Hamon Center for Therapeutic Oncology

Dallas, TX, United States

Hamon Center for Therapeutic Oncology

Dallas, TX, United States
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Kim J.,Children's Medical Center Dallas | Hu Z.,Children's Medical Center Dallas | Cai L.,Children's Medical Center Dallas | Li K.,Children's Medical Center Dallas | And 24 more authors.
Nature | Year: 2017

Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.

Richardson J.A.,CSIC - Biological Research Center | Xie X.-J.,Simmons Comprehensive Cancer Center | Gazdar A.F.,Hamon Center for Therapeutic Oncology | Girard L.,Simmons Comprehensive Cancer Center | And 5 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Carcinogenesis is an adaptive process between nascent tumor cells and their microenvironment, including the modification of inflammatory responses from antitumorigenic to protumorigenic. Radiation exposure can stimulate inflammatory responses that inhibit or promote carcinogenesis. The purpose of this study is to determine the impact of radiation exposure on lung cancer progression in vivo and assess the relevance of this knowledge to human carcinogenesis. Experimental Design: K-rasLA1 mice were irradiated with various doses and dose regimens and then monitored until death. Microarray analyses were performed using Illumina BeadChips on whole lung tissue 70 days after irradiation with a fractionated or acute dose of radiation and compared with age-matched unirradiated controls. Unique group classifiers were derived by comparative genomic analysis of three experimental cohorts. Survival analyses were performed using principal component analysis and k-means clustering on three lung adenocarcinoma, three breast adenocarcinoma, and two lung squamous carcinoma annotated microarray datasets. Results: Radiation exposure accelerates lung cancer progression in the K-rasLA1 lung cancer mouse model with dose fractionation being more permissive for cancer progression. A nonrandom inflammatory signature associated with this progression was elicited from whole lung tissue containing only benign lesions and predicts human lung and breast cancer patient survival across multiple datasets. Immunohistochemical analyses suggest that tumor cells drive predictive signature. Conclusions: These results demonstrate that radiation exposure can cooperate with benign lesions in a transgenic model of cancer by affecting inflammatory pathways, and that clinically relevant similarities exist between human lung and breast carcinogenesis. © 2014 American Association for Cancer Research.

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. .

Ishizumi T.,Tokyo Medical University | McWilliams A.,British Columbia Cancer Agency | MacAulay C.,British Columbia Cancer Agency | Gazdar A.,Hamon Center for Therapeutic Oncology | And 2 more authors.
Cancer and Metastasis Reviews | Year: 2010

Preinvasive bronchial lesions defined as dysplasia and carcinoma in situ (CIS) have been considered as precursors of squamous cell carcinoma of the lung. The risk and rate of progression of preinvasive lesions to invasive squamous cell carcinoma as well as the mechanism of progression or regression are incompletely understood. While the evidence for the multistage, stepwise progression model is weak with relatively few documented lesions that progress through various grades of dysplasia to CIS and then to invasive carcinoma, the concept of field carcinogenesis is strongly supported. The presence of high-grade dysplasia or CIS is a risk marker for lung cancer both in the central airways and peripheral lung. Genetic alterations such as loss of heterozygosity in chromosome 3p or chromosomal aneusomy as well as host factors such as the inflammatory load and levels of anti-inflammatory proteins in the lung influence the progression or regression of preinvasive lesions. CIS is different than severe dysplasia at the molecular level and has different clinical outcome. Molecular analysis of dysplastic lesions that progress to CIS or invasive cancer and rare lesions that progress rapidly from hyperplasia or metaplasia to CIS or invasive cancer will shed light on the key molecular determinants driving development to an invasive phenotype versus those associated with tobacco smoke damage. © 2010 Springer Science+Business Media, LLC.

Kaisani A.,Southwestern Medical Center | Delgado O.,Southwestern Medical Center | Fasciani G.,Southwestern Medical Center | Kim S.B.,Southwestern Medical Center | And 5 more authors.
Differentiation | Year: 2014

While mouse models have contributed in our understanding of lung development, repair and regeneration, inherent differences between the murine and human airways requires the development of new models using human airway epithelial cells. In this study, we describe a three-dimensional model system using human bronchial epithelial cells (HBECs) cultured on reconstituted basement membrane. HBECs form complex budding and branching structures on reconstituted basement membrane when co-cultured with human lung fetal fibroblasts. These structures are reminiscent of the branching epithelia during lung development. The HBECs also retain markers indicative of epithelial cell types from both the central and distal airways suggesting their multipotent potential. In addition, we illustrate how the model can be utilized to understand respiratory diseases such as lung cancer. The 3D novel cell culture system recapitulates stromal-epithelial interactions in vitro that can be utilized to understand important aspects of lung development and diseases. © 2014 International Society of Differentiation.

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