Friday, April 19, 2013
CHAPEL HILL, N.C. - A monoclonal antibody targeting a protein known as SFPR2 has been shown by researchers at the University of North Carolina to inhibit tumor growth in pre-clinical models of breast cancer and angiosarcoma.
In a paper published in the April 19 issue of Molecular Cancer Therapeutics, a team led by Nancy Klauber-DeMore, MD, professor of surgery and a member of UNC Lineberger Comprehensive Cancer Center, used a monoclonal antibody to target SFRP2 expressed in cells from triple-negative breast cancer and the aggressive blood-vessel malignancy angiosarcoma, reducing the rate of tumor growth. The antibody, created at the University of North Carolina, is the first therapeutic discovered that targets SFRP2.
“We showed in this paper that targeting SFRP2 with a monoclonal antibody in pre-clinical models inhibits tumor growth. This demonstrates that SFRP2 is a therapeutic target for cancer” said Dr. DeMore.
The DeMore lab first discovered the role of SFRP2 in tumor growth while looking to develop an alternative to the FDA-approved anti-angiogenesis drug known as Avastin (bevacizumab). Avastin targets the protein VEGF, which has also been tied to angiogenesis (the production of new blood vessels). Although Avastin is of benefit to some patients with cancer, not all tumors respond to Avastin, and of those that respond, some eventually progress. To find a solution for patients whose tumors are resistant to Avastin, DeMore began looking at other proteins linked to angiogenesis that could be used as therapeutic targets.
“We previously microdissected blood vessels from malignant human breast cancers and compared gene expression to blood vessels microdissected from normal tissue. We found a number of genes that were highly over-expressed in the malignant blood vessels compared to normal. One of those genes was SFRP2,” said Dr. DeMore.
The DeMore lab found that SFRP2 is expressed in a variety of human cancers, including breast, prostate, lung, pancreas, ovarian, colon, kidney tumors, and angiosarcomas, DeMore, working with Dr. Cam Patterson, Ernest and Hazel Craige Distinguished Professor of Cardiovascular Medicine, discovered that SFRP2 acted as a potent stimulator of angiogenesis, leading their team to hypothesize that targeting SFRP2 could inhibit tumor growth. In collaboration with Dr. Russ Mumper, the John A. McNeill Distinguished Professor in the Division of Molecular Pharmaceutics, their group developed a drug to target SFRP2. “Demonstrating that a monoclonal antibody to SFRP2 inhibits tumor growth in pre-clinical models opens up a new potential for drug development. This treatment is not presently available for human studies, but our efforts are focused on obtaining funding for further drug development that would lead to a clinical trial” said DeMore.
This work was supported by National Institute of Health (P50-CA58223, 1R01CA142657-01A1 and R01 HL61656), North Carolina TraCS Large Pilot Award, University Cancer Research Fund, Nancy DeMore Foundation and North Carolina Kickstart Commercialization Collaboration Award.
Tuesday, April 16, 2013
In research published April 8 in the Journal of Clinical Investigation, a research team led by William Kim, MD, member of the UNC Lineberger Comprehensive Cancer Center, and graduate student and first author Sara Hanna, linked melanoma metastases to a pair of transcription factors known as HIF1 and HIF2.
Researchers found that HIF1 and HIF2 are overexpressed in melanoma tumors. In healthy cells, HIF1 and HIF2 assist in regulating hypoxia, the state caused by low levels of oxygen in the blood. Hypoxia has been linked to metastases in several sold tumors, and the UNC team has found that it promotes the spread of melanoma from the skin to other sites in the body through the lymphatic system.
Patients who are diagnosed with early stage melanomas have a high rate of survival, but the prognosis worsens significantly once the tumors spread to other sites throughout the body. Using in vitro systems and mouse models, researchers suppressed the expression of HIF1 and HIF2 in the melanoma tumors. While the inactivation of the transcription factors did not reduce the growth of the initial tumors, it did reduce the rate at which the melanoma spread to other sites in the body.
Both HIF1 and HIF2 independently activate the protein kinase SRC using different signaling pathways. The SRC protein has been linked to several different cancers, and the identification of its role in melanoma suggests that existing therapies targeting SRC may prove to be a viable target for therapies aimed at reducing the spread and ultimate lethality of the cancer.
“What we are trying to do now is inhibit these pathways with drugs in the mice to see if we see a decrease of metastasis,” said Hanna.
UNC researchers who contributed to this article include Bhavani Krishnan, PhD; Sean Bailey; Stergios Moschos, MD; Pei-Fen Kuan, PhD; Marni Siegel and C. Ryan Miller, MD, PhD, of the Lineberger Cancer Center; and Lukas Osborne, E. Tim O’Brien III and Richard Superfine, PhD, of the UNC Department of Physics and Astronomy.
This research was supported by the National Institutes of Health (P30-DK-034987), the National Cancer Institute (3P30CA016086), the Department of Defense (W81XWH-09-2-0042) and the University Cancer Research Fund.
CHAPEL HILL, N.C. – Claudia Laskow has never been a shrinking violet. A breast cancer diagnosis and its treatment didn’t change that.
“No one is a stranger to Claudia,” said Jan, 58, her husband of nearly 33 years, who was hooked when they met in eighth grade. “If they don’t know her, they want to know her.”
“I’m just a social worker at heart who knows a sense of humor helps any situation,” said Claudia, 58, who holds a masters degree in social work and is a real estate agent in “the Village of Avon, on the Island of Hatteras, in the County of Dare.”
The Doylestown, Pa., natives moved to the Outer Banks in 1989 after falling in love with the surf and sand they enjoyed over many camping and fishing vacations. “We call ourselves long-time transients, but we’re here to stay,” said Jan, who runs a fire safety business and is assistant chief of the Avon Volunteer Fire Department.
Jan found the lump in Claudia’s left breast last July 4. Lumpectomy results revealed Stage II-B breast cancer and her family doctor — and family friend — Bentley Crabtree, MD, referred Claudia to UNC Hospitals.
“I know it’s where I’m supposed to be,” Claudia said. “Even before the diagnosis was confirmed, Jan’s brother who is on the board of the University of Pittsburgh Medical Center told us if I did have breast cancer I had to get to Lisa Carey at UNC Hospitals. Before we could ask for her by name, the referral was made, and she’s my medical oncologist. I’ve always believed things happen for a reason.”
Day One at UNC Hospitals was long, but good, Claudia said. It involved a full-day of meetings with key members of the multidisciplinary team that would be taking care of her through surgery, two separate chemotherapy regimens, radiation and the follow-up endocrine therapy. It’s the multidisciplinary patient-centered care for which UNC Health Care is known.
“We know our approach asks a lot of patients, and it can be overwhelming,” said Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor for Breast Cancer Research, Division Chief of Hematology and Oncology, and Physician-in-Chief, of the North Carolina Cancer Hospital. “Depending on the diagnosis, there can be up to six groups of physicians involved.
“The good news is we talk to patients about the value of the multidisciplinary decision making, how lots of decisions have to be made at the beginning about what is going to happen and in what order,” Dr. Carey said. “We have patient navigators to help with scheduling, questions and interpretations, and every patient gets a written plan.
“It’s always about what’s the optimal way of getting our patients through their treatment and giving them what they need, including the needs outside of the treatment. Our care is tailored to meet the needs of each individual patient.”
And that’s what Claudia — and Jan — felt and appreciated throughout the journey.
“We can’t say enough good things about everyone we’ve interacted with while in Chapel Hill,” Jan said. “From the parking attendants and receptionists to Claudia’s doctors, they all really care about patients. They’ve got a good thing going.”
Part of that good thing going was referring Claudia to SECU Family House, a 40-bedroom hospital hospitality house minutes from UNC Hospitals that provides comfortable, convenient and affordable housing for seriously ill adult patients and their family member caregivers.
Claudia stayed there Sunday nights through early Friday mornings while she had six weeks of radiation that wrapped up on April 8.
“I had to drive home for weekends to see my sweetie, be near the water, sleep in my own bed and sit on my own toilet,” Claudia said. “As wonderful as Family House is, there’s no place like home.”
But Family House was the ideal location for the former social worker to thrive.
“She could not have gotten the socialization she needed by herself in a hotel room,” said Jan. “She was able to help other patients—often just by listening and making them laugh — and probably gave way more than she got. But no one was keeping score.”
A born outdoorswoman, Claudia took it upon herself to maintain the herb garden at Family House. She brought her own clippers from home, bundled clippings for fellow residents and volunteers to take home to start/add to their own gardens and made lists of what additional herbs would round out the garden’s bounty.
“It was pure therapy,” Claudia said. “If I can’t put my toes in the water, let me have my hands in the dirt. Besides, I was finished with my radiation every day before most people were up and moving. How else was I going to spend my day? I could only be on my computer for so long.”
By her own admission, the chemotherapy kicked her butt.
“I let the nausea and other side effects get the upper hand,” she said. “They have anti-nausea medicine for a reason. If they tell you to take it, you should.”
“We encourage patients to be honest and tell us when they feel bad,” Dr. Carey said. “It’s our job to make them feel better, but it’s a collaborative approach. Being stoic is not realistic or appropriate.”
Despite some rough days, humor prevailed.
After losing her hair to chemotherapy — and Jan shaved his head in solidarity — Claudia sported seasonally appropriate hats and caps. She fashioned “costumes” for the chemotherapy infusion poles, the most memorable including a turkey hat for Thanksgiving.
Then there was the pink tutu and pink boxing gloves she donned her last day of chemotherapy, with the tutu reprising its role when Claudia rang the gong marking the completion of radiation.
“I don’t normally ‘do pink’ but with breast cancer, I had to make an exception,” Claudia said, pondering the possibility of a celebratory bonfire on the beach once she finishes all treatment and gets the word that her otherwise healthy body is cancer-free. Of course, the fire would be fueled by all the pink she’s ever worn.
“Claudia has done an amazing job, absolutely doing her part every step of the way,” Dr. Carey said. “As far as we can tell, her treatment has done what it’s supposed to do. Now we wait and pray, and hope it doesn’t come back.”
For now, Claudia and Jan are relishing getting back to their routine, just in time for the high season to crank up at the beach. They will celebrate their 59th birthdays AND their 33rd wedding anniversary on May 10. Two fish blissfully happy in the same net.
“I constantly remind her she’s 12 hours older and always will be,” Jan said.
“Yeah, I robbed the cradle, but I’m not complaining,” she said.
Wednesday, April 10, 2013
CHAPEL HILL, N.C. – Researchers at the University of North Carolina at Chapel Hill School of Medicine have “rationally rewired” some of the cell’s smallest components to create proteins that can be switched on or off by command. These “protein switches” can be used to interrogate the inner workings of each cell, helping scientists uncover the molecular mechanisms of human health and disease.
In the first application of this approach, the UNC researchers showed how a protein called Src kinase influences the way cells extend and move, a previously unknown role that is consistent with the protein’s ties to tumor progression and metastasis.
“This rationally designed control of protein conformations represents a breakthrough in computational protein design,” said senior study author Nikolay Dokholyan, PhD, a professor of biochemistry and biophysics. “We now have a new tool for delineating the activities of various proteins in living cells in a way that was never before possible.”
The research was published online ahead of print in the Proceedings of the National Academy of Sciences. In the study, Dokholyan created a “switch” that would make a protein wobbly and unable to do its job unless it was flipped “on” by a drug called rapamycin, which would stabilize the protein and let it perform its function.
The approach is a simpler and more reliable version of a protein engineering system pioneered three years ago by Dokholyan and Klaus Hahn, professor of pharmacology at UNC, called rapamycin regulated or RapR. In the old approach, the switching mechanism depended on two proteins and the drug. The first protein – the one the researchers wanted to study – was given the RapR modification and put in cells in tissue culture. The second protein was placed in the cells as well, but simply floated around until the addition of drug caused it to latch on to the modification in the first protein and turn it on. The problem with the approach was that some cells would have a lot of the first protein and less of the second, or vice versa.
“It became the Achilles heel of the technique, because there was variability in the results due to the different ratios between the proteins,” said Hahn. “What Dokholyan was able to do, which was extremely challenging from a protein engineering standpoint, was to combine the two parts into one.” Dokholyan and Hahn are members of the UNC Lineberger Comprehensive Cancer Center.
Dokholyan and his colleagues took the two proteins and broke them apart into their individual components, structures called alpha helices and beta sheets. They then rewired them together to make a whole new protein where the parts could interact with each other. When researchers compared this system, called uniRapR, with the previous approach, they found the new one gave cleaner, more reliable and more consistent results.
They then applied the technique to study Src kinase, a protein involved in the metastasis or spread of tumor cells. Scientists had postulated that Src kinase plays a role in cell motility, but previous methods have not allowed them to isolate its activity from other similar proteins.
Working both in cultured human cells and in the model organism zebrafish, the researchers showed that turning on Src causes the cell to extend its edges as part of cell movement. Now that they have dissected the role of one protein, the researchers plan to look at a variety of other kinases to understand their roles in the development, progression, and spread of cancer.
The research was funded in by the National Institutes of Health, the National Institute of Environmental Health Sciences, and the National Cancer Institute. Study co-authors from UNC were Onur Dagliyan; David Shirvanyants, PhD; Andrei V. Karginov, PhD; Feng Deng, PhD; Lanette Fee; and Srinivas N. Chandrasekaran. Co-authors from the University of Wisconsin, Madison, were Christina M. Freisinger, Gromoslaw A. Smolen, and Anna Huttenlocher.
]]>Thursday, April 4, 2013
CHAPEL HILL, N.C – Viruses have historically been classified into one of two types – those with an outer lipid-containing envelope and those without an envelope. For the first time, researchers at the University of North Carolina have discovered that hepatitis A virus, a common cause of enterically-transmitted hepatitis, takes on characteristics of both virus types depending on whether it is in a host or in the environment.
“The whole universe of virology is divided into two types of viruses – viruses that are enveloped and viruses that are not enveloped. If you look at any basic virology textbook, it will say that these are categories that distinguish all viruses,” said lead researcher Stanley M. Lemon, MD, professor of medicine and a member of the UNC Lineberger Comprehensive Cancer Center and the Center for Translational Immunology.
In a paper published online in Nature on March 31, Dr. Lemon’s team discovered that hepatitis A virus does not have an envelope when found in the environment, but acquires one from the cells that it grows in within the liver. It circulates in the blood completely cloaked in these membranes.
“What we have discovered is that a virus that has been classically considered to be ‘non-enveloped’, that is hepatitis A virus, actually hijacks membranes from the cells it grows in to wrap itself in an envelope. It steals membranes from the cell, as it leaves the cell, to cloak itself in this envelope that then protects it from antibodies. And that’s really novel. No one has shown that previously for a virus. It really blurs that classic distinction between these two types of viruses,” said Dr. Lemon.
Being enveloped in host membranes helps the virus to evade host immune systems and spread within the liver. Enveloped viruses are generally quite fragile in the environment, while non-enveloped viruses are hardier outside of a host and can survive for longer periods between hosts. Dr. Lemon believes the dual nature of hepatitis A virus allows it to use the advantages of both virus types to enhance its survivability.
“What hepatitis A virus has done, and we don’t totally understand how it has accomplished this, is to have the advantage of existing as a virus with no envelope and being very stable in the environment so it can be transmitted efficiently between people, but to wrap itself in a membrane to evade neutralizing antibodies and facilitate its spread within the host once it has infected a person,” said Lemon. While no other virus has been shown to exhibit this particular behavior, Dr. Lemon said that it is likely that hepatitis A virus is not unique in its dual nature.
Hepatitis A is endemic in developing nations that lack modern sanitation and clean water. The virus is transmitted orally and then passed back into the environment through feces. By not needing its envelope to survive outside the host, the virus gains the ability of non-enveloped viruses to survive longer and be transmitted efficiently.
One major question raised by the finding is why the hepatitis A vaccine works so well to contain the infection. The vaccine, one of the most effective in use, was thought to elicit neutralizing antibodies that attack the virus in the blood. Since it is now known that the envelope surrounding the virus in the blood prevents this, the vaccine cannot work as previously thought.
“It makes us rethink completely the mechanism underlying the well-documented efficacy of hepatitis A vaccine. I think this is one of the most important things to come out of the study,” said Dr. Lemon.
The research at UNC was funded by the National Institute of Allergy and Infectious Diseases. Future studies will investigate the mechanisms behind the vaccine’s effectiveness, Dr. Lemon said. While it was previously thought that vaccine-induced antibodies attacked the virus outside of the cell, the new findings suggest antibodies may actually be able to restrict viral replication within a cell.
“Understanding how this really good vaccine works will help us in the future to develop better vaccines for other viruses that we are having difficulty developing vaccines for,” said Dr. Lemon.
Chancellor Thorp will honor the recipients, who were chosen from nominations from the campus community, at an awards luncheon on April 27. Each will receive a $7,500 stipend and an award citation. With the growth of the endowment, each award is increasing from $6,000 to $7,500.
This year’s recipients are:
The original article was published by the University Gazette here.
The study was published online March 28 in Cancer, the journal of the American Cancer Society, by a team led by Ronald Chen, MD, MPH, assistant professor with the UNC Lineberger Comprehensive Cancer Center. The study is the first published population-based examination of racial disparities in prostate cancer treatment delay.
Using data from Medicare patients, Dr. Chen compared the treatment of 2,506 African American and 21,454 Caucasian patients diagnosed with early prostate cancer from 2004 to 2007. The data showed that, on average, African Americans experienced a seven-day longer delay in treatment.
“These are all patients with some form of insurance, i.e. Medicare, so it is not a lack of insurance that delays the care,” said Dr. Chen.
Multiple prior studies have found that the disparity in survival rates between African American and Caucasians diagnosed with prostate cancer is the highest of any malignancy – with African American men being 2.4 times more likely to die from the disease. Prostate cancer is the most common cancer among all American men, with more than 240,000 diagnoses per year. It ranks as the second leading cause of cancer death among men, killing more than 28,000 annually.
The treatment delay was more pronounced among patients who were diagnosed with aggressive, “high-risk,” prostate cancer, where African American patients experienced a 9-day longer delay compared to Caucasians.
“Other studies have shown that African American men are less likely to get screened, they get diagnosed with more advanced cancers, and they are less likely to get aggressive treatment when they are diagnosed. Now we have shown that African American patients also wait longer for treatment. I think all of these disparities together add up to contribute to a worse long-term survival outcomes for African American patients,” said Dr. Chen.
While the data did not reveal the impact of the delay on patient’s survival, Dr. Chen noted that the Institute of Medicine has identified timely delivery of care as an important indicator of the quality of that care. To determine the reasons behind the delay, further studies will need to focus on the personal and institutional factors that lead to the disparities in treatment.
“What our study does is that it identifies an area of need, an area of disparity. More studies are needed to figure out why and to find ways to address disparities in care,” said Dr. Chen.
Monday, March 25, 2013
CHAPEL HILL, N.C. – Researchers at the University of North Carolina at Chapel Hill have discovered that a protein found in the cells surrounding pancreatic cancers play a role in the spread of the disease to other parts of the body.
In a finding to be published in the March 25 issue of Oncogene, researchers in the lab of Carol Otey, PhD, found that the protein palladin enhances the ability of cancer-associated fibroblasts (CAFs) to assemble organelles known as invadopodia to break down the barriers between cells and create pathways for tumors to spread throughout the body. Otey is a professor in the Department of Cell Biology and Physiology and a member of UNC Lineberger Comprehensive Cancer Center.
“There’s a growing body of literature that shows that these cells have a role in cancer formation and metastasis,” said Otey.
Using both enzymatic action and physical force, the invadopodia create channels for tumor cells to migrate from their point of origin to other organs. Otey said that researchers, using cultured cancer cells suspended between layers of collagen, have been able to observe CAFs tunneling through the collagen layer and record cancer cells migrating through those channels.
In previous studies, researchers in the Otey lab and other labs have shown that CAFs surrounding pancreatic tumors express high levels of palladin. In healthy tissue, fibroblasts are the most common type of connective tissue found in mammals. In cancerous cells, CAFs are the most numerous cells found in the tumor microenvironment.
Researchers have begun focusing significant attention to the tumor microenvironment, as evidence grows that the cells and proteins found outside of cancer cells play a crucial role in tumor formation, growth and metastasis. Understanding the interplay between the microenvironment and the tumors could lead to new targets for treatment and screening, especially in cancers that are resistant to therapies that directly target the cancerous cells.
“Cells seem to be partnering together to form the tumor and promote its growth,” said Otey.
Using pharmacological inhibitors and gene-silencing approaches, Otey and the research team discovered that disrupting palladin in CAFs reduced the ability of the cells to form invadopodia. Increasing the level of palladin in CAFs, by contrast, increased the rate of growth and metastasis of tumors in mouse models. Their results indicate that palladin may be part of a molecular pathway that includes two additional molecules, protein kinase C and Cdc42.
“These results demonstrate that the behavior of CAFs plays a very important role in modulating the behavior of tumor cells, and also point to a specific molecular pathway that could be a useful drug target for inhibiting tumor progression,” said Otey. Since Otey discovered palladin more than a decade ago, researchers in her lab have examined the protein’s role in both healthy and cancerous cells. Citing her own work, research from the Brentnall lab at University of Washington, and corroborating work such as a study from the Cukierman lab at Temple University’s Fox Chase Cancer Center that found high levels of the palladin protein correlated strongly with low survival rates in renal carcinoma patients, Otey said that the evidence points toward a strong correlation between palladin expression in CAFs and the aggressiveness of tumor progression.
In future research, Otey plans to examine the levels of palladin in other types of cancer. As the Fox Chase study suggests, the mechanisms that she and her collaborators have discovered may play a role in cancers other than pancreatic.
“Knowing more about this may give us better tools to slow down metastasis,” said Otey.
Study co-authors from UNC include first author Silvia M. Goicoechea, Rafael García-Mata, Judy Staub, Alejandra Valdivia, Lisa Sharek, Jen Jen Yeh and Hong Jin Kim. Other study co-authors are Chris McCulloch from University of Toronto, Canada; Rosa Hwang from University of Texas M.D. Anderson Cancer Center, Houston, TX; and Raul Urrutia from Mayo Clinic College of Medicine, Rochester, Minn.
This study was supported by grants from the NIH (GM081505), the NSF, the Elsa U. Pardee Foundation and the UNC University Cancer Research Fund.
Oliver Smithies did not set out to become one of the world’s foremost pioneers in cancer research. He merely had a question that needed answering.
The path to that answer led to one of the greatest advances in modern biomedical research, a Nobel Prize and now recognition as a member of the first class of Fellows of the American Association for Cancer Research Academy. On April 5, Smithies, DPhil, Weatherspoon Eminent Distinguished Professor in the Department of Pathology and Laboratory Medicine and member of the UNC Lineberger Comprehensive Cancer Center, will join 106 other of the nation’s most accomplished cancer researchers as the first group to receive the honor.
Smithies shares his 2007 Nobel Prize with Mario Capecchi of the University of Utah and Martin Evans of University College London for their work in developing the technique of gene targeting. Gene targeting has become a cornerstone of modern genetics and pharmaceutical research, allowing for the breeding of research animals that have specific genes turned on and off to allow researchers to investigate the function of genes and assist in developing treatments for a variety of genetically based disorders, including cancer.
“It is possible to modify a gene in a living cell in a planned way. That’s gene targeting, and that was the first time anyone had been able to demonstrate that that was possible,” said Smithies.
In 1982, Smithies’ work as a geneticist revolved around finding a cure for sickle cell anemia. A decade earlier, researchers had developed the first genetic engineering techniques to allow molecular cloning, the modifying of an organism’s genome by introducing DNA fragments from another organism. After reading an article from a cancer researcher who had changed the behavior of a petri dish full of cells using genetic engineering techniques, Smithies wondered if he could use the same techniques to make a targeted modification to a gene.
“The initial experiments that I did at that time were trying to find a way to correct a genetic abnormality. I thought that what I would like to do is find a way of using the DNA from a normal individual to change the mutated gene in the person that had sickle cell anemia. In that way, I’d help that person live a normal life,” said Smithies.
It took Smithies three years to devise a working method. Unfortunately, the frequency of success was not high enough for clinical use, so Smithies began to look for another uses for gene targeting.
“It was too inefficient. It worked, but it worked very rarely,” said Smithies.
His search led him to the work of two researchers with whom he shared the Nobel Prize – Martin Evans and Mario Capecchi. Evans had isolated embryonic stem cells and shown that inserting those stem cells into a developing mouse egg would lead to them being incorporated into the developed mouse. Using this technique, now known as homologous recombination, Smithies was able to correct a faulty gene in a mouse.
“I thought that if I can modify the embryonic stem cell in a planned way, I could add changes in different genes. And that would be very valuable, even if it would be difficult to do,” said Smithies.
At the same time, Capecchi proved that gene targeting could be used to “knock out” genes from a mouse, effectively inactivating the genes. This improved the efficiency of the methods, creating a set of tools that have benefited researchers across the world and led to the development of the knockout mouse model of biological research. Both Evans and Capecchi have also been named to the AACR Academy.
“That’s why the three of us together were important in that work. First of all showing that it was possible, that was my work. Showing that you could do experiments with mice in tissue culture, that was Martin Evans’s work. Showing that you could get much better results and do important knock out experiments, that was Mario Capecchi’s work,” said Smithies.
The knockout mouse has become a central tool in the study of genetics. They have served as models for research into disorders such as cancer, aging, obesity, heart disease, diabetes, arthritis, anxiety and substance abuse.
“Smithies quickly recognized the potential for applying the gene targeting technology to creating preclinical animal models of complex diseases in humans such as cancer. He noted that the mouse system is particularly valuable because the effects of combinations of genetic changes can be studied, and because environmental influences can be varied in a controlled fashion. His work led to the ability to systematically study endogenous mouse models for cancer,” said Terry Magnuson, chair of the UNC Department of Genetics.
The inaugural class of Fellows will be inducted into the AACR Academy on April 5, 2013 at the National Museum of Women in the Arts in Washington, D.C. The induction ceremony will be followed by a meeting of the Academy on April 6, and special recognition of the inaugural Fellows during the opening plenary session on April 7. The AACR plans to induct new members annually at this event, with future classes consisting of no more than 11 fellows.
]]>Wednesday, March 20, 2013
Written by Elizabeth Swaringen for UNC Health Care
CHAPEL HILL, N.C. – Cindy Sills refuses to shed a tear for herself or the rare cancer she’s fighting.
“I’ve never shed a tear for this, and I won’t shed a tear,” said Cindy, 56, of Havelock, N.C. in Craven County. “This is a battle I have to win. God put me here for a reason: to raise awareness about sarcoma.”
The strong-willed, ever-positive mother of three and grandmother of five — two of whom were born since January — had already courted death once before with a ruptured esophagus nine years ago.
“If I wasn’t a strong person, I’d already be dead,” said this sprite of a woman who always wears something purple. “Remember, your attitude is 99 percent of everything.”
On July 23, her 35th wedding anniversary, Cindy was diagnosed with alveolar rhabdomyosarcoma, a cancerous tumor of the muscles that are attached to bones. Of unknown cause, it can occur many places in the body, most commonly in the head and neck, the urogenital tract, and the arms and legs. It is the most common soft tissue tumor in children, but it is extremely rare in adults.
“On a day that was our day, cancer invaded,” said Don, 55, who has known Cindy since they were both 12 years old. ‘We knew it was bad, but not how bad.”
“Hers is a very unusual and complicated situation,” said Joel E. Tepper, MD, Hector MacLean Distinguished Professor of Cancer Research in the Department of Radiation Oncology at the UNC School of Medicine, a member of UNC Lineberger Comprehensive Cancer Center and lead radiologist on Cindy’s health care team.
“This cancer is not common in adults, and the alveolar subtype is extremely rare,” Dr. Tepper said. “Also, Cindy presented with metastatic disease from an unusual tumor in her lower left leg. Because of its spread, the radiation field goes from her toes to her pelvis. That’s a huge expanse that has produced some technical challenges, but not insurmountable ones.”
Cindy’s treatment follows a pediatric protocol because there is no adult treatment protocol, Dr. Tepper said. “In children, alveolar rhabdomyosarcoma is well known and has been formally studied. Cindy is far from a textbook case, but she nicely illustrates how being a good physician is about understanding the disease process and modifying the treatment for individual patient needs.”
In coordination with a medical oncology team led by Juneko Grilley-Olson, MD, Cindy received chemotherapy and five weeks of radiation at the NC Cancer Hospital. Additional chemotherapy was coordinated with Cindy’s community hospital in New Bern, an outreach that’s appreciated and respected by patient and physicians alike.
“It’s been the best of care, here and there,” said Cindy. “The worst part is that my butt hurts because there’s no padding. I’ve lost over 50 pounds since the diagnosis. The silver lining is I get warm sheets and blankets with my treatment.”
And it’s clear that kind of attitude is helping Cindy, Don and her health care team, said Dr. Tepper.
“Attitude is important,” Dr. Tepper said. “If you come in with a negative attitude, you lose the incentive to do the things you need to do to make it through treatment. I don’t know if it cures the cancer any better, but a positive attitude gets you through treatment easier. Cindy’s doing great, and she is easy to work with because of her attitude.”
While in Chapel Hill, Cindy and Don stayed at SECU Family House, the 40-bedroom hospital hospitality house minutes from UNC Hospitals that provides comfortable, convenient and affordable housing for seriously ill adult patients and their family member caregivers.
“Family House has been a saving grace for us,” said Cindy. “It’s a comfort and healing for both of us. We’re able to talk and pray with others who are going through similar situations. It’s like we have a new family. And I like the idea of volunteers fixing dinner.”
As for the sarcoma awareness raising it’s gone hand-in-hand with Cindy and Don’s daily routines since July 23.
Don, a retired US Marine Corps master sergeant (MSgt.) who works a civilian logistics job at the Marine Corps Air Station at Cherry Point, immediately set to work searching online for any information he and Cindy could read about sarcoma in preparation for her treatment.
He also consulted the Patient and Family Resource Center at the NC Cancer Hospital where sarcoma information was still scarce, but where Tina Shaban, center director, followed up with other helpful advice.
“People are not just a disease,” Shaban said. “Our job is to work with patients and their families as individuals with unique needs and talk through what it is they need most. It’s about helping to identify gaps in what’s missing whether it’s information, support or care so they have a good understanding about what they are facing. While cancer is never easy, knowing what to expect helps.”
“We didn’t find a lot of information about sarcoma and what we did find wasn’t good news,” said Don. “We knew immediately we had to use Cindy’s fight to raise awareness. It desperately needs to be out there in the public eye which will help funding for research, treatment and ultimately a cure.”
Don set up a Facebook site called Cindy's Rainbow for tracking their journey. It also includes poems he’s written for and about Cindy, which she said, “I could hear a 1,000 times.” The site now has 300 members and is growing.
Through the Sarcoma Foundation of America website, Cindy and Don connected with Landon Cooper, an ultra runner who established Miles 2 Give, a 3,000-mile race across the U.S. for sarcoma cancer research awareness.
The race began Feb. 14 in San Francisco and will conclude July 4 in Washington, D.C. Runners cover 21 miles a day, and each day is dedicated to someone on the sarcoma journey – a patient, family member, friend or a loved one lost to the disease. Cindy’s day is June 3.
But for Don, every day is Cindy’s day.
“She is an amazing woman, and I can’t not be by her side,” said Don, about his best friend for life. “I’ve made arrangements at work so I can be with her in Chapel Hill. I’d trade places with her if I could.
“With the sequestration fall-out, I’m facing a furlough. But we’ll do OK. All that pales in the face of Cindy’s disease. We just want to survive sarcoma now.”
What happens if a G protein is always on? The outcome is often tragic. For example, in approximately 80% of the cases of uveal melanoma, either of two closely related G proteins, Galpha-q and Galpha-11 (gene names GNAQ and GNA11) are mutated so that they cannot shut off. These mutations “drive” these melanomas and are referred to as driver mutations since they promote these cancers. However, knowing that these mutated G proteins often lead to uveal melanoma is only the first step toward a treatment. How can we use this knowledge to help patients with uveal melanoma?
In the Sondek lab, we’ve focused on improving our understanding of how the movement of information controlled by G proteins is regulated. In a 2010 paper published in the journal Science, we showed how an activated G protein, Galpha-q in the on state, interacts with one of its primary molecular targets within the cell by determining the structure of the two molecules bound together at atomic resolution. This structure is a 3-D roadmap for how to prevent the G proteins with driver mutations found in most cases of uveal melanoma from communicating with their molecular targets.
We know that certain mutated G proteins found in the eye can result in uveal melanoma and we have a model for how to prevent these mutated G proteins from communicating with their targets. And yet there’s still a long way to go before this knowledge can help treat patients with uveal melanoma. Fortunately, a postdoctoral fellow in the Sondek lab, Dr. Thomas Charpentier, was inspired by this work to develop that next step that will help take us from the laboratory to clinical application. Dr. Charpentier devised a method to measure the interaction of Galpha-q in the on state with its molecular targets. He adapted this method so that it works with exceptionally small amounts of protein and with hundreds of samples at a time. We are now collaborating with Prof. Bill Janzen and the UNC Center for Integrative Chemical Biology and Drug Discovery to screen their collection of 100,000 small molecules for ones that prevent the mutated G proteins from communicating with their targets. We intend to turn the molecules we find into effective drugs for the treatment of uveal melanoma.
This exciting and potentially life-saving work was stalled due to a lack of funds. We are grateful to CURE OM and the Melanoma Research Foundation for the opportunity to continue this work in the ongoing effort to eliminate uveal melanoma and save lives.
]]>Thursday, March 7, 2013
CHAPEL HILL, N.C. - Locally advanced squamous cell carcinoma of the head and neck is a potentially curable disease in nearly every patient at the time of diagnosis, yet despite the most aggressive efforts, up to 30-50 percent of patients may ultimately succumb to the disease. For diseases where outcomes are so uncertain, medical science frequently addresses the need by intensifying therapy. In the case of head and neck cancer, one of the great questions of the current day is whether or not addition of multiple drugs to radiation therapy is superior to the current standard of care therapy with one drug and radiation. In particular, physicians have wondered if the addition of the more tolerable targeted biologic therapy to chemotherapy results in improved patient outcomes. Unfortunately, the data suggests that it does not.
A team of scientists, including Neil Hayes, MD, MPH, from UNC Lineberger Comprehensive Cancer Center, report results of a clinical trial comparing treatments for this cancer, the seventh most common tumor type in the United States.
Standard therapy for SCCHN is a combination of the drug cisplatin and radiotherapy. The clinical trial compared this combination to the combination with the addition of a small-molecule inhibitor of the epidermal growth factor receptor called Erlotinib. EGFR is a therapeutic target for this type of cancer and at least one other EGFR is approved for multiple uses in the treatment of head and neck cancer, including in combination with radiation. To date, no data has been published on the use of EGFR inhibitors in combination with chemotherapy and radiation.. The goal of the current study was to determine if adding EGRF inhibition improved efficacy when combined with standard of care radiation. Unfortunately, it improved neither clinical response rate nor progression free survival.
Their results were published in the early online March 4, 2013 issue of the Journal of Clinical Oncology.
Dr. Hayes, associate professor of medicine, explains, “There has been great enthusiasm and some confusion about the combinations of chemotherapy and biologic therapy such as EGFR inhibitors in conjunction with radiation in the treatment of squamous cell carcinomas of the head and neck. For the moment, the data are clearly showing no added benefit. Since the study was initially designed, it is interesting to note that novel theories have emerged about subgroups of patients who might be more likely to benefit from the specific therapies under consideration. Future investigations will clearly rely more on patients selected by the molecular tumor characteristics.”
Between December 2006 and October 2011, 204 patients with locally advanced SCCHN were recruited to the study. Participants were assigned to receive either cisplatin and radiotherapy or the same chemoradiotherapy with Erlotinab.
Other institutions participating in the study were the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, Washington; Multicare Health Systems in Covington, Washington; University of New Mexico in Albuquerque, New Mexico; Medical University of South Carolina in Charleston; the University of Miami in Florida; Coastal Carolina Radiation Oncology in Wilmington, North Carolina; and the University of Tennessee in Memphis.
Funding for the study was provided to the University of Washington by Genentech in San Francisco, California, and Astellas Pharma Global Development in Northbrook, Illinois.
Friday, March 1, 2013
CHAPEL HILL, N.C. – In an article published as the cover story of the March 2013 issue of Nature Chemical Biology, Lindsey James, PhD, research assistant professor in the lab of Stephen Frye, Fred Eshelman Distinguished Professor in the UNC School of Pharmacy and member of the UNC Lineberger Comprehensive Cancer Center, announced the discovery of a chemical probe that can be used to investigate the L3MBTL3 methyl-lysine reader domain. The probe, named UNC1215, will provide researchers with a powerful tool to investigate the function of malignant brain tumor (MBT) domain proteins in biology and disease.
“Before this there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first in class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets,” said Dr. James.
Chromatin regulatory pathways play a fundamental role in gene expression and disease development, especially in the case of cancer. While many chemical probes work through the inhibition of enzyme activity, L3MBTL3 functions as a mediator of protein-to-protein interactions, which have been historically difficult to target with small, drug-like molecules.The researchers found three to four further disease subtypes within TN tumors, with more than 75 percent of the tumors falling into the basal-like subtype. Further research is needed to identify the distinct biomarkers shared by the expanded subtypes of TN cancers. The ultimate goal will be to target the individual biomarkers of these subtypes and create therapies that target their individual biology, according to Dr. Perou.
“Many people believe that protein-protein interactions are difficult to target. Often they have a large surface area, so it is hard for small molecules to go in and intervene,” said Dr. James.
Almost 40 percent of the genes that drive cancer can be mapped to dysfunction within signaling pathways. In the last five years, chemical probe development has allowed researchers to make fundamental observations of the role of these pathways in cancer development, as well as pointing to potential targets for new therapies. Each of the complex interactions within the signaling pathways represents a potential point where a therapy can be applied, and the probes allow researchers to interact with these processes at the molecular level and observe the overall effect of their perturbation on the disease state.
In a 2008 Nature Chemical Biology commentary, Dr. Frye outlined the qualities that make a good chemical probe. To Frye, a good chemical probe must be highly selective to enable specific questions to be asked and it must function as well in a cell as in the test tube, providing clear quantitative data with a well understood mechanism of action in either situation. It also must be available to all academic researchers without restrictions on its use, a criteria that the L3MBTL3 probe fulfills through the Frye lab’s commitment to provide researchers with the probe free of charge on request and UNC1215 is already available through commercial vendors as well.
This research was supported by NIH grants (RC1GM090732 and R01GM100919) and the University Cancer Research Fund.
Friday, Feb. 22, 2013
CHAPEL HILL, N.C. -- Inflammatory response plays a major role in both health protection and disease generation. While the symptoms of disease-related inflammatory response have been know, scientists have not understood the mechanisms that underlie it.
In a paper published in Cell Reports Feb. 21, a team lead by Xian Chen, associate professor of biochemistry and biophysics and member of the UNC Lineberger Comprehensive Cancer Center, mapped the complex interactions of proteins that control inflammation at the molecular level.
The inflammatory response acts as a first line of defense for the immune system. Cytokines are generated to contain infection, preventing the occurrence or spread of diseases, including cancerous tumors. An overproduction or underproduction of these cytokines during disease-related inflammatory responses can lead to a variety of disease such as arthritis, asthma and some kinds of cancer.
The team found that chronic inflammatory response is mediated by the interaction of the protein phosphatase PP2Ac and an adaptor protein of Toll-like receptors (TLRs) MyD88 in a type of the immune cells (macrophages) showing tolerance to persistent stimulation of endotoxin (LPS).
Within endotoxin-tolerized macrophages, “PP2Ac is constitutively activated and operates on a switch that exists to convert pro-inflammatory MyD88 to immunosuppressant MyD88,” said Chen.
Studying interactions of the protein network that underlies inflammation, the research team found that PP2Ac disrupts the pro-inflammatory signaling pathway mediated by the complex of MyD88 and TLR4. As a result of this disruption, both constitutively active PP2Ac and MyD88 move within the cellular nucleus, where they bound with the epigenetic machinery and alter the chromatin structure of a class of pro-inflammatory genes that leads to the silencing of this class of the genes.
“In the nucleus, in a MyD88-dependent way constitutively active PP2Ac reprograms the epigenetic machinery,” said Chen.
With the discovery of PP2Ac behavior, Chen’s research establishes a previously unknown link between cellular signaling and epigenetic regulation, which affects the genetic blueprint of inflammation. By mapping out the signaling pathway, as well the epigenetic machinery targeted by abnormally activated PP2Ac within the cells under chronic inflammation, the research identifies potential targets of immunomodulation for future therapies for inflammation-related disorders and cancers.
“Not only did we identify individual targets, but we also identified those interconnected targets in networks of dynamic protein interactions. That will set up the base for future network medicine, as targets on single genes and targets can have off-target side effects. To increase the precision of the drug targets, we reveal individual proteins but also their interactions as targets,” said Chen.
This work is supported by NIH grants to Dr. Chen(NIH R01AI064806 and NIH 1U24CA160035).