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Researchers from UT Southwestern Medical Center have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types. The nanovaccine consists of tumor antigens – tumor proteins that can be recognized by the immune system – inside a synthetic polymer nanoparticle. Nanoparticle vaccines deliver minuscule particulates that stimulate the immune system to mount an immune response. The goal is to help people’s own bodies fight cancer. “What is unique about our design is the simplicity of the single-polymer composition that can precisely deliver tumor antigens to immune cells while stimulating innate immunity. These actions result in safe and robust production of tumor-specific T cells that kill cancer cells,” said Dr. Jinming Gao, a Professor of Pharmacology and Otolaryngology in UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. A study outlining this research, published online in Nature Nanotechnology, reported that the nanovaccine had anti-tumor efficacy in multiple tumor types in mice. The research was a collaboration between the laboratories of study senior authors Dr. Gao and Dr. Zhijian “James” Chen, Professor of Molecular Biology and Director of the Center for Inflammation Research. The Center was established in 2015 to study how the body senses infection and to develop approaches to exploit this knowledge to create new treatments for infection, immune disorders, and autoimmunity. Typical vaccines require immune cells to pick up tumor antigens in a “depot system” and then travel to the lymphoid organs for T cell activation, Dr. Gao said. Instead, nanoparticle vaccines can travel directly to the body’s lymph nodes to activate tumor-specific immune responses. “For nanoparticle vaccines to work, they must deliver antigens to proper cellular compartments within specialized immune cells called antigen-presenting cells and stimulate innate immunity,” said Dr. Chen, also a Howard Hughes Medical Institute Investigator and holder of the George L. MacGregor Distinguished Chair in Biomedical Science. “Our nanovaccine did all of those things.” In this case, the experimental UTSW nanovaccine works by activating an adaptor protein called STING, which in turn stimulates the body’s immune defense system to ward off cancer. The scientists examined a variety of tumor models in mice: melanoma, colorectal cancer, and HPV-related cancers of the cervix, head, neck, and anogenital regions. In most cases, the nanovaccine slowed tumor growth and extended the animals’ lives. Other vaccine technologies have been used in cancer immunotherapy. However, they are usually complex – consisting of live bacteria or multiplex biological stimulants, Dr. Gao said. This complexity can make production costly and, in some cases, lead to immune-related toxicities in patients. With the emergence of new nanotechnology tools and increased understanding of polymeric drug delivery, Dr. Gao said, the field of nanoparticle vaccines has grown and attracted intense interest from academia and industry in the past decade. “Recent advances in understanding innate and adaptive immunity have also led to more collaborations between immunologists and nanotechnologists,” said Dr. Chen. “These partnerships are critical in propelling the rapid development of new generations of nanovaccines.” The investigative team is now working with physicians at UT Southwestern to explore clinical testing of the STING-activating nanovaccines for a variety of cancer indications. Combining nanovaccines with radiation or other immunotherapy strategies such as “checkpoint inhibition” can further augment their anti-tumor effectiveness. Study lead authors from UT Southwestern were Dr. Min Luo, research scientist; Dr. Hua Wang, Instructor of Molecular Biology; and Dr. Zhaohui Wang, postdoctoral fellow. Other UTSW researchers involved included graduate students Yang Li, Chensu Wang, Haocheng Cai, and Mingjian Du; Dr. Gang Huang, Instructor of Pharmacology and in the Simmons Comprehensive Cancer Center; Dr. Xiang Chen, research specialist; Dr. Zhigang Lu, Instructor of Physiology; Dr. Matthew Porembka, Assistant Professor of Surgery and a Dedman Family Scholar in Clinical Care; Dr. Jayanthi Lea, Associate Professor of Obstetrics and Gynecology and holder of the Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology; Dr. Arthur Frankel, Professor of Internal Medicine and in the Simmons Comprehensive Cancer Center; and Dr. Yang-Xin Fu, Professor of Pathology and Immunology, and holder of the Mary Nell and Ralph B. Rogers Professorship in Immunology. Their work was supported by the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, a UTSW Small Animal Imaging Resource grant and a Simmons Comprehensive Cancer Center support grant.


News Article | May 8, 2017
Site: www.rdmag.com

UT Southwestern Medical Center researchers have identified the cells that directly give rise to hair as well as the mechanism that causes hair to turn gray – findings that could one day help identify possible treatments for balding and hair graying. “Although this project was started in an effort to understand how certain kinds of tumors form, we ended up learning why hair turns gray and discovering the identity of the cell that directly gives rise to hair,” said Dr. Lu Le, Associate Professor of Dermatology with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “With this knowledge, we hope in the future to create a topical compound or to safely deliver the necessary gene to hair follicles to correct these cosmetic problems.” The researchers found that a protein called KROX20, more commonly associated with nerve development, in this case turns on in skin cells that become the hair shaft. These hair precursor, or progenitor, cells then produce a protein called stem cell factor (SCF) that the researchers showed is essential for hair pigmentation. When they deleted the SCF gene in the hair progenitor cells in mouse models, the animal’s hair turned white. When they deleted the KROX20-producing cells, no hair grew and the mice became bald, according to the study. Dr. Le, who holds the Thomas L. Shields, M.D. Professorship in Dermatology, said he and his researchers serendipitously uncovered this explanation for balding and hair graying while studying a disorder called Neurofibromatosis Type 1, a rare genetic disease that causes tumors to grow on nerves. Scientists already knew that stem cells contained in a bulge area of hair follicles are involved in making hair and that SCF is important for pigmented cells, said Dr. Le, a member of the Hamon Center for Regenerative Science and Medicine. What they did not know in detail is what happens after those stem cells move down to the base, or bulb, of hair follicles and which cells in the hair follicles produce SCF – or that cells involved in hair shaft creation make the KROX20 protein, he said. If cells with functioning KROX20 and SCF are present, they move up from the bulb, interact with pigment-producing melanocyte cells, and grow into pigmented hairs. But without SCF, the hair in mouse models was gray, and then turned white with age, according to the study. Without KROX20-producing cells, no hair grew, the study said. UT Southwestern researchers will now try to find out if the KROX20 in cells and the SCF gene stop working properly as people age, leading to the graying and hair thinning seen in older people – as well as in male pattern baldness, Dr. Le said. The research also could provide answers about why we age in general as hair graying and hair loss are among the first signs of aging. Other researchers include first author Dr. Chung-Ping Liao, Assistant Instructor; Dr. Sean Morrison, Professor and Director of the Children’s Medical Center Research Institute at UT Southwestern and of Pediatrics, and Howard Hughes Medical Institute Investigator, who holds the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern and the Mary McDermott Cook Chair in Pediatric Genetics; and Reid Booker, a former UT Southwestern researcher. The research was supported by the National Cancer Institute, Specialized Programs of Research Excellence (SPORE) grant, National Institutes of Health, the Dermatology Foundation, the Children’s Tumor Foundation, and the Burroughs Wellcome Fund.


News Article | November 18, 2016
Site: www.eurekalert.org

DALLAS - November 18, 2016 - Proactive outreach to cirrhosis patients in a safety net health system successfully doubled their screening rates for liver cancer, UT Southwestern Medical Center researchers found. Cirrhosis (liver disease) patients are at high risk to develop liver cancer, which is increasing in frequency an average of 3 percent annually and has a five-year overall survival rate of just 17.5 percent. "Finding ways to reach patients at high risk of liver cancer is critical. Liver cancer has the fastest increasing mortality rate among solid tumors in the U.S.," said first author Dr. Amit G. Singal, Associate Professor of Internal Medicine and Clinical Sciences, and a member of the Harold C. Simmons Comprehensive Cancer Center. "This high mortality is primarily due to low rates of liver cancer screening and high rates of late-stage diagnosis." The study randomly divided 1,800 cirrhosis patients at Parkland Health & Hospital System in Dallas into three groups. The first group received mailed outreach invitations for screening ultrasound. The second group received similar outreach plus patient navigation, and the third received their usual care. Researchers learned that the group receiving mailed outreach invitations were most likely to schedule an ultrasound, which doubled the overall rate of screening. The study appears in the journal Gastroenterology. "Our study is one of the first interventions to improve liver cancer screening and early detection among at-risk patients. The vulnerable patient population we studied in our safety net health system are those who are at highest risk of dying from liver cancer, so this intervention helped those who might benefit the most," said Dr. Singal. Only one-fourth of patients with cirrhosis in routine care are currently screened every six months for liver cancer with an ultrasound as recommended by national guidelines. Symptoms are not usually present when the cancer is in its early stages. "Our research previously demonstrated that liver cancer screening is underused in clinical practice, with lower rates of screening among racial/ethnic minorities and socioeconomically disadvantaged patients," said senior author Dr. Ethan Halm, Director of the Center for Patient-Centered Outcomes Research, Chief of the William T. and Gay F. Solomon Division of General Internal Medicine, and Professor of Internal Medicine and Clinical Sciences. "Our new study presents a model of a proactive, population health outreach strategy that can improve liver cancer screening and early detection among those at highest risk of adverse outcomes." Dr. Halm holds the Walter Family Distinguished Chair in Internal Medicine in Honor of Albert D. Roberts, M.D. According to the National Cancer Institute, liver cancer is diagnosed in an estimated 39,230 people annually. In 2013, there were an estimated 54,954 people living with this cancer in the U.S. Risk factors include a diagnosis of fatty liver disease, hepatitis B, hepatitis C, cirrhosis, or a combination of these diseases. Additional UT Southwestern faculty who contributed to the study include: Dr. Jasmin A. Tiro, Associate Professor of Clinical Science and member of the Simmons Cancer Center; and Dr. Jorge A. Marrero, Medical Director of Liver Transplantation, Associate Vice President, Clinical Transformation Officer, and Professor of Internal Medicine. Dr. Tiro, Dr. Marrero, Dr. Halm, and Dr. Singal are all members of the Simmons Cancer Center. Dr. Noel O. Santini from Parkland Health & Hospital System also contributed to the study. This study was conducted as part of UT Southwestern's Center for Patient-Centered Outcomes Research with support from the Agency for Healthcare Research & Quality, the National Institutes of Health, and the National Cancer Institute. Dr. Singal reported being on the speaker bureau for Bayer Pharmaceutical and receiving grant funding from Gilead Pharmaceuticals. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 47 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. Cancer that starts in the liver is called primary liver cancer. There are often no symptoms for early-stage liver cancer. Liver cancer can also develop in the bile ducts within the liver. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. . To automatically receive news releases from UT Southwestern via email, subscribe at http://www. .


News Article | December 12, 2016
Site: www.eurekalert.org

DALLAS, Dec. 12, 2016 - UT Southwestern Medical Center researchers have found that intermittent fasting inhibits the development and progression of the most common type of childhood leukemia. This strategy was not effective, however, in another type of blood cancer that commonly strikes adults. "This study using mouse models indicates that the effects of fasting on blood cancers are type-dependent and provides a platform for identifying new targets for leukemia treatments," said Dr. Chengcheng "Alec" Zhang, Associate Professor of Physiology at UT Southwestern and senior author of the study, published online today by Nature Medicine. "We also identified a mechanism responsible for the differing response to the fasting treatment," he added. The researchers found that fasting both inhibits the initiation and reverses the progression of two subtypes of acute lymphoblastic leukemia, or ALL - B-cell ALL and T-cell ALL. The same method did not work with acute myeloid leukemia (AML), the type that is more common in adults. ALL, the most common type of leukemia found in children, can occur at any age. Current ALL treatments are effective about 90 percent of the time in children, but far less often in adults, said Dr. Zhang, who also holds the Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. The two types of leukemia arise from different bone marrow-derived blood cells, he explained. ALL affects B cells and T cells, two types of the immune system's disease-fighting white blood cells. AML targets other types of white blood cells such as macrophages and granulocytes, among other cells. In both ALL and AML, the cancerous cells remain immature yet proliferate uncontrollably. Those cells fail to work well and displace healthy blood cells, leading to anemia and infection. They may also infiltrate into tissues and thus cause problems. The researchers created several mouse models of acute leukemia and tried various dietary restriction plans. They used green or yellow florescent proteins to mark the cancer cells so they could trace them and determine if their levels rose or fell in response to the fasting treatment, Dr. Zhang explained. "Strikingly, we found that in models of ALL, a regimen consisting of six cycles of one day of fasting followed by one day of feeding completely inhibited cancer development," he said. At the end of seven weeks, the fasted mice had virtually no detectible cancerous cells compared to an average of nearly 68 percent of cells found to be cancerous in the test areas of the non-fasted mice. Compared to mice that ate normally, the rodents on alternate-day fasting had dramatic reductions in the percentage of cancerous cells in the bone marrow and the spleen as well as reduced numbers of white blood cells, he said. The spleen filters blood. "In addition, following the fasting treatment, the spleens and lymph nodes in the fasted ALL model mice were similar in size to those in normal mice. Although initially cancerous, the few fluorescent cells that remained in the fasted mice after seven weeks appeared to behave like normal cells," he said. "Mice in the ALL model group that ate normally died within 59 days, while 75 percent of the fasted mice survived more than 120 days without signs of leukemia." Fasting is known to reduce the level of leptin, a cell signaling molecule created by fat tissue. In addition, previous studies have shown weakened activity by leptin receptors in human patients with ALL. For those reasons, the researchers studied both leptin levels and leptin receptors in the mouse models. They found that mice with ALL showed reduced leptin receptor activity that then increased with intermittent fasting, he said. "We found that fasting decreased the levels of leptin circulating in the bloodstream as well as decreased the leptin levels in the bone marrow. These effects became more pronounced with repeated cycles of fasting. After fasting, the rate at which the leptin levels recovered seemed to correspond to the rate at which the cancerous ALL cells were cleared from the blood," he added. Interestingly, AML was associated with higher levels of leptin receptors that were unaffected by fasting, which could help explain why the fasting treatment was ineffective against that form of leukemia. It also suggests a mechanism - the leptin receptor pathway - by which fasting exerts its effects in ALL, he said. "It will be important to determine whether ALL cells can become resistant to the effects of fasting," he said. "It also will be interesting to investigate whether we can find alternative ways that mimic fasting to block ALL development." Given that the study did not involve drug treatments, just fasting, researchers are discussing with clinicians whether the tested regimen might be able to move forward quickly to human clinical trials Current or former UT Southwestern coauthors in Physiology involved in this research include: co-lead authors Instructor Dr. Zhigang Lu and postdoctoral researcher Dr. Jingjing Xie; senior research associate Dr. Guojin Wu; research scientist Dr. Jinhui Shen, now in Biophysics; and former Instructor Dr. Xunlei Kang. Other UTSW researchers include Dr. Robert Collins, Professor of Internal Medicine; Dr. Weina Chen, Associate Professor of Pathology; Dr. Min Luo, research scientist, Harold C. Simmons Comprehensive Cancer Center; Dr. Lily Jun-Shen Huang, Associate Professor of Cell Biology; Dr. James Amatruda, Associate Professor of Pediatrics, Internal Medicine, and Molecular Biology; Dr. Tamra Slone, Assistant Professor of Pediatrics; Dr. Naomi Winick, Professor of Pediatrics; and Dr. Philipp Scherer, Professor of Internal Medicine and Cell Biology. Dr. Collins holds the Sydney and J.L. Huffines Distinguished Chair in Cancer Research in Honor of Eugene Frenkel, M.D., and the H. Lloyd and Willye V. Skaggs Professorship in Medical Research; Dr. Amatruda holds the Nearburg Family Professorship in Pediatric Oncology Research and is a Horchow Family Scholar in Pediatrics; Dr. Winick holds the Lowe Foundation Professorship in Pediatric Neuro-Oncology; and Dr. Scherer holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research. Researchers from Central South University School of Xiangya Medicine, China, also participated. The research was supported by the National Institutes of Health; the National Heart, Lung, and Blood Institute; Leukemia & Lymphoma Society awards; and the Cancer Prevention and Research Institute of Texas (CPRIT). UTSouthwestern's Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 47 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs and its education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the National Cancer Institute as a National Clinical Trials Network Lead Academic Participating Site. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.


News Article | December 20, 2016
Site: www.eurekalert.org

DALLAS - Dec. 20, 2016 - UT Southwestern Medical Center researchers have invented a transistor-like threshold sensor that can illuminate cancer tissue, helping surgeons more accurately distinguish cancerous from normal tissue. In this latest study, researchers were able to demonstrate the ability of the nanosensor to illuminate tumor tissue in multiple mouse models. The study is published in Nature Biomedical Engineering. "We synthesized an imaging probe that stays dark in normal tissues but switches on like a light bulb when it reaches solid tumors. The purpose is to allow surgeons to see tumors better during surgery," said senior author Dr. Jinming Gao, Professor of Oncology, Pharmacology and Otolaryngology with the Harold C. Simmons Comprehensive Cancer Center. The nanosensor amplifies pH signals in tumor cells to more accurately distinguish them from normal cells. "Cancer is a very diverse set of diseases, but it does have some universal features. Tumors do not have the same pH as normal tissue. Tumors are acidic, and they secrete acids into the surrounding tissue. It's a very consistent difference and was discovered in the 1920's," said Dr. Baran Sumer, Associate Professor of Otolaryngology, and co-senior author of the study. The researchers hope the improved surgical technology can eventually benefit cancer patients in multiple ways. "This new digital nanosensor-guided surgery potentially has several advantages for patients, including more accurate removal of tumors, and greater preservation of functional normal tissues," said Dr. Sumer. "These advantages can improve both survival and quality of life." For example, this technology may help cancer patients who face side effects such as incontinence after rectal cancer surgery. "The new technology also can potentially assist radiologists by helping them to reduce false rates in imaging, and assist cancer researchers with non-invasive monitoring of drug responses," said Dr. Gao. According to the National Cancer Institute, there are 15.5 million cancer survivors in the U.S., representing 4.8 percent of the population. The number of cancer survivors is projected to increase by 31 percent, to 20.3 million, by 2026. Dr. Sumer and Dr. Gao were joined in this study by Dr. Gang Huang, Instructor of Pharmacology; Dr. Xian-Jin Xie, Professor of Clinical Sciences; Dr. Rolf Brekken, Professor of Surgery and Pharmacology and an Effie Marie Cain Research Scholar; and Dr. Xiankai Sun, Director of Cyclotron and Radiochemistry Program in Department of Radiology and Advanced Imaging Research Center, Associate Professor of Radiology, and holder of the Dr. Jack Krohmer Professorship in Radiation Physics; Dr. Joel Thibodeaux, Assistant Professor of Pathology and Director of Cytopathology, Parkland Memorial Hospital. Additional UT Southwestern researchers who contributed to the study include: Dr. Tian Zhao, Dr. Xinpeng Ma, Mr. Yang Li, Dr. Zhiqiang Lin, Dr. Min Luo, Dr. Yiguang Wang, Mr. Shunchun Yang and Ms. Zhiqun Zeng in the Harold C. Simmons Comprehensive Cancer Center; and Dr. Saleh Ramezani in the Department of Radiology. Dr. Gao and Dr. Sumer are scientific co-founders of OncoNano Medicine, Inc. The authors declare competing financial interests in the full-text of the Nature Biomedical Engineering article. UT Southwestern Medical Center has licensed the technology to OncoNano Medicine and has a financial interest in the research described in the article. Funding for the project includes grants from the Cancer Prevention and Research Institute of Texas. Dr. Gao and Dr. Sumer are investigators for two Academic Research grants and OncoNano Medicine was the recipient of a CPRIT Product Development Research grant. Research reported in this press release was supported by the National Cancer Institute under Award Number R01 CA192221 and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 47 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. . To automatically receive news releases from UT Southwestern via email, subscribe at http://www.


News Article | February 21, 2017
Site: www.eurekalert.org

DALLAS - Feb. 20, 2017 - How we think and fall in love are controlled by lightning-fast electrochemical signals across synapses, the dynamic spaces between nerve cells. Until now, nobody knew that cancer cells can repurpose tools of neuronal communication to fuel aggressive tumor growth and spread. UT Southwestern Medical Center researchers report those findings in two recent studies, one in the Proceedings of the National Academy of Sciences (PNAS) and the second in Developmental Cell "Many properties of aggressive cancer growth are driven by altered cell signaling," said Dr. Sandra Schmid, senior author of both papers and Chair of Cell Biology at UT Southwestern. "We found that cancer cells are taking a page from the neuron's signaling playbook to maintain certain beneficial signals and to squelch signals that would harm the cancer cells." The two studies find that dynamin1 (Dyn1) - a protein once thought to be present only in nerve cells of the brain and spinal cord - is also found in aggressive cancer cells. In nerve cells, or neurons, Dyn1 helps sustain neural transmission by causing rapid endocytosis - the uptake of signaling molecules and receptors into the cell - and their recycling back to the cell surface. These processes ensure that the neurons keep healthy supplies at the ready to refire in rapid succession and also help to amplify or suppress important nerve signals as necessary, Dr. Schmid explained. "This role is what the cancer cells have figured out. Aggressive cancer cells have usurped the mechanisms that neurons use for the rapid uptake and recycling of neural transmitters. Instead of neural transmitters, the cancer cells use Dyn1 for rapid uptake and recycling of EGF (epidermal growth factor) receptors. Mutations in EGF receptors are drivers of breast and lung cancers," she said of the Developmental Cell study. In order to thrive, cancer cells must multiply faster than nearby noncancerous cells. EGF receptors help them do that, she explained. Cancer cell survival is another factor in disease progression. In the PNAS study, the Schmid lab found that aggressive cancer cells appear to have adapted neuronal mechanisms to thwart a key cancer-killing pathway triggered by activating "death receptors" (DRs) on cancer cells. Specifically, aggressive cancer cells appear to have adapted ways to selectively activate Dyn1 to suppress DR signaling that usually leads to cancer cell death. "It is amazing that the aggressive cancers use a signaling pathway to increase the activity of EGF and also turn on Dyn1 pathways to suppress cancer death - so you have this vicious circle," said Dr. Schmid, who holds the Cecil H. Green Distinguished Chair in Cellular and Molecular Biology. She stressed that less aggressive cancers respond to forms of chemotherapy that repress EGF signaling and/or die in response to the TRAIL-DR pathway. However, aggressive lung and breast cancer cells have adapted ways to commandeer the neuronal mechanisms identified in these studies. The hope is that this research will someday lead to improved strategies to fight the most aggressive cancers, she said. Currently, her laboratory is conducting research to identify Dyn1 inhibitors as potential anticancer drugs using a 280,000-compound library in a shared facility at UT Southwestern. "Cancer is a disease of cell biology. To grow, spread, and survive, cancer cells modify normal cellular behavior to their advantage. They can't reinvent the underlying mechanisms, but can adapt them. In these studies, we find that some cancer cells repurpose tools that neurons use in order to get a competitive advantage over nearby normal cells," she said. Lead author of the PNAS study is Dr. Carlos Reis, a former postdoctoral researcher. Other UT Southwestern co-authors in Cell Biology are Dr. Nawal Bendris, a former postdoctoral researcher, and Dr. Ping-Hung Chen, a postdoctoral fellow. This research was supported by grants from the National Institutes of Health (NIH) and the Cancer Prevention and Research Institute of Texas (CPRIT). Dr. Chen is lead author of the Developmental Cell study. Other UT Southwestern co-authors include: Dr. Bendris, Dr. Reis, and Dr. Marcel Mettlen, Assistant Professor of Cell Biology. Researchers from Taiwan also participated. This study received support from the NIH and a National Science Council of Taiwan grant. Other assistance came from the National Cancer Institute-supported Harold C. Simmons Comprehensive Cancer Center and the Texas Institute for Brain Injury and Repair-supported Whole Brain Microscopy Facility, both of which are located at UT Southwestern. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated comprehensive cancer center in North Texas and one of just 47 NCI-designated comprehensive cancer centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. To automatically receive news releases from UT Southwestern via email, subscribe at http://www.


Late-stage liver cancer is a major challenge for therapeutic intervention. Drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers explained. UT Southwestern scientists crafted synthetic "dendrimer" nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the journal, Proceedings of the National Academy of Sciences. "We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease," said Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center. "We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development." Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17 percent, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. Critical to understanding this problem, and developing the new therapy, was a close collaboration between Dr. Siegwart and Dr. Hao Zhu, Assistant Professor at the Children's Medical Center Research Institute at UT Southwestern, and a practicing oncologist. "Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers," said Dr. Zhu, also Assistant Professor of Internal Medicine and Pediatrics at UT Southwestern. The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma - the most common form of liver cancer - prompted the authors to develop non-toxic carriers and explore "miRNA" therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect. To address this problem, UTSW scientists chemically synthesized more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Dr. Siegwart said. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity. The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival. The multidisciplinary UTSW research team included Dr. Kejin Zhou, Liem Nguyen, Jason Miller, Dr. Yunfeng Yan, Dr. Petra Kos, Dr. Hu Xiong, Lin Li, Dr. Jing Hao, and Jonathan Minnig. The Siegwart Research Group uses a materials chemistry approach to tackle challenges in cancer therapy and diagnosis. The lab is currently focused on the development of improved materials for effective delivery of siRNA, miRNA, mRNA, and CRISPR strategies to manipulate gene expression in tumors and develop the next generation of cancer therapies. Journal reference: Proceedings of the National Academy of Sciences


News Article | January 26, 2016
Site: www.cemag.us

UT Southwestern Medical Center chemists have successfully used synthetic nanoparticles to deliver tumor-suppressing therapies to diseased livers with cancer, an important hurdle scientists have been struggling to conquer. Late-stage liver cancer is a major challenge for therapeutic intervention. Drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers explain. UT Southwestern scientists crafted synthetic “dendrimer” nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the journal Proceedings of the National Academy of Sciences. “We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease,” says Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center. “We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development.” Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17 percent, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. Critical to understanding this problem, and developing the new therapy, was a close collaboration between Siegwart and Dr. Hao Zhu, Assistant Professor at the Children’s Medical Center Research Institute at UT Southwestern, and a practicing oncologist. “Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers,” says Zhu, also Assistant Professor of Internal Medicine and Pediatrics at UT Southwestern. The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma — the most common form of liver cancer — prompted the authors to develop non-toxic carriers and explore “miRNA” therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect. To address this problem, UTSW scientists chemically synthesized more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Siegwart says. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity. The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival. The multidisciplinary UTSW research team included Dr. Kejin Zhou, Liem Nguyen, Jason Miller, Dr. Yunfeng Yan, Dr. Petra Kos, Dr. Hu Xiong, Lin Li, Dr. Jing Hao, and Jonathan Minnig. The Siegwart Research Group uses a materials chemistry approach to tackle challenges in cancer therapy and diagnosis. The lab is currently focused on the development of improved materials for effective delivery of siRNA, miRNA, mRNA, and CRISPR strategies to manipulate gene expression in tumors and develop the next generation of cancer therapies. The research was supported by the Cancer Prevention and Research Institute of Texas (CPRIT), the Welch Foundation, the American Cancer Society, and the Mary Kay Foundation. Additional support for individual researchers included the Howard Hughes Medical Institute (HHMI), the Pollack Foundation, the National Institutes of Health, and the Burroughs Wellcome Fund.


News Article | March 30, 2016
Site: phys.org

Understanding the structure of this enzyme, separase, could lead to better treatments for cancer, which occurs when cells divide out of control, said Dr. Hongtao Yu, Professor of Pharmacology and a Howard Hughes Medical Institute (HHMI) Investigator at UT Southwestern. "Chromosomes contain the genetic blueprint for life, and must be precisely duplicated and equally partitioned during each cell division. The cohesin complex forms a molecular ring to encircle the duplicated chromosomes and tether them together until the moment of chromosome separation," said Dr. Yu, senior author of the study published online in Nature. "In organisms from fungi to humans, separase - an enzyme that breaks down proteins - cleaves and opens the cohesin ring to allow chromosome separation and subsequent partition into the two new daughter cells." Despite its central role in cell biology, the atomic structure of separase has eluded scientists since its discovery nearly two decades ago. This situation left a void in the understanding of the enzyme's mechanism and regulation, the researchers said. "We determined the atomic structure of separase from a fungus that can grow at high temperatures. The structure reveals how separase recognizes and cleaves the cohesin ring, allowing the chromosomes to separate," said Dr. Yu, a Michael L. Rosenberg Scholar in Medical Research and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "This particular protein is very unstable in species that grow at normal temperature, such as human body temperature, but was more stable in the high-temperature fungus that we studied." Because of the enzyme's role in cell division, chemical inhibitors of separase are expected to block cell proliferation and therefore may have therapeutic value in treating cancer. "The fungal separase that we studied is very similar to human separase. For that reason, we believe our structure will aid in the design of such inhibitors," he said, "because once you have the shape of the structure, you can computationally look for molecules that will bind to it." Study co-authors included Dr. Zhonghui Lin, a research specialist at the HHMI and in the Department of Pharmacology, and Dr. Xuelian "Sue" Luo, Associate Professor of Pharmacology and Biophysics. Explore further: New key mechanism in cell division discovered More information: Structural basis of cohesin cleavage by separase, Nature, DOI: 10.1038/nature17402

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