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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 | March 1, 2017
Site: www.eurekalert.org

It's what's missing in the tumor genome, not what's mutated, that thwarts treatment of metastatic melanoma with immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson Cancer Center report in Science Translational Medicine. Whole exome sequencing of tumor biopsies taken before, during and after treatment of 56 patients showed that outright loss of a variety of tumor-suppressing genes with influence on immune response leads to resistance of treatment with both CTLA4 and PD1 inhibitors. The team's research focuses on why these treatments help 20-30 percent of patients -- with some complete responses that last for years - but don't work for others. Their findings indicate that analyzing loss of blocks of the genome could provide a new predictive indicator. "Is there a trivial or simple (genomic) explanation? There doesn't seem to be one," said co-senior author Andrew Futreal, Ph.D., professor and chair of Genomic Medicine and co-leader of MD Anderson's Moon Shots Program™. "There's no obvious correlation between mutations in cancer genes or other genes and immune response in these patients." "There are, however, pretty strong genomic copy loss correlates of resistance to sequential checkpoint blockade that also pan out for single-agent treatment," Futreal said. Doctoral candidate Whijae Roh, co-lead author, Futreal, and co-senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, and colleagues analyzed the genomic data for non-mutational effects. "We found a higher burden of copy number loss correlated to response to immune checkpoint blockade and to lower immune scores, a measure of immune activation in the tumor's microenvironment," said Roh, a graduate student in the University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences. "We also found copy loss has an effect that is independent of mutational load in the tumors." Melanoma tumors with larger volumes of genetic alterations, called mutational load, provide more targets for the immune system to detect and are more susceptible to checkpoint blockade, although that measure is not conclusive alone. "Combining mutational load and copy number loss could improve prediction of patient response," Wargo said. When the team stratified patients in another data set of patients by whether they had high or low copy loss or high or low mutational load, they found that 11 of 26 patients with high mutational load and low copy loss had a clinical benefit, while only 4 or 26 with low mutational load and high copy loss benefited from treatment. In the trial, patients were treated first with the immune checkpoint inhibitor ipilimumab, which blocks a brake called CTLA4 on T cells, the immune system's specialized warriors, freeing them to attack. Patients whose melanoma did not react then went on to anti-PD1 treatment (nivolumab), which blocks a second checkpoint on T cells. Biopsies were taken, when feasible, before, during and after treatment for molecular analysis to understand response and resistance. To better understand the mechanisms at work, the team analyzed tumor genomes for recurrent copy loss among 9 tumor biopsies from patients who did not respond to either drug and had high burden of copy number loss. They found repeated loss of blocks of chromosomes 6, 10 and 11, which harbor 13 known tumor-suppressing genes. Analysis of a second cohort of patients confirmed the findings, with no recurrent tumor-suppressor loss found among any of the patients who had a clinical benefit or long-term survival after treatment. Ipilimumab sometimes wins when it fails The researchers also found a hint that treatment with ipilimumab, even if it fails, might prime the patient's immune system for successful anti-PD1 treatment. The team analyzed the genetic variability of a region of the T cell receptors, a feature of T cells that allows them to identify, attack and remember an antigen target found on an abnormal cell or an invading microbe. They looked for evidence of T cell "clonality," an indicator of active T cell response. Among eight patients with longitudinal samples taken before treatment with both checkpoint types, all three who responded to anti-PD1 therapy had shown signs of T cell activation after anti-CTLA treatment. Only one of the five non-responders had similar indicators of T cell clonality. "That's evidence that anti-CTLA4 in some cases primes T cells for the next step, anti-PD1 immunotherapy. It's well known that if you don't have T cells in the tumor, anti-PD1 won't do anything, it doesn't bring T cells into the tumor," Futreal says. Overall, they found that T cell clonality predicts response to PD1 blockade but not to CTLA-4 blockade. "Developing an assay to predict response will take an integrated analysis, thinking about genomic signatures and pathways, to understand the patient when you start therapy and what happens as they begin to receive therapy," Wargo said. "Changes from pretreatment to on-therapy activity will be important as well." The Science Translational Medicine paper is the third set of findings either published or presented at scientific meetings by the team, which is led by Futreal and Wargo, who also is co-leader of the Melanoma Moon Shot™. Immune-monitoring analysis showed that presence of immune infiltrates in a tumor after anti-PD1 treatment begins is a strong predictor of success. They also presented evidence that the diversity and composition of a patient's gut bacteria also affects response to anti-PD1 therapy. The serial biopsy approach is a hallmark of the Adaptive Patient-Oriented Longitudinal Learning and Optimization™ (APOLLO) platform of the Moon Shots Program™, co-led by Futreal that systematically gathers samples and data to understand tumor response and resistance to treatment over time. The Moon Shots Program™ is designed to reduce cancer deaths by accelerating development of therapies, prevention and early detection from scientific discoveries. Futreal holds the The Robert A. Welch Distinguished University Chair in Chemistry at MD Anderson. Co-authors with Roh, Futreal and Wargo are co-first authors Pei-Ling Chen, M.D., of Genomic Medicine and Pathology, and Alexandre Reuben, Ph.D., of Surgical Oncology; also Christine Spencer, Feng Wang, Ph.D., Zachary Cooper, Ph.D., Curtis Gumbs, Latasha Little, Qing Chang, Wei-Shen Chen, M.D., and Jason Roszik, Ph.D., of Genomic Medicine; Michael Tetzlaff, Ph.D., M.D., and Victor Prieto, M.D., Ph.D., of Pathology; Peter Prieto, M.D., Vancheswaran Gopalakrishnan, Jacob L. Austin-Breneman, Hong Jiang, Ph.D., and Jeffrey Gershenwald, M.D., of Surgical Oncology; John Miller, Ph.D., Oncology Research for Biologics and Immunotherapy Translation (ORBIT); Sangeetha Reddy, M.D., Division of Cancer Medicine; Khalida Wani, Ph.D., Mariana Petaccia De Macedo, M.D., Ph.D., Eveline Chen, and Alexander Lazar, M.D., Ph.D., of Translational Molecular Pathology; Michael Davies, M.D., Ph.D., Hussein Tawbi, M.D., Ph.D., Patrick Hwu, M.D., Wen-Jen Hwu, M.D., Ph.D., Adi Diab, M.D., Isabella Glitza, M.D., Ph.D., Sapna Patel, M.D., Scott Woodman, M.D., Ph.D., and Rodabe Amaria, M.D., of Melanoma Medical Oncology; Jianhua Hu, Ph.D., of Biostatistics; Padmanee Sharma, M.D., Ph.D., and James Allison, Ph.D., of Immunology; Lynda Chin, M.D., University of Texas System; and Jianhua Zhang Ph.D., of the Institute for Applied Cancer Science. Wargo, Sharma and Allison are all members of the Parker Institute for Cancer Immunotherapy. The research was funded by MD Anderson's Melanoma Moon Shot™, the Melanoma Research Alliance Team Science Award, the John G. and Marie Stella Kenedy Memorial Foundation, the University of Texas System STARS program; the Cancer Prevention and Research Institute of Texas; the American Society of Clinical Oncology; Conquer Cancer Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; and grants from the National Cancer Institute of the National Institutes of Health (U54CA163125, 1K08CA160692-01A1, T32CA009599, NIH T32 CA009666, R01 CA187076-02) and MD Anderson's Institutional Tissue Bank (2P30CA016672) Spencer and Gopalakrishnan are graduate students in The University of Texas Health Science Center at Houston School of Public Health.

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.

Patients successfully treated for breast, colon and other cancers can go on to develop an often-fatal form of leukemia, sometimes years after completion of treatment, due to a genetic mutation leading to secondary malignancies known as therapy-related myeloid neoplasms (t-MNs). A study conducted by researchers at The University of Texas MD Anderson Cancer Center revealed pre-leukemic mutations, called clonal hematopoiesis, may predict whether patients develop t-MNs. Clonal hematopoiesis appears to function as a biomarker for patients who develop t-MNs, a leukemia recognized for its extremely poor prognosis. The study findings were published today in The Lancet Oncology and presented at the annual meeting of the American Society of Hematology in San Diego. "Therapy-related myeloid neoplasms occur in about 5 percent of cancer patients who were treated with chemotherapy and/or radiation therapy," said Andy Futreal, Ph.D., chair ad interim of Genomic Medicine. "In most cases, it is fatal, and currently there is no way to predict who is at risk or prevent it." Being able to detect t-MNs earlier is crucial given that the disease usually occurs three to eight years following chemotherapy and/or radiation therapy. "T-MNs are a problem that needs urgent attention," said Koichi Takashi, M.D., assistant professor of Leukemia and Genomic Medicine and a co-author on the Lancet Oncology paper. "Since many cancer patients are now living longer, t-MNs are an increasing concern for many cancer survivors." Futreal's team studied 14 patients with t-MNs and found traces of pre-leukemic mutations or clonal hematopoiesis in 10. To determine if pre-leukemic mutations could reliably predict whether the patients would develop leukemia, the researchers compared prevalence of pre-leukemic mutations in the 14 patients with 54 patients who did not develop t-MNs after therapy. "We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs (71 percent) versus those who did not (26 percent)," said Futreal. "We also validated these findings in a separate cohort of patients. Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MNs development." In the sample of 14 patients with t-MNs, the team looked at samples of bone marrow at the time of t-MNs development and blood samples obtained at the time of their primary cancer diagnosis. "We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis," said Takahashi. "Based on this finding, we believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed." MD Anderson study team participants included Hagop Kantarjian, M.D.; Courtney DiNardo, M.D.; Simona Colla, Ph.D.; Farhad Ravandi, M.D.; and Guillermo Garcia-Manero, M.D., all of Leukemia; Feng Wang, Ph.D.; Li Zhao, Ph.D.; Curtis Gumbs; and Jianhua Zhang, Ph.D., Genomic Medicine; Denaha Doss; Kanhav Khanna; and Erika Thompson, Genetics; Keyur Patel, M.D., Ph.D.; and Carlos Bueso-Ramos, M.D., Ph.D., Hematopathology; Sativa Neelapu, M.D.; and Felipe Samaniego, M.D., Lymphoma and Myeloma; Xuelin Hang, Ph.D., Biostatistics; and Xifend Wu, M.D., Ph.D., Epidemiology. The study also included participation by Kyoto University, Kyoto, Japan. The study was funded by the Cancer Prevention and Research Institute of Texas (R120501 and RP100202); the Welch Foundation (G-0040); the UT System STARS Award (PS100149); the Edward P. Evans Foundation; the Fundacion Ramon Areces; the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer Award; the National Cancer Institute SPORE Career Development Grant; the Khalifa Scholar Award; the National Institutes of Health (P30 CA016672); and donations to MD Anderson's MDS/AML Moon Shot Program.

News Article | December 4, 2016
Site: www.eurekalert.org

Patients who potentially could benefit most from participation in clinical trials due to poor prognoses often are not included based on eligibility criteria, such as existing medical illnesses. A novel study at The University of Texas MD Anderson Cancer Center revealed some patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), who traditionally could not be considered for clinical trials, responded well and were safely treated in this setting. The study, led by Guillermo Garcia-Manero, M.D., professor of Leukemia, followed 109 patients with AML and MDS undergoing treatment with azacitidine (AZA) and vorinostat. Research results were presented Dec. 3 at the 58th Annual Meeting of the American Society for Hematology in San Diego. "Most cancer clinical studies exclude patients with co-morbidities, active or recent malignancies, organ dysfunction or poor performance status," said Garcia-Manero. "How these criteria protect patients is unclear. Although some are based on clinical reasoning, it seems these criteria are in place more to protect the drug or intervention being studied rather than the patient." The study initially enrolled 30 patients age 17 and older who had not previously been treated for AML or MDS. Patients eligible for the study had either poor performance, poor renal or hepatic function or any other active systemic disorder such as other cancer. Sixty-day survival was 83 percent with low-grade gastrointestinal side effects reported. The study was expanded to include an additional 79 patients. Sixty-day survival for the second group was 79 percent with a median overall survival of 7.6 months. The average event-free survival was 4.5 months. Again, only low-grade gastrointestinal side effects were observed. The study was designed with "stopping rules" that included monitoring of side effects and complete response rates. Patients were immediately placed on another therapy if their assigned therapy did not indicate there would be a complete response within a 60-day period. To define the minimum expected survival and response rates that would trigger the stopping rules, researchers relied on prior data of 181 patients previously treated at MD Anderson. "Participation in clinical trials is fundamental for the development of new therapeutic interventions," said Guillermo Montalban-Bravo, M.D., fellow in Leukemia, a research team member. "Despite this need, only three to five percent of patients with cancer treated in the U.S. currently are enrolled in clinical trials." The study points to further evaluation of standard exclusion criteria, potentially increasing the pool of patient likely to benefit from therapy, with the aim of future larger clinical trials specifically treating patients with AML and MDS. MD Anderson research team participants included: Elias Jabbour, M.D.; Gautam Borthakur, M.D.; Courtney DiNardo, M.D.; Naveen Pemmaraju, M.D.; Jorge Cortes, M.D.; Srdan Verstovsek, M.D.; Tapan Kadia, M.D.; Naval Daver, M.D.; William Wierda, M.D., Ph.D.; Yesid Alvarado, M.D.; Marina Konopleva, M.D., Ph.D.; Farhad Ravandi, M.D.; Zeev Estrov, M.D.; Nitin Jain, M.D.; Ana Alfonso Pierola, M.D., Ph.D.; Mark Brandt; Troy Sneed; Hui Yang, M.D., Ph.D.; Sherry Pierce; Elihu Estey, M.D.; Zachary Bohannan, and Hagop Kantarjian, M.D., all of Leukemia; Carlos Bueso-Ramos, M.D., Ph.D., Hematopathology; and Xuelin Huang, Ph.D. and Hsiang-Chun Chen, Biostatistics. The study was funded by the Cancer Prevention and Research Institute of Texas (RP140500), the National Institutes of Health (P30 CA016672), Merck Sharpe and Dohme Corp. (NCT00948064), the Dr. Kenneth B. McCredie Chair in Clinical Leukemia Research endowment, the Edward P. Evans Foundation, the Fundación Ramón Areces, and the MD Anderson MDS/AML Moon Shots Program.

News Article | February 1, 2017
Site: www.medicalnewstoday.com

Some cancer cells have a trick up their sleeve to avoid cell death: boosting maintenance of telomeres, the protective "end caps" on chromosomes, a research team led by Jackson Laboratory (JAX) Professor Roel Verhaak reports in Nature Genetics. The findings open avenues for functional studies that may yield insight into how to steer cancer cells away from immortalizing and back to normal death programming. Moreover, harnessing telomere maintenance mechanisms could be a potential approach to selectively retarding aging. The 2009 Nobel Prize in Physiology or Medicine to Elizabeth Blackburn, Carol Greider and Jack Szostak established the roles of telomeres and telomerase in the aging of cells and organisms. In most cells, telomeres shorten over time to the point where cell division is no longer possible, leading to cell death. Certain cells, such as stem cells and germ cells, are capable of ongoing division because they contain active telomerase, an enzyme that lengthens telomeres. It has been long known to researchers that cancer cells reactivate telomerase through telomerase reverse transcriptase (TERT) transcription, but the mechanisms behind this remain elusive. "These cancer cells are hijacking a mechanism to maintain telomeres, enabling them to continue to divide," Verhaak says. The researchers scanned 18,430 samples from cancerous and non-neoplastic tissues to determine and compare their telomere lengths and query them for telomerase activity. The analysis, which included samples from 31 different cancer types, showed that telomeres were generally shorter in tumors than in healthy tissues, and longer in soft tissue tumors and brain tumors compared to other cancers. They found that the majority - 73 percent - of cancers expressed TERT (which in turn drives reactivation of telomerase). In addition to the expected mutations and genomic rearrangements driving TERT expression, the researchers discovered an important new mechanism: TERT promoter methylation. In methylation, clumps of molecules called methyl groups attach to a segment of DNA and can change the activity of that segment without changing its genetic sequence. Methylation in DNA sequences known as promoters, as the researchers found in most of the cancer samples, typically acts to repress gene transcription, the process of making an RNA copy of a gene sequence. Counterintuitively, Verhaak says, "we found that TERT DNA promoter methylation resulted in TERT expression. We think that because of the DNA methylation, mRNA transcription-repressing proteins are no longer able to bind." About 22 percent of the tumor cells lacked detectable TERT expression. "There could be a number of reasons for this," says Floris Barthel, a JAX postdoctoral associate and first author of the study. "Maybe not all tumors harbor immortalized cells with a telomere maintenance mechanism, or there are alternative mechanisms at play, or perhaps TERT expression that falls below the detection threshold we used is still sufficient to maintain telomeres." Future studies are needed to elucidate the telomere maintenance mechanisms, or lack thereof, in these tumors, he notes. Siyuan Zheng of the University of Texas M.D. Anderson Cancer Center co-led the study with Verhaak. Coauthors include Samirkumar Amin, a JAX postdoctoral associate. The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a National Cancer Institute-designated Cancer Center, a facility in Sacramento, Calif., and a genomic medicine institute in Farmington, Conn. It employs 1,800 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. This project is supported by grants from the National Institutes of Health (R01CA190121 and P01CA085878) and the Cancer Prevention and Research Institute of Texas (R140606), and by Cancer Center Support Grants P30CA16672 and P30CA034196. Article: Systematic analysis of telomere length and somatic alterations in 31 cancer types, Barthel et al., Nature Genetics, doi:10.1038/ng.3781, published online 30 January 2017.

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.

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 | February 15, 2017
Site: www.prweb.com

Today, angelMD announced an investment syndicate with Curtana Pharmaceuticals, a leader in brain cancer treatment technology. Orrin Ailloni-Charas, MD, MBA is the syndicate leader for the first investment through angelMD in 2017. Dr. Ailloni-Charas is a practicing physician in Northern California, and he received his medical degree at the New York University School of Medicine before going on to earn an MBA at Columbia University. Based in Austin, TX, Curtana Pharmaceuticals was founded by Gregory Stein, MD and Santosh Kesari, MD on the shared goal of developing first in class, small molecule therapeutics for Gioblastoma (GBM) treatment. GBM is one of the deadliest malignant primary brain tumors in adults, and there are approximately ten thousand new cases per year in the United States. The treatments for GBM and other malignant gliomas are valued at $380 million per year in the U.S. and approximately $1 billion world-wide. "Glioblastoma is a devastating disease, and we're excited to facilitate investor participation in a company attacking this space in a novel way. This is a perfect opportunity to do life-saving work while making smart investment decisions at the same time,” stated Dr. Ailloni-Charas. CT-179, Curtana’s leading treatment, is an Olig2 transcription factor inhibitor that kills GBM and GBM cancer stem cells. Currently in the preclinical stage, CT-179 is awaiting Investigational New Drug (IND) filing, no later than first quarter of 2018. “It is particularly validating for our company and technology platform to be selected by angelMD for inclusion in its portfolio,” said Gregory Stein, M.D., M.B.A. and Chief Executive Officer, Curtana Pharmaceuticals.  “Anchored by physicians, angelMD's investors are well versed on the challenges of treating brain cancer. Curtana remains laser-focused on developing a novel therapy targeting cancer stem cells to dramatically improve treatment success and survival times.” angelMD is an investment platform and marketplace connecting innovative medical startups, physicians, investors and industry partners. Leading physicians from all over the US have joined the angelMD Scientific Advisory Board and Leaders Club to help source, evaluate and advise companies in biotechnology, medical device and healthcare technology. For more information, visit http://www.angelmd.co. Curtana Pharmaceuticals was founded on a mission to develop the first truly targeted therapies for the treatment of the most aggressive types of brain cancer. The company’s drug development program is based on the pioneering research of Dr. Santosh Kesari, who is currently the Chairman of the Department of Translational Neuro-oncology and Neuro-therapeutics at the John Wayne Cancer Institute. Curtana’s senior leadership brings years of experience in the pharmaceutical industry, with extensive backgrounds in the development of new molecular entities for the treatment of cancer as well as CNS disorders. Curtana initiated operations in San Diego, California in 2013. Following the award of a highly prestigious and competitive grant ($7.6M) from the Cancer Prevention and Research Institute of Texas (CPRIT) in August 2014, the company relocated its lab and offices to Austin, Texas.

HOUSTON--(BUSINESS WIRE)--Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, today announced that the Company received notice of a Product Development award totaling approximately $16.9 million from the Cancer Prevention and Research Institute of Texas (“CPRIT”) to support clinical studies of its lead product candidate BPX-501. Assuming suc

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