Winship Cancer Institute
Winship Cancer Institute
News Article | April 24, 2017
In lung cancer patients who were taking immunotherapy drugs targeting the PD-1 pathway, testing for CD8 T cell activation in their blood partially predicted whether their tumors would shrink. The results are scheduled for publication in PNAS. Drugs targeting PD-1 or its ligand PD-L1 re-activate "exhausted" CD8 T cells by promoting their expansion and unleashing their ability to destroy cancer cells. Researchers at Emory Vaccine Center, led by co-senior author Rafi Ahmed, PhD, have been intensively studying the cells that are revived after inhibitory signals from PD-1 are blocked. Ahmed is director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. Winship Cancer Institute investigators Rathi Pillai, MD and Suresh Ramalingam, MD, Winship's deputy director, teamed up with Alice Kamphorst, PhD and Ahmed's group to examine blood samples from 29 advanced non-small cell lung cancer patients undergoing immunotherapy treatment. The patients were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, known as checkpoint inhibitors (nivolumab, pembrolizumab or atezolizumab). Blood samples were obtained before starting treatment and before each new treatment cycle, which lasted two to three weeks. Most patients (70 percent) displayed an increase in the number of proliferating CD8 T cells in their blood after starting PD-1 targeted treatment -- an observable effect on the immune system. However, not all patients with an immunological response experienced a "partial clinical response", meaning that their tumors shrank by at least 30 percent. All patients with partial responses survived at least one year, while just one out of seven patients with progressive disease was reported to survive one year. Survival times for three patients were not available. An early increase in activated PD-1+ CD8 T cells appears important. 80 percent of patients with clinical benefit exhibited PD-1+ CD8 T cell responses within 4 weeks of treatment initiation. In contrast, 70 percent of patients with disease progression had either delayed or absent PD-1+ CD8 T cell responses. "We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue," Ahmed says. "We believe some of the activated T cells in patients' blood may be on their way to the tumor." Proliferating CD8 T cells displayed high levels of PD-1, as well as other molecules that influence their activity, which may be targets for combination therapies. The Emory/Winship team recently published a paper in Science, incorporating data from this study, showing that the costimulatory molecule CD28 is required for proliferation following PD-1-targeted treatment. The current study supports a straightforward idea: if CD8 T cells appear to respond to immunotherapy, that's a good sign. "Our ability to detect proliferating T cells in the blood and correlate this with clinical benefit is exciting since this captures a real-time assessment of the immune system's response to PD-1 directed therapies and is a readily accessible test from our patients' perspective," Pillai says. While looking for activated T cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information, says co-senior author Ramalingam. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with current treatment or combine it with something else. "We are already doing larger studies to confirm these observations and extend them to other cancers beyond lung cancer," he says. This work was funded in part by the National Institutes of Health and the T. J. Martell Foundation.
News Article | May 15, 2017
"The NCI comprehensive cancer center designation signifies Winship's outstanding research and education programs are changing the lives of the citizens of Georgia for the better," says Winship Executive Director Walter J. Curran, Jr., MD. "As the first and only NCI-designated comprehensive cancer center in the state, our clinicians and researchers work tirelessly to substantially lessen the burden of cancer on the lives of Georgia's residents." An estimated 50,000 Georgians will be diagnosed with cancer this year. About a third of them will receive some component of their treatment at one of Winship's clinical locations in metropolitan Atlanta. For patients, Winship's innovative research translates into better ways of detecting and diagnosing cancer. Patients also have full access to teams of experts using approaches to cancer not available outside of a top research cancer center. Winship has over 250 clinical trials enrolling patients in pursuit of better approaches to nearly every type of cancer. Emory President Claire E. Sterk says that the NCI comprehensive cancer center designation will help improve the health and well-being of Georgia citizens. "Winship's achievement is the result of years of hard work and commitment by many people, both within the university and the greater Georgia community. The NCI comprehensive cancer center designation will help Emory expand its extraordinary faculty of scientists and innovative thinkers by attracting new and highly qualified investigators," she says. "We thank Governor Deal and the Georgia Congressional Delegation for their support of Emory's mission to better serve Georgia's citizens." "Earning the NCI comprehensive cancer center designation is a tremendous honor for Winship Cancer Institute and the state of Georgia," says Governor Nathan Deal. "This distinction elevates Georgia as a model for superb cancer care and scientific discovery." For all Georgians, the comprehensive cancer center designation recognizes that Winship researchers are studying the environmental and genetic issues unique to cancer in Georgia with the very specific goals of reducing the risk of cancer and detecting cancer at the earliest possible stage. "Winship is the only institution of its kind in the state. It has become Georgia's epicenter of cancer research, education, and care," explains Jonathan S. Lewin, MD, Emory University's executive vice president for health affairs and president, CEO, and chairman of the board of Emory Healthcare. "Winship is a gateway to clinical trial enrollment for metro Atlanta and beyond, importantly including our historically underserved populations." Winship's comprehensive cancer center designation was awarded after a rigorous evaluation process conducted by the NCI that included submission of a written grant and a site visit conducted by more than two dozen scientists from peer institutions. During that visit, the review committee watched videotaped remarks from former President Jimmy Carter supporting Winship's application. He said: "I never knew that my own life would be saved by research that was funded through the NCI and its program that laid the foundation for such centers as Winship. Recently, I needed the very care that I have advocated for, care that exists through NCI's cancer center program." Winship earned its first NCI cancer center designation in 2009, and the grant was renewed in 2012. Established 80 years ago by a foundational gift from Robert W. Woodruff, Winship Cancer Institute continues to receive funding support from the Robert W. Woodruff Health Sciences Center Fund, Inc. Mr. Woodruff believed that no cancer patient should ever have to travel outside the state of Georgia for care. The NCI comprehensive cancer center designation for Winship continues to make that vision a reality. "Winship is fulfilling Robert Woodruff's vision of a world-class cancer center," says Curran. "Through outstanding research discoveries and patient care, Winship is leading the way in ending cancer as we know it here in Georgia and around the world." To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/winship-cancer-institute-awarded-nci-designated-comprehensive-cancer-center-status-300457403.html
News Article | February 16, 2017
ARLINGTON, Va., February 16, 2017 -- The 2017 Multidisciplinary Thoracic Cancers Symposium, co-sponsored by the American Society for Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO) and The Society of Thoracic Surgeons (STS), will feature advances in surgery, radiation therapy, chemotherapy and novel molecular biologic therapies for thoracic malignancies such as lung cancer. The symposium will be held March 16-18, 2017, at the San Francisco Marriott Marquis. Press registration for the meeting is available online. Researchers from across the country will present findings on new combination therapies, targeted therapies, immunotherapy, next-generation sequencing, advanced radiation and surgical techniques, supportive care and guidelines for screening and prevention. Selected top-rated studies will be featured in news briefings held in-person and available online for registered reporters. Three keynote addresses will examine personalized surgical approaches, clinical trials in non-small cell lung cancer (NSCLC) and immunotherapeutic strategies to manage lung cancer. Keynote speakers include Valerie W. Rusch, MD, of Memorial Sloan Kettering Cancer Center in New York; Walter J. Curran, Jr., MD, of Winship Cancer Institute of Emory University in Atlanta; and Julie R. Brahmer, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore. Press Registration: Credentialed journalists from accredited news organizations are invited to attend and report on the 2017 Multidisciplinary Thoracic Cancers Symposium. Reporters registered by March 7, 2017, will receive the embargoed press kit prior to the meeting. The press policies and registration form are available online. News Briefings: Two news briefings will highlight top-rated abstracts selected from the general program. Briefings will be available live on-site in San Francisco and via webcast for registered press, with audio recordings and presenter slides posted online after each briefing. The final press program will be announced in late February. Press Office: Registered reporters are invited to check in at the on-site press office in the Foothill F room of the San Francisco Marriott Marquis, open during business hours on Thursday and Friday. More Information: More information is available at the 2017 Multidisciplinary Thoracic Cancers Symposium website, http://www. . ASTRO is the premier radiation oncology society in the world, with more than 11,000 members who are physicians, nurses, biologists, physicists, radiation therapists, dosimetrists and other health care professionals that specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, the Society is dedicated to improving patient care through professional education and training, support for clinical practice and health policy standards, advancement of science and research, and advocacy. ASTRO publishes three medical journals, International Journal of Radiation Oncology * Biology * Physics and Practical Radiation Oncology and Advances in Radiation Oncology; developed and maintains an extensive patient website, http://www. ; and created the Radiation Oncology Institute, a non-profit foundation to support research and education efforts around the world that enhance and confirm the critical role of radiation therapy in improving cancer treatment. To learn more about ASTRO, visit http://www. . Founded in 1964, the American Society of Clinical Oncology (ASCO) is committed to making a world of difference in cancer care. As the world's leading organization of its kind, ASCO represents more than 40,000 oncology professionals who care for people living with cancer. Through research, education, and promotion of the highest-quality patient care, ASCO works to conquer cancer and create a world where cancer is prevented or cured, and every survivor is healthy. ASCO is supported by its affiliate organization, the Conquer Cancer Foundation. Learn more at http://www. , explore patient education resources at http://www. , and follow us on Facebook, Twitter, LinkedIn, and YouTube. Founded in 1964, The Society of Thoracic Surgeons is a not-for-profit organization representing approximately 7,200 cardiothoracic surgeons, researchers, and allied health care professionals worldwide who are dedicated to ensuring the best possible outcomes for surgeries of the heart, lung, and esophagus, as well as other surgical procedures within the chest. The Society's mission is to enhance the ability of cardiothoracic surgeons to provide the highest quality patient care through education, research, and advocacy.
News Article | May 12, 2017
When cancer cells split off from a tumor to seed deadly metastases, they are thought to travel as clusters or packs, a phenomenon known as collective invasion. The members of an invasive pack are not all alike, scientists at Winship Cancer Institute of Emory University have learned. Lung cancer cells making up an invasive pack have specialized roles as leaders and followers, which depend on each other for mobility and survival, the scientists report in Nature Communications. The differences between leaders and followers -- and their interdependence -- could be keys for future treatments aimed at impairing or preventing cancer metastasis, says senior author Adam Marcus, PhD, associate professor of hematology and medical oncology at Winship Cancer Institute and Emory University School of Medicine. "We're finding that leader and follower cells have a symbiotic relationship and depend on each for survival and invasion," he says. "Because metastatic invasion is the deadliest aspect of cancer, our goal is to find agents that disrupt that symbiotic relationship." Marcus and former graduate student Jessica Konen, PhD began by observing how a mass of lung cancer cells behaves when embedded in a 3-D protein gel. The cells generally stick together, but occasionally, a few cells extend out of the mass like tentacles, with the leader cell at the tip. "We saw that when the leader cell became detached or died unexpectedly, the followers could no longer move," says Konen, now a postdoctoral fellow at MD Anderson. "In one particular movie, we saw a leader cell come out away from the rest of the cells, and then seem to realize that nobody was following him. He actually did a 180, and went back to grab cells to bring with him." To study what makes leader and follower cells different from each other, Marcus and Konen developed a technique for marking the cultured cells with a laser, thus changing them from fluorescent green to red, and then isolating red cells. They call this technique SaGA, for spatiotemporal genomic and cellular analysis. Once isolated, the leader cells maintain their invasive behavior and have a distinctive shape. When added back to purified followers, leader cells will restore followers' mobility and tentacle-like invasive behavior, even if the leaders are only 1 percent of the mix. While the leader cell state is durable, followers will "spawn" new leaders after a month or two of growth in culture, Marcus says. Leaders show several differences from follower cells in the patterns of genes that are turned on or off. For example, leader cells secrete more VEGF (vascular endothelial growth factor) than followers do. VEGF is important for the growth of blood vessels and is the target of anti-cancer drugs such as bevacizumab, known commercially as Avastin. By themselves, leader cells do not need VEGF for invasive behavior, but VEGF appears to be important for pack formation because it is a mobility factor leaders provide followers. In contrast, what followers provide leaders is the ability to grow and survive. When growing separately from followers, leaders increase their numbers at a slower rate, have erratic cell cycles and have more "blebs", which are bulges of the cell membrane. Contact with followers rescues these problems, the researchers found. Other molecular differences between leaders and followers include traction-generating FAK (focal adhesion kinase) activity in leader cells and growth-promoting Notch signaling in followers - both potential avenues for disrupting the symbiotic relationship between leaders and followers. A related paper on the potential use of FAK inhibitors against lung cancer was recently published in JCI Insight by Marcus and his colleagues. The Nature Communications paper covers lung cancer cells; a similar phenomenon of collective invasion led by distinctive cells has been observed in breast cancer, but different genes and biochemical pathways appear to be important in each system. "I think what's needed for collective invasion will depend on the environmental stresses the cancer cells face, and it may shift with treatment," Marcus says. As described, the SaGA technique depends upon first having a photo-convertible fluorescent green protein called Dendra in the cells. Marcus' lab is now testing whether similar approaches could work when studying tumor organoids derived from cancer patients, either using Dendra or with photo-convertible dyes. Marcus stresses that SaGA can be applied to additional cell types or environments, or other types of cancer cell behavior such as drug resistance. His lab continues to study the genetic and/or epigenetic basis for the differences between leader and follower cells. A video explaining SaGA won first prize in a contest organized by the Association of American Medical Colleges in 2015. The research was supported by the National Cancer Institute (R21CA201744, P30CA138292, F31CA180511, U24CA180924, U24CA19436201) and by Winship Cancer Institute developmental funds.
News Article | February 16, 2017
Scientists at Winship Cancer Institute of Emory University have mapped a vast spider web of interactions between proteins in lung cancer cells, as part of an effort to reach what was considered "undruggable." This approach revealed new ways to target cells carrying mutations in cancer-causing genes. As an example, researchers showed sensitivity to an FDA-approved drug, palbociclib, for a gene that is commonly mutated in lung cancer cells, which is now being tested in a clinical study. The results are published online in Nature Communications. Many genes that drive the growth of cancer cells don't have any drugs available against them. For "tumor suppressor" genes, researchers are often not sure how to go after them. When the tumor suppressors are gone, cells often become more deranged, but there's no bullseye left to target. Exploiting the cancer cells' derangement remains a daunting challenge, says senior author Haian Fu, PhD. "Our approach is to place tumor suppressors in the context of a network of cancer-associated proteins and link tumor suppressors to drugs through a known drug target protein," Fu says. "In this way, changes in a tumor suppressor may be linked with the response of the target to the connected drug." The study is part of a push by the National Cancer Institute's Cancer Target Discovery and Development (CTD2) network to translate genomics data into therapeutic strategies, he says. Emory is a member of the NCI CTD2 network. Fu holds the Winship Partner in Research endowed chair and is leader of Winship's Discovery and Developmental Therapeutics Program, director of the Emory Chemical Biology Discovery Center and professor of pharmacology and hematology and medical oncology. Co-corresponding author Fadlo Khuri, MD, maintains his professor appointment at Winship Cancer Institute and is now president of the American University of Beirut in Lebanon. Cancer researchers have been searching for ways to target mutations in the gene STK11/LKB1, found in 15 to 25 percent of non-small cell lung cancers. The tumor suppressor STK11/LKB11 encodes an enzyme that is thought to regulate cell migration and metabolism. One of the Winship team's newly identified interactions -- a "thread" in the spider web -- suggested that palbociclib, recently approved against metastatic breast cancer, may work against cells carrying mutations in LKB1, through LKB1's connection to CDK4, the target of palbociclib. That prediction was supported by genomic data analysis and cell culture experiments: lung cancer cells with LKB1 defects showed a tendency of increased sensitivity to palbociclib. Now a study led by Taofeek Owonikoko, MD, at Winship is using LKB1 status as a biomarker for interpreting the effect of palbociclib. If cells are complex machines, then a number of ways exist for figuring out how the machines' parts, dominated by proteins, fit together. Some of them involve multiple washing steps to remove nonspecific partners after breaking cells apart, but FRET (Förster resonance energy transfer) does not. If two fluorescent molecules with colors that are near on the spectrum are close enough (less than 10 nanometers), that proximity can be detected by FRET. Fu and his colleagues established a large-scale platform for tagging proteins with two different fluorescent molecules, introducing them into cancer cells, and then detecting interactions between the proteins. They call this network of cancer-associated proteins "OncoPPI." Starting with a set of 83 lung cancer-related proteins, the team detected more than 260 interactions that were not known previously. They tested the interactions several times, in different orientations, and in other lung cancer cell lines with selected interactions to establish reliability. More than 80 percent of the interactions the researchers detected could be confirmed by another method (GST pulldown). As an additional example to illustrate the utility of a protein interaction web, the team focused on the prominent oncoprotein Myc, which was also considered "undruggable." But the researchers could connect Myc indirectly through NSD3 to another protein called Brd4, against which inhibitors have been developed. Brd4 inhibitors are being currently tested in clinical trials. This finding revealed a new pathway Brd4-NSD3-Myc as potential targets for therapeutic intervention, Fu says. The OncoPPI research was supported by the National Cancer Institute Cancer Target Discovery and Development (CTD2) network (U01CA168449), lung cancer program project (P01CA116676) and Winship Cancer Institute (P30CA138292) and the Georgia Research Alliance, and the Emory University Research Committee. The clinical study of palbociclib is sponsored by Pfizer. Co-first authors are research associate Zenggang Li, PhD, now at Michigan State University, instructor Andrei Ivanov, PhD and Xiangya Hospital medical student Rina Su, now at Chao-yang Hospital, Capital Medical University in Beijing, China. Emory/Winship co-authors include Qi Qi, PhD, Philip Webber, PhD, Yuhong Du, PhD, Wei Zhou, PhD, Adam Marcus, PhD, Carlos Moreno, PhD, Lee Cooper, PhD and Margaret Johns, PhD, graduate students Valentina Gonzalez-Pecchi and Lauren Rusnak, and visiting medical student Songlin Liu. Collaborators from UT Southwestern contributed to the paper.
News Article | February 15, 2017
Physicians’ Education Resource®, (PER®), will host the 21st Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas and Myeloma, and the symposium will be co-chaired by Andre Goy — who is professor of medicine, chief of lymphoma and director at John Theurer Cancer Center, chair of oncology for Hackensack Meridian Health Network in Hackensack, New Jersey — and Sager Lonial, who is a professor and chair of the Department of Hematology and Medical Oncology at Emory School of Medicine, chief medical officer of the Winship Cancer Institute of Emory University in Atlanta, Georgia. “We are in the midst of unprecedented changes in medicine particularly in oncology,” said Goy. “Symposiums such as Miami Hematology, offer an opportunity for each attendee to share directly with world experts how such changes can truly reshape patients’ care.” The 21st Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas and Myeloma is designed to facilitate application of the rapid changes seen in oncology while treating hematological malignancies. As health care continues to rapidly evolve, it becomes critical not only to be able to choose the best option for each patient precision medicine but also in an era with so many options available— to appreciate the best sequence of therapies to optimize outcome. This will be addressed throughout the three-day-conference during the well-known and highly interactive Medical Crossfire® discussion panels and real-world case discussions. In addition, Amy E. Herman, will speak on “The Art of Perception and its Connection to the Art of Clinical Medicine.” Herman is a leading expert in professional development, training some of the most influential industry leaders around the world, including the FBI, CIA, Scotland Yard and the Peace Corps. Previously, Herman was the director of the educational development for Thirteen/WNET, the public television station, serving New Jersey and New York. The three-day symposium will be held at the Trump International Miami on Feb.23-25 in Sunny Isles Beach, Florida, located 3.5 miles from the Miami International Airport and 13 miles from the Fort Lauderdale International Airport. About PER® Since 1995, PER® has been the educational resource of choice for live and online activities focusing on oncology and hematology. PER® provides high-quality, evidence-based activities featuring leading national and international faculty with a focus on practice-changing advances and standards of care in treatment and disease management. Activities also include topics on emerging strategies currently under investigation, supportive care, diagnosis and staging, prevention, screening and early detection, and practice management. With the rapid advances occurring in the field of oncology, understanding how to use molecular data to diagnose and stage patients, selecting the most appropriate candidates for novel therapeutic agents, individualizing treatment based on tumor type, and referring patients to clinical trials will continue to ensure the highest level of patient care is provided. PER® serves the oncology health care community, including physicians, fellows, advanced practice nurses, nurses, physician assistants, pharmacists, and researchers. PER® is part of the Cranbury, N.J.-based Michael J. Hennessy Associates, Inc. family of businesses. Learn more at http://www.gotoper.com and http://www.mjhassoc.com
News Article | November 18, 2016
Arecoline -- the stimulant component of areca nuts -- has anticancer properties, researchers at Winship Cancer Institute of Emory University have discovered. The findings are scheduled for publication in Molecular Cell. Areca nuts are chewed for their stimulant effects in many Asian countries, and evidence links the practice to the development of oral and esophageal cancer. Analogous to nicotine, arecoline was identified as an inhibitor of the enzyme ACAT1, which contributes to the metabolism-distorting Warburg effect in cancer cells. Observers of health news have complained that coffee, as a widely cited example, is implicated in causing cancer one week and absolved the next. Arecoline is not another instance of the same trend, stresses senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. "This is just a proof of principle, showing that ACAT1 is a good anticancer target," Chen says. "We view arecoline as a lead to other compounds that could be more potent and selective." Chen says that arecoline could be compared to arsenic, a form of which is used as a treatment for acute promyelocytic leukemia, but is also linked to several types of cancer. Plus, arecoline's cancer-promoting effects may be limited if it is not delivered or absorbed orally, he says. When arecoline first arose in a chemical screen, Chen says: "It sounded like a carcinogen to me. But it all depends on the dose and how it is taken into the body." The co-first authors of the paper are Jun Fan, PhD, assistant professor of radiation oncology, and postdoctoral fellow Ruiting Lin, PhD. Co-authors at Winship include Taofeek Owonikoko, MD, Manila Gaddh, MD, Martha Arellano, MD, H. Jean Khoury, MD, Sumin Kang, PhD, Paul Doetsch, PhD, Sagar Lonial, MD and Walter Curran, MD. The Warburg effect, named after 1931 Nobel laureate Otto Warburg, describes how cancer cells tend to favor the inefficient use of glucose, known as glycolysis, and de-emphasize their mitochondria. Cancer cells benefit from this metabolic distortion because the byproducts of glycolysis can be used as building blocks for fast growth. Chen's laboratory had previously identified the mitochondrial thiolase ACAT1 (acetyl-CoA acetyltransferase) as a control valve regulating the Warburg effect. In this paper, the researchers showed that ACAT1 enzymatic activity was higher in several types of cancer cells, even though the levels of ACAT1 protein are about the same. The reason is that the protein clusters together as tetramers in cancer cells. Tyrosine kinases, often on overdrive in cancer cells, "hijack" ACAT1 and nudge it into tetramers, which are enzymatically more active. But arecoline, identified in a screen of 2000 FDA-approved small molecule compounds, can inhibit ACAT1 and prevent it from forming tetramers. Arecoline forms a chemical bond with part of the ACAT1 protein, the researchers showed. Arecoline appears to do what the researchers proposed it would: it steers cells' metabolism away from glycolysis. The compound inhibited the growth of human lung cancer and leukemia cells both in culture and grafted into mice, and did not affect the growth of normal blood cells. The enzyme ACAT1 seems to have a double role. It breaks down ketones and the amino acid isoleucine, and it also modifies other proteins through acetylation, which is how it regulates the Warburg effect. Genetic mutations in ACAT1 lie behind a very rare metabolic disorder called beta-ketothiolase deficiency. Complete inhibition of ACAT1 could induce side effects resembling that disorder. But when the Winship team incompletely "knocked down" ACAT1 in cells using arecoline or genetic tools, the main effect was on protein acetylation, not on ketone metabolism, Chen says. While the researchers did not see obvious toxicity when treating mice with arecoline, more extensive pharmacokinetic and toxicology studies with arecoline and similar compounds are needed, he says.
News Article | November 17, 2016
Arecoline -- the stimulant component of areca nuts -- has anticancer properties, researchers at Winship Cancer Institute of Emory University have discovered. The findings are scheduled for publication in Molecular Cell. Areca nuts are chewed for their stimulant effects in many Asian countries, and evidence links the practice to the development of oral and esophageal cancer. Analogous to nicotine, arecoline was identified as an inhibitor of the enzyme ACAT1, which contributes to the metabolism-distorting Warburg effect in cancer cells. Observers of health news have complained that coffee, as a widely cited example, is implicated in causing cancer one week and absolved the next. Arecoline is not another instance of the same trend, stresses senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. "This is just a proof of principle, showing that ACAT1 is a good anticancer target," Chen says. "We view arecoline as a lead to other compounds that could be more potent and selective." Chen says that arecoline could be compared to arsenic, a form of which is used as a treatment for acute promyelocytic leukemia, but is also linked to several types of cancer. Plus, arecoline's cancer-promoting effects may be limited if it is not delivered or absorbed orally, he says. When arecoline first arose in a chemical screen, Chen says: "It sounded like a carcinogen to me. But it all depends on the dose and how it is taken into the body." The co-first authors of the paper are Jun Fan, PhD, assistant professor of radiation oncology, and postdoctoral fellow Ruiting Lin, PhD. Co-authors at Winship include Taofeek Owonikoko, MD, Manila Gaddh, MD, Martha Arellano, MD, H. Jean Khoury, MD, Sumin Kang, PhD, Paul Doetsch, PhD, Sagar Lonial, MD and Walter Curran, MD. The Warburg effect, named after 1931 Nobel laureate Otto Warburg, describes how cancer cells tend to favor the inefficient use of glucose, known as glycolysis, and de-emphasize their mitochondria. Cancer cells benefit from this metabolic distortion because the byproducts of glycolysis can be used as building blocks for fast growth. Chen's laboratory had previously identified the mitochondrial thiolase ACAT1 (acetyl-CoA acetyltransferase) as a control valve regulating the Warburg effect. In this paper, the researchers showed that ACAT1 enzymatic activity was higher in several types of cancer cells, even though the levels of ACAT1 protein are about the same. The reason is that the protein clusters together as tetramers in cancer cells. Tyrosine kinases, often on overdrive in cancer cells, "hijack" ACAT1 and nudge it into tetramers, which are enzymatically more active. But arecoline, identified in a screen of 2000 FDA-approved small molecule compounds, can inhibit ACAT1 and prevent it from forming tetramers. Arecoline forms a chemical bond with part of the ACAT1 protein, the researchers showed. Arecoline appears to do what the researchers proposed it would: it steers cells' metabolism away from glycolysis. The compound inhibited the growth of human lung cancer and leukemia cells both in culture and grafted into mice, and did not affect the growth of normal blood cells. The enzyme ACAT1 seems to have a double role. It breaks down ketones and the amino acid isoleucine, and it also modifies other proteins through acetylation, which is how it regulates the Warburg effect. Genetic mutations in ACAT1 lie behind a very rare metabolic disorder called beta-ketothiolase deficiency. Complete inhibition of ACAT1 could induce side effects resembling that disorder. But when the Winship team incompletely "knocked down" ACAT1 in cells using arecoline or genetic tools, the main effect was on protein acetylation, not on ketone metabolism, Chen says. While the researchers did not see obvious toxicity when treating mice with arecoline, more extensive pharmacokinetic and toxicology studies with arecoline and similar compounds are needed, he says. The research was supported by the National Cancer Institute (CA140515, CA183594, CA174786, CA175316, CA169937), the T.J. Martell Foundation, an American Cancer Society seed grant and the Georgia Cancer Coalition.
News Article | January 17, 2017
Researchers have found that a particular mutation in melanoma and other types of cancer is fueled by a high-fat diet. Typically, cancer cells thrive on glucose, the body's simple sugar of choice for energy, so it was thought that diet high in fat but low in carbohydrates can keep the disease at bay. However, in a study published in the journal Cell Metabolism, researchers have shown that the BRAF V600E mutation will show faster growth in response to high-fat diets. Jing Chen, Ph.D. and colleagues only explored just one mutation but the results of their work point to the possibility of a "precision diet" being used to help treat cancers individually. "For certain mutations, it could be possible to design dietary regimens that may prevent or delay tumor progression," explained Chen. Cancer cells showing preference for glucose and taking up more of the simple sugar is referred to as a phenomenon called the Warburg effect. Diets low in carbohydrates have been used as a clinical countermeasure but the results of the current study show that those who fight cancer should take the other route and do away with low-carb diets. BRAF V600E occurs in over 60 percent of all melanomas and is found in all of the hairy cell types of leukemia. In colorectal cancers, the mutation is present in 10 percent of cases, while 5 percent of multiple myelomas also have it. There are drugs designed to target BRAF V600E but resistance commonly develops. During ketogenesis, fat is broken down by the body for energy. This usually occurs when blood glucose levels are low and results in the production of an alternate energy source: acetoacetate. In cancer cells with the BRAF V600E mutation, production of acetoacetate is stimulated. The energy source also binds mutated proteins and promotes oncogenic activity, promoting a cycle. To test if cancer cells with the mutation would respond to external sources of acetoacetate, the researchers fed mice with diets where over 90 percent of calories were from fat. Mice with grafted tumors showed increased cancer cell growth while those with tumors from melanoma cells with other oncogenic mutations did not exhibit the same. Additionally, the researchers observed that drugs that lower lipids, such as statins, fenofibrate, and niacin, were able to slow down the growth of BRAF V600E tumors even when mice were fed normal diets. Acetoacetate levels also dropped when lipid-lowering drugs were used. The researchers said they can't provide specific diet suggestions at the moment because there is more to be learned about what sort of dietary fat triggers the production of acetoacetate. They also noted that dehydroacetic acid, a chemical structurally similar to acetoacetate, is capable of limiting acetoacetate-related tumor growth in cancer cells with the V600E mutation. However, the chemical's anti-cancer properties still have to be studied, especially if it could alter cellular metabolism. Chen and colleagues' work received funding support from the Winship Cancer Institute, the Jamie Rabinowitch Davis Foundation, Charles Harris Run for Leukemia, the Melanoma Research Foundation, the T.J. Martell Foundation, the Joel A. Katz Music Medicine Fund, and the National Cancer Institute. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.
News Article | March 30, 2016
Scientists have devised a triple-stage "cluster bomb" system for delivering the chemotherapy drug cisplatin, via tiny nanoparticles designed to break up when they reach a tumor. Details of the particles’ design and their potency against cancer in mice were published this week in PNAS. They have not been tested in humans, although similar ways of packaging cisplatin have been in clinical trials. What makes these particles distinctive is that they start out relatively large — 100 nanometers wide — to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge "bomblets" just 5 nanometers in size. Inside tumor cells, a second chemical step activates the platinum-based cisplatin, which kills by crosslinking and damaging DNA. Doctors have used cisplatin to fight several types of cancer for decades, but toxic side effects — to the kidneys, nerves and inner ear — can limit its effectiveness. The PNAS paper is the result of a collaboration between a team led by professor Jun Wang, PhD at the University of Science and Technology of China, and researchers led by professor Shuming Nie, PhD, in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Nie is a member of the Discovery and Developmental Therapeutics research program at Winship Cancer Institute of Emory University. The lead authors are graduate student Hong-Jun Li and postdoctoral fellows Jinzhi Du, PhD, and Xiao-Jiao Du, PhD. "The negative side effects of cisplatin are a long-standing limitation for conventional chemotherapy," says Jinzhi Du. "In our study, the delivery system was able to improve tumor penetration to reach more cancer cells, as well as release the drugs specifically inside cancer cells through their size-transition property." The researchers showed that their nanoparticles could enhance cisplatin drug accumulation in tumor tissues. When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery of a limited dose of cisplatin could restrain the toxic side effects during cancer treatment. The researchers also showed that the nanoparticles were effective against a cisplatin-resistant lung cancer model and an invasive metastatic breast cancer model in mice. In the lung cancer model, a dose of free cisplatin yielded just 10 percent growth inhibition, while the same dose clothed in nanoparticles yielded 95 percent growth inhibition, the researchers report. In the metastatic breast cancer model, treating mice with cisplatin clothed in nanoparticles prolonged animal survival by weeks; 50 percent of the mice were surviving at 54 days with nanoparticles compared with 37 days for the same dose of free cisplatin. Enhanced efficacy in three different tumor models demonstrate that this strategy may be applicable to several types of cancer, Jinzhi Du says. Source: Emory University