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News Article | September 15, 2016
Site: www.cemag.us

Researchers with the Harold C. Simmons Comprehensive Cancer Center successfully developed a synthetic polymer that can transport a drug into lung cancer cells without going inside of normal lung cells. Since conventional chemo drugs indiscriminately kill all rapidly dividing cells to halt the growth of cancer, these selective nanoparticles could decrease side effects by reducing drug accumulation in normal cells. “The discovery that nanoparticles can be selective to certain cells based only on their physical and chemical properties has profound implications for nanoparticle-based therapies because cell type specificity of drug carriers could alter patient outcomes in the clinic,” says corresponding author Dr. Daniel Siegwart, Assistant Professor of Biochemistry at UT Southwestern Medical Center and with Simmons Cancer Center. “At the same time, a deeper understanding of nanoparticle interactions in the body opens the door to predict patient responses to existing liposome and nanoparticle therapies, and offers the potential to create future drug carriers customized according to individual genetic profiles.” The findings appear in the Proceedings of the National Academy of Sciences. The scientists tested hundreds of polymers to make the surprising discovery that cells could respond differently to the same drug carrier, even when those cancerous and normal cells came from the lungs of the same patient. “These functional polyester nanoparticles provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies,” says co-author Dr. John Minna, Professor and Director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research, and Director of the W.A. “Tex” and Deborah Moncrief Jr. Center for Cancer Genetics at UT Southwestern. The researchers developed new chemical reactions to create a diverse library of polymers that could deliver nucleic acid drugs while possessing enough structural diversity to discover cancer cell-specific nanoparticles. This is an important step to improving tailored cancer therapies to an individual’s specific genetic makeup. “The ability to specifically target cancer cells using nanoparticles could alter how we administer drugs to patients,” says Minna, Professor of Pharmacology and Internal Medicine, and with Simmons Cancer Center, who holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research, and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology. “It is already possible to use genetic sequencing to customize drug regimens for each patient. We may also be able to customize the drug carrier to predictably improve patient responses.” Nanoparticles are tiny spheres (1,000 times smaller than the width of a human hair) that can improve the solubility and delivery of drugs to cells. In this study, Cancer Center researchers delivered short interfering RNA (siRNA)-based drugs to disrupt the functioning and growth of tumor cells by eliminating the proteins the cells need to survive. Amazingly, the cancer selective nanoparticles stayed inside of tumors in mice for more than one week, while nonselective control nanoparticles were cleared within a few hours. This translated to improved siRNA-mediated cancer cell death and significant suppression of tumor growth. Support for this latest research came from the Cancer Prevention and Research Institute of Texas (CPRIT), Welch Foundation, American Cancer Society, UTSW’s Friends of the Comprehensive Cancer Center, the UTSW Translational Pilot Program, and the NIH National Cancer Institute SPORE grant in Lung Cancer. The Special Program of Research Excellence (SPORE) in Lung Cancer program, now in its 18th year, is the largest thoracic oncology effort in the U.S. Other UT Southwestern researchers involved in the study are Research Scientists Dr. Yunfeng Yan and Dr. Kenneth Huffman; Postdoctoral Researchers Dr. Hu Xiong and Dr. Petra Kos; Graduate Student Researchers Jason Miller and Sussana Elkassih with the UT Graduate School of Biomedical Sciences; Dr. James Kim, Assistant Professor of Internal Medicine and with the Hamon Center for Therapeutic Oncology Research; Dr. Li Liu, Assistant Professor of Radiology; Dr. Kejin Zhou, Assistant Instructor with Simmons Cancer Center; and researchers Dr. Ryan Carstens and John Norman. 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.

News Article | December 6, 2016
Site: www.eurekalert.org

DALLAS - Dec. 6, 2016 - Researchers at UT Southwestern Medical Center have found a new biomarker for glioma, a common type of brain cancer, that can help doctors determine how aggressive a cancer is and that could eventually help determine the best course of treatment. Researchers from the Harold C. Simmons Comprehensive Cancer Center found that high expression of a gene called SHOX2 predicted poor survival in intermediate grade gliomas. "As an independent biomarker, SHOX2 expression is as potent as the currently best and widely used marker known as IDH mutations," said Dr. Adi Gazdar, Professor of Pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology and a member of the Simmons Cancer Center. According to the National Cancer Institute, cancers of the brain and nervous system affect nearly 24,000 people annually. In 2013, there were an estimated 152,751 people living with brain and other nervous system cancer in the United States. The overall 5-year survival rate is 33.8 percent. Knowing the probable survival status of an individual patient may help physicians choose the best treatment. In combination with IDH mutations or several other biomarkers, SHOX2 expression helped to identify subgroups of patients with a good prognosis even though other biomarkers had predicted a bad prognosis. "Our findings are based on analysis of previously published studies. They will have to be confirmed in prospective studies, and their clinical contribution and method of use remain to be determined," said Dr. Gazdar, who holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research. The findings are published in EBiomedicine. This work in brain cancer research is supported by the National Institutes of Health. Long-term goals of Dr. Gazdar's lab are to the determine molecular and genetic basis of human cancers, and to develop molecular insights to provide prognostic and diagnostic therapies in the treatment of human cancers. A former researcher at the National Cancer Institute, Dr. Gazdar's efforts there and at UT Southwestern have resulted in the collection and analysis of more than 2,500 human tumor specimens as well as the establishment of more than 400 lung, breast, ovary, and other types of tumor cell lines. Additional UT Southwestern researchers who contributed to the current study include Dr. Yu-An Zhang, Instructor in the Hamon Center for Therapeutic Oncology Research; Dr. Yunyun Zhou, Computational Biologist in the Department of Clinical Sciences; Dr. Xin Luo, Data Scientist in the Department of Bioinformatics; Dr. Luc Girard, Assistant Professor in the Hamon Center for Therapeutic Oncology Research; and Dr. Guanghua Xiao, Associate Professor in the Department of Clinical Sciences and a member of the Simmons Cancer Center. 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. Generally speaking, gliomas arise due to aberrations in normal brain cells. Depending on the nature of the aberration, the glioma can be fast- , intermediate- or slow-growing. Gliomas do not metastasize or travel to other parts of the body. Patients with gliomas commonly present with headaches, seizures, weakness, or vision changes. Decades ago, patients were treated with aggressive regimens that resulted in significant side effects without an improvement in the quantity or quality of life. Today, treatments for gliomas are much more sophisticated. Because scientists have a better understanding of the underlying biology and genetics of gliomas, physicians are able to tailor treatments to maximize effectiveness while minimizing unwanted side effects. 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. .

Du L.,University of Texas Health Science Center at San Antonio | Zhao Z.,University of Texas Health Science Center at San Antonio | Ma X.,University of Texas Health Science Center at San Antonio | Hsiao T.-H.,University of Texas Health Science Center at San Antonio | And 6 more authors.
Oncogene | Year: 2014

The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types. The role of DAB2 in lung tumorigenesis, however, is not fully characterized, and the mechanisms of DAB2 dysregulation in lung cancer are not defined. Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function. We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3′UTR of the DAB2 mRNA. Using in vitro and in vivo approaches, we demonstrate that miR-93 overexpression has an important role in promoting lung cancer cell growth, and that its oncogenic function is primarily mediated by downregulating DAB2 expression. Our clinical investigations further indicate that high tumor levels of miR-93 are correlated with poor survival of lung cancer patients. The correlations of both low DAB2 and high miR-93 expression levels with poor patient survival strongly support the critical role of the miR-93/DAB2 pathway in determining lung cancer progression. © 2014 Macmillan Publishers Limited.

Yang L.,Mayo Medical School | Kwon J.,Mayo Medical School | Popov Y.,Beth Israel Deaconess Medical Center | Gajdos G.B.,Mayo Medical School | And 7 more authors.
Gastroenterology | Year: 2014

Background & Aims Vascular endothelial growth factor (VEGF)-induced angiogenesis is implicated in fibrogenesis and portal hypertension. However, the function of VEGF in fibrosis resolution has not been explored. Methods We developed a cholecystojejunostomy procedure to reconstruct biliary flow after bile duct ligation in C57BL/6 mice to generate a model of fibrosis resolution. These mice were then given injections of VEGF-neutralizing (mcr84) or control antibodies, and other mice received an adenovirus that expressed mouse VEGF or a control vector. The procedure was also performed on macrophage fas-induced apoptosis mice, in which macrophages can be selectively depleted. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, vascular permeability, real-time polymerase chain reaction, and flow cytometry assays. Results VEGF-neutralizing antibodies prevented development of fibrosis but also disrupted hepatic tissue repair and fibrosis resolution. During fibrosis resolution, VEGF inhibition impaired liver sinusoidal permeability, which was associated with reduced monocyte migration, adhesion, and infiltration of fibrotic liver. Scar-associated macrophages contributed to this process by producing the chemokine (C-X-C motif) ligand 9 (CXCL9) and matrix metalloproteinase 13. Resolution of fibrosis was impaired in macrophage fas-induced apoptosis mice but increased after overexpression of CXCL9. Conclusions In a mouse model of liver fibrosis resolution, VEGF promoted fibrogenesis, but was also required for hepatic tissue repair and fibrosis resolution. We observed that VEGF regulates vascular permeability, monocyte infiltration, and scar-associated macrophages function.

Sullivan J.P.,Hamon Center for Therapeutic Oncology Research | Sullivan J.P.,Simmons Comprehensive Cancer Center | Minna J.D.,Hamon Center for Therapeutic Oncology Research | Minna J.D.,Simmons Comprehensive Cancer Center | And 3 more authors.
Cancer and Metastasis Reviews | Year: 2010

The discovery of rare tumor cells with stem cell features first in leukemia and later in solid tumors has emerged as an important area in cancer research. It has been determined that these stem-like tumor cells, termed cancer stem cells, are the primary cellular component within a tumor that drives disease progression and metastasis. In addition to their stem-like ability to self-renew and differentiate, cancer stem cells are also enriched in cells resistant to conventional radiation therapy and to chemotherapy. The immediate implications of this new tumor growth paradigm not only require a re-evaluation of how tumors are initiated, but also on how tumors should be monitored and treated. However, despite the relatively rapid pace of cancer stem cell research in solid tumors such as breast, brain, and colon cancers, similar progress in lung cancer remains hampered in part due to an incomplete understanding of lung epithelial stem cell hierarchy and the complex heterogeneity of the disease. In this review, we provide a critical summary of what is known about the role of normal and malignant lung stem cells in tumor development, the progress in characterizing lung cancer stem cells and the potential for therapeutically targeting pathways of lung cancer stem cell self-renewal. © 2010 Springer Science+Business Media, LLC.

Ou Y.-H.,Southwestern Medical Center | Torres M.,Southwestern Medical Center | Ram R.,Southwestern Medical Center | Formstecher E.,Hybrigenics | And 10 more authors.
Molecular Cell | Year: 2011

The innate immune-signaling kinase, TBK1, couples pathogen surveillance to induction of host defense mechanisms. Pathological activation of TBK1 in cancer can overcome programmed cell death cues, enabling cells to survive oncogenic stress. The mechanistic basis of TBK1 prosurvival signaling, however, has been enigmatic. Here, we show that TBK1 directly activates AKT by phosphorylation of the canonical activation loop and hydrophobic motif sites independently of PDK1 and mTORC2. Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, TBK1 is recruited to the exocyst, where it activates AKT. In cells lacking TBK1, insulin activates AKT normally, but AKT activation by exocyst-dependent mechanisms is impaired. Discovery and characterization of a 6-aminopyrazolopyrimidine derivative, as a selective low-nanomolar TBK1 inhibitor, indicates that this regulatory arm can be pharmacologically perturbed independently of canonical PI3K/PDK1 signaling. Thus, AKT is a direct TBK1 substrate that connects TBK1 to prosurvival signaling. © 2011 Elsevier Inc.

Rivera L.B.,Hamon Center for Therapeutic Oncology Research | Bradshaw A.D.,Medical University of South Carolina | Brekken R.A.,Hamon Center for Therapeutic Oncology Research
Cellular and Molecular Life Sciences | Year: 2011

SPARC is a matricellular protein, able to modulate cell/ECM interactions and influence cell responses to growth factors, and therefore is particularly attuned to contribute to physiological processes involving changes in ECM and cell mobilization. Indeed, the list of biological processes affected by SPARC includes wound healing, tumor progression, bone formation, fibrosis, and angiogenesis. The process of angiogenesis is complex and involves a number of cellular processes such as endothelial cell proliferation, migration, ECM degradation, and synthesis, as well as pericyte recruitment to stabilize nascent vessels. In this review, we will summarize current results that explore the function of SPARC in the regulation of angiogenic events with a particular emphasis on the modulation of growth factor activity by SPARC in the context of blood vessel formation. The primary function of SPARC in angiogenesis remains unclear, as SPARC activity in some circumstances promotes angiogenesis and in others is more consistent with an anti-angiogenic activity. Undoubtedly, the mercurial nature of SPARC belies a redundancy of functional proteins in angiogenesis as well as cell-type-specific activities that alter signal transduction events in response to unique cellular milieus. Nonetheless, the investigation of cellular mechanisms that define functional activities of SPARC continue to contribute novel and exciting paradigms to vascular biology. © 2011 Springer Basel AG.

Ribeiro N.,University of Porto | Sousa S.R.,University of Porto | Sousa S.R.,Polytechnic Institute of Porto | Brekken R.A.,Hamon Center for Therapeutic Oncology Research | Monteiro F.J.,University of Porto
Journal of Cellular Biochemistry | Year: 2014

There is a growing socioeconomic recognition that clinical bone diseases such as bone infections, bone tumors and osteoporotic bone loss mainly associated with ageing, are major issues in today's society. SPARC (secreted protein, acidic and rich in cysteine), a matricellular glycoprotein, may be a promising therapeutic target for preventing or treating bone-related diseases. In fact, SPARC is associated with tissue remodeling, repair, development, cell turnover, bone mineralization and may also participate in growth and progression of tumors, namely cancer-related bone metastasis. Yet, the function of SPARC in such biological processes is poorly understood and controversial. The main objective of this work is to review the current knowledge related to the activity of SPARC in bone remodeling, tumorigenesis, and bone metastasis. Progress in understanding SPARC biology may provide novel strategies for bone regeneration and the development of anti-angiogenic, anti-proliferative, or counter-adhesive treatments specifically against bone metastasis. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

Wang L.,Hamon Center for Therapeutic Oncology Research
Nature communications | Year: 2013

The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance.

Gazdar A.F.,Hamon Center for Therapeutic Oncology Research | Gazdar A.F.,British Columbia Cancer Research Center | Girard L.,Hamon Center for Therapeutic Oncology Research | Lockwood W.W.,British Columbia Cancer Research Center | And 3 more authors.
Journal of the National Cancer Institute | Year: 2010

Lung cancer cell lines have made a substantial contribution to lung cancer translational research and biomedical discovery. A systematic approach to initiating and characterizing cell lines from small cell and non-small cell lung carcinomas has led to the current collection of more than 200 lung cancer cell lines, a number that exceeds those for other common epithelial cancers combined. The ready availability and widespread dissemination of the lines to investigators worldwide have resulted in more than 9000 citations, including multiple examples of important biomedical discoveries. The high (but not perfect) genomic similarities between lung cancer cell lines and the lung tumor type from which they were derived provide evidence of the relevance of their use. However, major problems including misidentification or cell line contamination remain. Ongoing studies and new approaches are expected to reveal the full potential of the lung cancer cell line panel. © 2010 The Author.

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