast Center of Excellence from the American College of Radiography; a Center for In Vitro Maturation Excellence by SAGE In Vitro Fertilization; a Center of Biomedical Research Excellence by the National Institutes of Health; and a Neonatal Resource Services Center of Excellence. It is one of the largest and most prestigious research facilities in high risk and normal obstetrics, gynecology and newborn pediatrics in the nation, and is a member of the National Cancer Institute’s Gynecologic Oncology Group.
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PHILADELPHIA ? Head and neck cancer is the sixth most common type of cancer and is on the rise in some demographic groups, including young women without any known risk factors. Now, researchers at Fox Chase Cancer Center report that estrogen may increase the movement of precancerous cells in the mouth and thus promote the spread of the disease within the oral cavity.
The new results, published in the January issue of Cancer Prevention Research, a journal of the American Association for Cancer Research, may lead to novel chemoprevention strategies in the future.
Margie Clapper, Ph.D., co-leader of the Cancer Prevention and Control Program at Fox Chase Cancer Center and Cancer Prevention Research editorial board member, and colleagues had previously reported that estrogen metabolism changes following smoke exposure in the lungs and may contribute to lung cancer. This study on estrogen and lung cancer first appeared in the June 3, 2010, issue of Cancer Prevention Research.
To find out if this female hormone influences development of head and neck cancer, Ekaterina Shatalova, Ph.D., a postdoctoral fellow at Fox Chase Cancer Center and researcher on this study, examined the impact of estrogen on precancerous and cancerous cells.
They found that estrogen induces the expression of an enzyme called cytochrome P450 1B1 (CYP1B1), which is responsible for breaking down toxins and metabolizing estrogen. Interestingly, CYP1B1 induction occurred only in precancerous cells, which are neither totally normal nor cancerous. Surprisingly, estrogen did not induce CYP1B1 in cancer cells.
With closer investigation, the researchers found that depleting the expression of CYP1B1 diminished the ability of precancerous cells to move and divide, as compared to similar cells with normal levels of CYP1B1. Estrogen also reduced cell death in the precancerous cells, irrespective of the amount of CYP1B1 present.
“In the future, we would like to find a natural or dietary agent to deplete the CYP1B1 enzyme and see if we can prevent oral cancer at the precancerous stage,” said Shatalova.
“Our previous studies showed that the CYP1B1 enzyme sits at the hub of changes that occur in the lungs after smoke exposure. We were now able to look at its role in a more direct fashion by removing it from precancerous cells of the oral cavity,” Clapper said. “We found that cells lacking it move slower. CYP1B1 could be a wonderful target in precancerous lesions of the head and neck, because by attacking it, we might stop these lesions from progressing or moving to a more advanced stage.”
In addition, patients diagnosed with head and neck cancer are at a high risk of developing a second primary tumor, which is associated with poorer overall survival. Finding a way to reduce these subsequent tumors could improve patients’ survival.
These results may help researchers to “understand factors that cause head and neck cancer, in addition to the traditional risk factors of tobacco and alcohol exposure,” said Jennifer R. Grandis, M.D., professor and director of the Head and Neck Cancer Program at the University of Pittsburgh School of Medicine, and an editorial board member for Cancer Prevention Research.
However, because these results are limited to a single premalignant cell line, said Grandis, further studies are needed to validate these findings in head and neck cancer in a human population.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes 33,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowships and career development awards. The AACR Annual Meeting attracts more than 18,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. Including Cancer Discovery, the AACR publishes seven major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. AACR journals represented 20 percent of the market share of total citations in 2009. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists.
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MAYWOOD, Ill. — A little-known morphinelike drug is potentially more potent, longer lasting and less likely to cause constipation than standard morphine, a study led by a Loyola University Health System anesthesiologist has found.
The drug, morphine-6-0-sulfate, has a similar chemical structure to standard morphine. Dr. Joseph Holtman Jr. and colleagues reported that a study they performed in rats “demonstrated potential clinical advantages of morphine-6-0-sulfate compared to morphine.”
Holtman is first author of the study, published in the December 2010 issue of the European Journal of Pharmacology.
Holtman is medical director of Loyola’s Pain Specialty Service and a professor in the departments of Anesthesiology and Molecular Pharmacology and Therapeutics of Loyola University Chicago Stritch School of Medicine. He directed the study while he was at the University of Kentucky’s College of Medicine. He joined Loyola on March 1, 2010.
Opioids, such as morphine, oxycodone and hydrocodone, are standard drugs for treating moderate to severe pain, including cancer pain. But these drugs can have significant side effects, including constipation, nausea, vomiting, drowsiness, cognitive dysfunction and slowed breathing and heart rates. And while opioids work well for conditions such as back pain and post-operative pain, the drugs are less effective against neuropathic pain, such as tingling, burning or shooting pain.
Constipation is a common side effect of morphine and can be so uncomfortable that some patients limit their use of the drug. Doctors typically do not discharge surgery patients until they have had a bowel movement and this can extend hospital stays.
Holtman and colleagues tested standard morphine and morphine-6-0-sulfate on rats. The animals received the drugs three ways — by mouth, by IV and by injection into the space surrounding the spinal cord.
The rats underwent several well-established tests to determine their sensitivity to pain. In one such test, researchers focused a very warm light beam on the tail and measured how long it took for the rat to flick the tail.
In this tail-flick test, morphine-6-0-sulfate was 10 times more potent than standard morphine when administered in the space surrounding the spinal cord, five times more potent when administered by IV and two times more potent when given by mouth. Morphine-6-0-sulfate maintained its maximum effect for three hours, compared with 1½ hours for standard morphine. And it took rats 25 days to build tolerance to morphine-6-0-sulfate, compared with 10 days with standard morphine.
Morphine-6-0-sulfate also was more potent than standard morphine for neuropathic and inflammatory pain.
Researchers found that morphine-6-0-sulfate could cause constipation, but only at doses 10 to 20 times higher than the effective doses.
The findings suggest that morphine-6-0-sulfate “may be an interesting potential drug for further study,” Holtman and colleagues wrote.
Co-authors of the study, all at the University of Kentucky, are Peter Crooks, Jaime Johnson-Hardy and Elzbieta Wala.
The study was funded by Insys Therapeutic, Inc., which is has a license to develop the drug for possible use in humans.
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