The article "Cells on the Move" written by Elise Lamar and published in the May 2012 issue of HHMI Bulletin quotes UNC Lineberger member James Bear, PhD, and discusses his research.
Dr. Bear is an associate professor of Cell and Development Biology.
The HHMI Bulletin is a quarterly publication that provides information about the biomedical research and science education programs supported by Howard Hughes Medical Institute.
]]>Dr. Berg is an assistant professor in the Department of Genetics.
]]>Thomas Shea, MD, Director of the Bone Marrow and Stem Cell Transplant Program and Associate Director for Outreach Programs at UNC Lineberger and Don Gabriel, MD, PhD, Professor of Medicine in the division of hematology/oncology, were both co-authors on the clinical trial, which measured the effect of maintenance lenalidomide therapy on disease-free progression after transplant.
The phase 3 study demonstrated that maintenance therapy with lenalidomide, an oral drug that can be taken for many months or even years, is associated with significant improvement in outcomes for patients with newly diagnosed myeloma who have undergone a transplant. The probability of surviving free of disease progression (the primary end point) for three years was 59 percent in the lenalidomide group, as compared with 35 percent in the placebo group.
“The results of this trial will change our treatment of multiple myeloma patients,” said Dr. Shea.
“While lenalidomide has some risks, including an increase in people developing second cancers, it generally appears to be well-tolerated when given long-term and was associated with a delay in time to progression of the myeloma as well as an improvement in overall survival” he added.
Shea noted that another study in France showed similar improvement in delaying progression of the myeloma following transplant, but did not improve how long patients lived after their transplant compared to those receiving a placebo. Additional studies need to be conducted and longer follow-up of the current studies will need to be undertaken to confirm whether there is a real survival benefit of lenalidomide therapy for these patients.
The US trial was supported by the National Cancer Institute. Celgene provided the lenalidomide and placebo used in this trial.
]]>The Center for International Bone Marrow & Transplant Research, an international organization dedicated to improving transplant outcomes, publishes outcomes data each year for transplantation centers across the United States.
In its most recent report covering the years 2007-2009 (published in 2011), UNC Cancer Care’s Bone Marrow and Stem Cell Transplantation Program was rated an “overperforming” center. Based on a risk adjusted assessment, UNC’s bone marrow and stem cell transplantation patients had a much higher survival rate than expected, despite the high level of complexity of the cases that were treated. These results were for all patients who underwent a transplant from a related or unrelated donor. Out of 156 centers from across the country, UNC was one of only 14 to achieve this ranking.
“We are extremely pleased to achieve this distinction as these excellent results reflect the hard work and dedication of the many faculty and staff at UNC who are involved with our program”, said Thomas Shea, MD, Director of the Stem Cell Transplant Program and Associate Director for Outreach programs at UNC Lineberger.
The Center for International Bone Marrow & Transplant Research, an international organization dedicated to improving transplant outcomes, publishes outcomes data each year for transplantation centers across the United States.
]]>His lab aims to understand a very basic unsolved problem in biology: how do proteins that interact with DNA find their proper targets in living cells? The DNA sequence information in the human genome is read and interpreted by proteins. Without interactions between proteins and DNA, life would not exist. His lab studies how proteins are directed to specific parts of the genome so that they can do their specific job. Using molecular technologies, they can determine the location of thousands of protein-DNA interactions in a single experiment. They then use these data to reconstruct the rules that proteins used to find out where it was supposed to go. Their studies may lead to better predictions of where defective proteins that cause cancer bind to the genome.
Dr. Lieb is director of the Carolina Center for Genome Sciences, created in 2001 to make significant advances in basic genomic research, as well as translate these discoveries to improving healthcare, education and society. As the Center’s second director after Dr. Terry Magnuson, now vice dean for research in the UNC School of Medicine, he wants to build on what Magnuson established by making technologies accessible to the clinic, understanding individual genomes and how the individual differences from person to person affect their propensity for disease and how they’re treated for disease. “The role of the center is to develop tools and techniques that are going to be ready for the clinic in 10 years,” Dr. Lieb explains.
The Center will be helped in its mission with the completion of the new Genome Science Center that will house new sequencing and microscopy technology as well as a diverse mix of scientists. “We’re hoping that the mix of expertise and technology all together in the one building will lead the way to the next 10 years of genome science and that a synergy will develop among scientists in the new building and across campus.”
Dr. Lieb describes the University Cancer Research Fund as a vital catalyst both for UNC’s national prominence in genetics and for his own research. “I received a UCRF seed grant for a project with Dr. Ian Davis that has gone on to attract many times the amount of funding from the initial seed grant.“ Davis is a pediatric oncologist and scientist who is partnering with Dr. Lieb on a project involving Ewing Sarcoma, a malignant bone and soft tissue tumor of children and young adults. They published their findings of how a gene associated with the cancer alters the way DNA is packaged in cells and leads to cancer and are now working with UNC drug discovery scientists to develop a drug that targets the aberrant gene.
“UCRF has helped many UNC scientists through the purchase of high-throughput DNA sequencing machines and the accompanying computational capacity and personnel. We are now able to do many experiments that were not possible before.”
Dr. Lieb has been honored for his research at the local and national level as a Hettleman Prize winner and a V Foundation Scholar. The Hettleman Prize for Artistic and Scholarly Achievement by Young Faculty is an annual award given to outstanding UNC faculty while the V Foundation Scholar grant, named in memory of NCSU men’s basketball coach Jim Valvano, is a national honor.
Dr. Lieb credits his mentors for shaping his practice of science and his career. “At UNC, biology professor Pat Pukkila, my undergraduate professor, taught me how to do basic laboratory techniques and how to care about the problem you’re studying. At Berkeley, during my doctoral training, Barbara Meyer, a member of the National Academy of Sciences, taught me the importance of being rigorous and precise and that no detail is too small, advice that has served me well. At Stanford, during my postdoctoral fellowship, Patrick Brown, also a member of the Academy, and a trained pediatrician with an active lab, had diverse interests. His motto was always ‘charge ahead.’ He was very freewheeling in his interests and intellectual endeavors. That’s one of the reasons my lab is all over the place in terms of model systems.”
After being in California for eight years, Jason was drawn back to Chapel Hill. “It was one of the few places in the country where I knew that the quality of science was very high and the quality of life was very high. It’s a great place for my family and for my career.”
In his chosen environment, Dr. Lieb thrives on science. “There are so many questions, and how do you choose among all the questions, and narrow them down to what’s interesting and what’s soluble? You’re always pushing the edge of what’s possible in an experiment to try to answer the question that’s been a big roadblock in the field. You really want your questions to be at the interface of what’s interesting and what’s possible. That’s what you try to do.”
]]>Dr. Garcia’s project will receive more than $330,000 to focus on the most common pediatric brain cancer, medulloblastoma. Current therapy for this cancer can cause severe long-term side effects for patients and the cancer is ultimately fatal for many children.
Medulloblastoma occurs in the cerebellum, where new nerve cells are born in children’s rapidly-developing brains. Dr. Garcia will use preclinical models to study how a protein that controls brain growth, called Aspm, may actually drive the growth of medulloblastoma. Her goal is to validate whether blocking Aspm is a potential treatment, with the ultimate goal of targeting Aspm in children with this cancer.
Dr. Garcia earned her undergraduate degree in Biochemistry at University of Navarra, Spain and her PhD Molecular and Cellular Biology at University of Barcelona, Spain.
]]>With this grant, Dr. Der is planning to test an inhibitor of a protein in the Ras oncoprotein pathway, ERK. His project is designed to predict methods by which pancreatic cancer cells may compensate for ERK inhibition and become resistant to this drug, so that he and his colleagues can devise a strategy to overcome the cells’ resistance and ensure that the drug is effective in treating pancreatic cancer.
“Multi-gene tests have been shown to provide valuable information beyond the information provided by the current pathology-based biomarkers,” says Aleix Prat, MD, a research fellow at UNC Lineberger Comprehensive Cancer Center in the laboratory of Charles Perou, PhD, May Goldman Shaw Distinguished Professor of Molecular Oncology Research. “However, multi-gene tests are not readily available in most of the world due to cost, assay turnaround times, and other logistic issues.”
Dr. Prat is presenting his findings at the best abstracts session of the 4th IMPAKT Breast Cancer Conference in Brussels, Belgium on May 3, 2012. IMPAKT is an annual conference that was launched in 2009 by the Breast International Group (BIG) and the European Society for Medical Oncology, in collaboration with a multidisciplinary alliance of European breast cancer organizations and patient groups - referred to as partners.
Dr. Prat and colleagues addressed this problem by trying to improve the current pathology-based biomarkers to better represent data coming from a particular multi-gene test known as the PAM50 breast cancer intrinsic classifier.
“The PAM50 breast cancer intrinsic classifier identifies two major groups of hormonal receptor-positive breast cancer known as the Luminal A and Luminal B subtypes. These two molecular entities have different risks of relapse and responses to chemotherapy,” Dr. Prat said.
Alongside the development of this multi-gene assay, clinicians have devised pathology-based surrogate assays for the identification of the Luminal A and B subtypes. “In the absence of multi-gene assays, these pathology-based assays are clinically valuable,” Dr. Prat explained. “However, we observed that current pathology-based definitions of the Luminal A and B subtypes still show a 30-40 percent discordance rate compared to multi-gene tests such as the PAM50 breast cancer intrinsic classifier.”
The researchers examined differences in gene expression between Luminal A and B tumors using the PAM50 test. They also collected clinical-pathological features from 2,950 primary tumors across four independent studies. Using statistical methods, they tested the independent prognostic significance of those features.
They found that the expression of progesterone receptor was one of the most discriminatory molecules. “Addition of the quantitative scoring of the progesterone receptor into the current pathology-based Luminal A definition appears to better identify the subgroup of patients that have an outstanding survival when treated with endocrine therapy alone, and therefore do not need systemic chemotherapy,” Dr. Prat said. “This subpopulation of patients is likely to represent around 30 percent of the patients with low-risk pathology-defined Luminal A tumors.”
“Current pathology-based definitions of the Luminal A and B subtypes are valuable, but can be improved for the management of hormonal receptor-positive breast cancer,” the researcher concluded. “We believe that we have an improvement based upon the progesterone receptor, and given that progesterone receptor is widely used, our improvement could be widely and quickly adopted if further validated.”
Study co-author is Joel Parker, PhD, director of bioinformatics at UNC Lineberger.
This work was supported by funds from the National Cancer Institute’s Breast SPORE program (P50-CA58223-09A1), by RO1-CA138255, by the Breast Cancer Research Foundation, and the Sociedad Española de Oncología Médica (SEOM).
To better shape the next phase of CER, a team of scientists reviewed literature and conducted interviews with 41 comparative effectiveness researchers at the Agency for Healthcare Research and Quality’s Cancer Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Comparative Effectiveness Research Consortium.
Based on these interviews and further analysis, these scientists, members of the AHRQ Cancer DEcIDE Data Committee, developed recommendations to improve, accelerate and implement the use of CER to inform cancer care and clinical practice. The team reports in the April 20, 2012 online issue of the journal Cancer.
Their review includes discussion of data sets with recommendations on how better to identify those that are relevant to addressing individual research questions, and how to evaluate them. It characterizes the explosive growth in information technology and recent advances in research methods, and the large population-based data that are consequently now more available for research. In contrast to data collected for clinical trials, many of these data sets were not initially collected to support research, let alone address specific research questions. For example, the National Cancer Institute’s SEER-Medicare data links cancer registry data to administrative and insurance claims data from Medicare. Together they have been used to analyze important questions such as the relative benefits of one type of radiation therapy for prostate cancer compared to another. These and similar data have been used to address a wide range of research questions for which prospective clinical trials are not feasible, practical, or sufficiently timely.
To aid CER researchers, the team conducted interviews and research and identified relevant data sets for cancer CER research. They organized these sets into useful categorical classifications, and presented characterizations of the data and examples of their use. They then propose recommendation to both maximize their immediate utility for CER, and also to inform the development of the next generation of data so that it may be more useful for research.
“We often find that similar concepts are measured in very different ways between data sets, making them difficult to compare in research. One recommendation we have for the CER community is to develop uniform definitions and consistent ways of collecting and coding data so that they can be more useful in research,” says Anne-Marie Meyer, PhD, the study’s lead author and the UNC Facility Director for the Integrated Cancer Information and Surveillance System (ICISS) at UNC Lineberger Comprehensive Cancer Center. “Longer-established systems also need to be enhanced to extend their ability to answer important questions in the context of contemporary cancer care.” She is an epidemiologist research associate at UNC Lineberger.
The authors cite a need to establish systematic, standardized measures of collection and coding of data, pointing out that the lack of global standardization inhibits data pooling, comparability among multiple sources, and the ability to generalize findings in the context of the population’s diversity.
Bill Carpenter, PhD, assistant professor of health policy and management at the UNC Gillings School of Global Public Health, and UNC PI for the AHRQ-funded Cancer DEcIDE CER Consortium, explains, “In addition, we need to develop a forum and a process for overcoming issues of data ownership, access, and governance. Much data is currently proprietary, and so the process of gaining access to them is bureaucratically cumbersome and time consuming. As a result, the majority of time in a research project is spent gaining access to data rather than examining them and answering important questions that can improve patient care quality and cancer outcomes.” He is faculty director for ICISS.
The reviewers suggest strategies such as enhancing national cancer registries’ collection of data on genetic markers; increasing transferability of data with open-source, open-access tools; and more intermediate outcomes such as time to disease progression or recurrence, toxicities, and treatment side-effects.
They recommend improving study design and population sampling and developing methods to leverage existing data.
Dr. Meyer notes, “It is important to recognize that new methods can extend the utility of existing data, but they cannot always correct for problems in the way data were collected. Only through improvements in study design and dataset development can some of these barriers be overcome. As such, new efforts to develop extensive new data would be well-served to incorporate diverse research perspectives, including those of methodologists. Many limitations or data errors can be corrected up-front and ensure that these data will be useful in the future.”
Addressing these recommendations will not necessarily be easy, and may involve changing longstanding paradigms in data ownership and governance. The team points out the need for developing codified relationships among federal agencies, their contractors and many data holders to facilitate timely data sharing for research that supports the public good. Standardized relationships between state and federal agencies help reassure data holders that their data will be used appropriately and will facilitate the timeliness of data for research and enable quick turn-around on important questions.
“With the internet, we have seen an astounding democratization of information. In this context, data liquidity should be our new standard: we should aspire to create new data that can be used broadly, by many audiences, to address many questions. As this happens, competitive advantage among researchers and research organizations will no longer be a function of ‘who owns the data,’ and will instead become, ‘Who can articulate the important questions, and appropriately and expeditiously analyze the data to correctly answer them?’” says Carpenter.
They underscore the need for improved access to data, but recognize the critical concern for data security, privacy and confidentiality.
Carpenter continues, “Data security and the privacy and confidentiality of the individuals whose data are collected must remain paramount. But we must be thoughtful about this. We cannot set up systems that so emphasize these needs as to be impractical and thus not useable. To be successful here, we must incorporate both technological and administrative systems to protect the data, but we must also emphasize the importance of building and protecting an essential trust fabric between the people whose data are collected, the data collectors, and the researchers. No successful relationship can get off the ground without trust, or be perpetuated without steadfast stewardship.”
Their final recommendation describes the advantages of a collaborative, multidisciplinary approach to represent and articulate the different approaches, cultures, terminology, measures, and priorities for cancer CER. Research must move beyond the silos. They cite the recently established Patient Centered Outcomes Research Institute (PCORI) as the obvious choice to lead such an effort.
Meyer concludes, “In recognition of the value and importance of CER, the Patient Centered Outcomes Research Institute (PCORI) was created as a hub of CER and a center for leading and coordinating the national discussion on it. Though still in its formative stages, it has advanced very quickly under the leadership of Dr. Joe Selby. It has recently revised its initial research agenda, and is expected to begin engaging researchers in important CER in the very near future. UNC has been in consistent contact with the founding members of PCORI and, with Dr. Ethan Basche – a member of the PCORI Methods Committee – joining the UNC faculty in the next few months, we look forward to continuing to engage in this discussion, contribute to this important research, and develop new knowledge to help patients make the best health care decisions possible given their specific needs and priorities.”
Additional study authors are Amy P. Abernethy, MD, Duke University; Til Sturmer, MD, PhD, UNC; and Michael Kosorok, PhD, UNC.
]]>The finding offers a new glimpse into the private lives of stem cells that could help scientists use them to grow new neurons or other cells to replace those that have been lost in patients with Parkinson’s and other diseases. “Despite the huge potential of stem cells for therapeutic use, very few people have actually investigated their basic biology,” said study senior researcher Mohanish Deshmukh, PhD, professor of cell & developmental biology at the University of North Carolina at Chapel Hill. “These results could have significant implications from a therapeutic perspective”.
Of all the important things our bodies’ cells do, staying alive is clearly key. But a cell’s ability to die when something goes wrong is equally critical. For example, a faulty self-destruct button is one factor that allows cancer cells to proliferate unchecked and cause tumors.
Deshmukh and his colleagues discovered stem cells are extremely sensitive to DNA damage, which can be caused by factors like chemicals, radiation or viruses. The experiment showed that virtually 100 percent of human embryonic stem cells treated with a DNA-damaging drug killed themselves within 5 hours, as compared to 24 hours for other types of cells. “That’s an incredibly rapid rate of death,” said Deshmukh, who also is a member of the UNC Neuroscience Center and Lineberger Comprehensive Cancer Center.
The hair-trigger suicidal response is an important adaptation for embryonic stem cells, said the UNC School of Medicine researcher, because a slower response could allow DNA damage to proliferate and harm the embryo. “Mutations that develop in these cells could be catastrophic for the developing organism, so it would make sense for these cells to be rapidly eliminated.”
The key to the stem cells’ quick response is that they pre-activate a critical protein called Bax, the researchers found. In most cells, Bax is is kept in an inactive form, waiting for a long chain of events to rouse it into action if the cell becomes damaged enough to kill itself. In human embryonic stem cells, the team found Bax standing at attention in its active form in the Golgi apparatus, a part of the cell that processes and modifies proteins.
“What these cells do is very clever,” said Deshmukh. “They have activated Bax, but they’ve also parked it in a safe little compartment—the Golgi.” If the cell detects DNA damage, Bax zips over to the mitochondrion (the cell’s power plant), where it signals other proteins to shut the cell down.
It’s like starting a 100-yard race at the 80-yard line, said Deshmukh. You’re guaranteed to get to the finish line first because you did most of the work before the race began. However, there are built-in safeguards against a hair trigger activation of death. Pre-activated Bax is housed in the Golgi keeping the protein from accidentally triggering cell death when it’s not warranted.
This extreme sensitivity to DNA damage lasts only a few days during early development. After the embryonic stem cells begin differentiating into early progenitors that give rise to specific cell types (like heart cells or skin cells), Bax reverts to its inactive state.
UNC Co-first authors of this study are - Raluca Dumitru and Vivian Gama. Other UNC Co-authors include B. Matthew Fagan, Jacquelyn J Bower, Vijay Swahari and Larysa H Pevny. The study was funded by grants from the National Institutes of Health (National Institute of General Medical Sciences) and UNC’s University Cancer Research Fund.
]]>DeSimone, based in the College of Arts and Sciences at UNC, also is William R. Kenan Jr. Professor of Chemical Engineering at N.C. State University.
With the new class of members announced by the academy, there are 2,152 active members and 430 foreign associates. The academy was established by Congress in 1863 as an official adviser to the federal government, upon request, in any matter of science or technology. Candidates for membership can only be formally nominated by academy members.
DeSimone has more than 280 publications and holds 130-plus patents. His work currently focuseson nanomedicine. In 2004 DeSimone and his students at UNC-Chapel Hill and N.C. State invented a new technology to create nanoparticles called PRINT (Particle Replication In Non-wetting Templates). With PRINT, DeSimone and his team were the first to successfully adapt manufacturing techniques from the computer industry to make advances in medicine, including improved approaches to cancer treatment and diagnosis. Other projects include developing a nanoparticle vaccine for prostate cancer and creating particles that mimic red blood cells. DeSimone co-founded Liquidia Technologies, a Triangle-based nanotechnology company, to further develop the PRINT technology. Liquidia currently has its first product – a nanoparticle flu vaccine – in clinical trials.
DeSimone is also a member of the UNC Lineberger Comprehensive Cancer Center, an adjunct member at Memorial Sloan-Kettering Cancer Center in New York and the director of both the Institute for Advanced Materials, Nanoscience and Technology and the Institute for Nanomedicine at UNC.
In 2005, he was elected to the National Academy of Engineering, also a private, independent nonprofit that provides engineering leadership in service to the nation. That same year, he was also elected to the American Academy of Arts and Sciences.
National Academy of Sciences announcement link: http://www.nasonline.org/news-and-multimedia/news/2012_05_01_NAS_Election.html
DeSimone photo: http://go.unc.edu/Me5k3
]]>Watch a video interview with Dr. Milowsky about bladder cancer
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