Newswise — DALLAS – Nov. 23, 2016 – UT Southwestern Medical Center researchers recently received $5.8 million in support from the Cancer Prevention and Research Institute of Texas (CPRIT). The funding will allow UT Southwestern researchers to:

Understand how melanoma spreads through the bodyInvestigate the life cycle of cancer cells and how they ariseDiscover new treatments for germ cell cancers in childrenPredict nuclear export signals in proteinsThis amount also includes $2 million in recruitment grants to help UT Southwestern attract new cancer researchers. UT Southwestern currently has 34 cancer researchers who have been recruited to Texas and UT Southwestern with assistance from CPRIT funding.

Cumulatively, UT Southwestern researchers have been awarded nearly $337 million from CPRIT, including the latest awards, which have helped attract additional awards in basic science research, translational research, and outreach and prevention programs.

“Breakthroughs in cancer treatment are frequently born from basic research into the origins, development, and metastasis of cancer cells,” said Dr. Melanie Cobb, Interim Director of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, Professor of Pharmacology, and holder of the Jane and Bill Browning, Jr. Chair in Medical Science. “The extraordinary support we have received from CPRIT makes it possible for our researchers to focus on cracking the code of cancer, ultimately leading to better care for cancer patients.”

To date, CPRIT has awarded $1.67 billion in grants to Texas researchers, institutions and organizations. The agency began making awards in 2009 after Texas voters overwhelmingly approved a 2007 constitutional amendment committing $3 billion to the fight against cancer.

CPRIT provides funding through its academic research, prevention, and product development research programs. Programs made possible with CPRIT funding have reached all 254 counties of the state, brought more than 129 distinguished researchers to Texas, advanced scientific and clinical knowledge, and provided more than 3 million lifesaving education, training, prevention, and early detection services to Texans, according to CPRIT.

Awards to UT Southwestern researchers were:

Individual Investigator Awards

Dr. Sean Morrison, Professor of Pediatrics and Director of the Children’s Medical Center Research Institute at UT Southwestern. He holds the Mary McDermott Cook Chair in Pediatric Genetics as well as the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern. He also is an Investigator of the Howard Hughes Medical Institute.

Mechanisms of melanoma metastasis - $892,521Dr. Qing Zhong, Associate Professor of Internal Medicine and Biochemistry

Primary Cilia in Cell Cycle Control and Tumorigenesis - $900,000Individual Investigator Research Awards for Cancer in Children and Adolescents

Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine. He holds the Nearburg Family Professorship in Pediatric Oncology Research and is a Horchow Family Scholar in Pediatrics.

Targeting the HNF4A and WNT/beta-catenin pathways in childhood malignant yolk sac tumors - $1,169,499Individual Investigator Research Awards for Computational Biology

Dr. Nick Grishin, Professor of Biophysics and Biochemistry, an Investigator of the Howard Hughes Medical Institute and a Virginia Murchison Linthicum Scholar in Biomedical Research; and Dr. Yuh Min Chook, Professor of Pharmacology and Biophysics. Dr. Chook is a Eugene McDermott Scholar in Medical Research.

Prediction of nuclear export signals in proteins - $844,989The 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.

About UT Southwestern Medical Center

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.

UT Southwestern Medical Center Project Summaries for CPRIT Awards

Individual Investigator Award: Dr. Sean Morrison

Most cancer deaths are the result of tumor metastasis, in which cancer cells spread to other sites in the body. The molecular mechanisms that allow cancer cells to spread are complex and poorly understood. Dr. Morrison, Director of the Children’s Medical Center Research Institute at UT Southwestern (CRI), aims to change this situation using funding from the CPRIT award to study mechanisms of melanoma metastasis.

Dr. Morrison’s research will build on earlier work that found metastasis of human melanoma cells to be limited by oxidative stress, caused by the generation inside cancer cells of highly toxic reactive molecules known as reactive oxygen species. Most melanoma cells that enter the blood die from oxidative stress. Dr. Morrison believes the rare melanoma cells that survive during metastasis undergo specific metabolic adaptations that allow them to withstand the oxidative stress.

Increasing our understanding of these mechanisms is crucial to develop new pro-oxidant therapies that could prevent metastasis by exacerbating oxidative stress or by preventing the metabolic adaptations used by cancer cells to survive during metastasis. This work represents a fundamental shift in strategy away from the use of anti-oxidants for cancer therapy, which appear to promote cancer cell survival and which have been shown in clinical trials to promote cancer progression.

Individual Investigator Award: Dr. Qing Zhong

Primary cilium, an unappreciated cell organelle that acts as an antenna for a cell to receive signals from the environment, is frequently lost in many types of cancer cells – including breast, prostate, kidney, and pancreatic cancers. It is not clear whether this loss is caused by cancer or possibly a driving event in tumor initiation and progression. Primary ciliogenesis is often associated with exit from the cell cycle to quiescence. The causal relationship of these two events is not determined yet.

The Zhong laboratory recently discovered a powerful ciliogenesis “rewiring” system. By suppressing the expression of a key inhibitor of ciliogenesis, primary cilia formation is robustly promoted, which correlates with exit from the cell cycle to quiescence in normal human cells. Interestingly, this cell cycle arrest effect is largely abolished by oncogene activation in human cancer cells. Dr. Zhong proposes that primary cilia and their associated structures likely elicit a previously undescribed cell cycle checkpoint that is disrupted in cancer cells. This CPRIT-supported project will dissect the detailed mechanism of this signaling pathway and its crucial function in tumor initiation and progression.

Individual Investigator Research Award for Cancer in Children and Adolescents: Dr. James Amatruda

Yolk sac tumor (YST) is a cancer of the germ cells, the cells that give rise to the ovary and testis. YST is the most common type of germ cell cancer in children. While most children with YST are cured, about 10 percent will die of the disease. Chemotherapy agents used for treating YST can cause a host of long-term adverse health effects in survivors. Work in the Amatruda laboratory is aimed at developing new treatments that will target the tumors more effectively and specifically, sparing normal tissue.

Recently, the laboratory studied the DNA genome of YSTs and discovered that the tumors commonly have alterations in two cellular growth-promoting pathways. This finding suggests that inappropriate activity of these pathways “reprograms” a normal developing germ cell into a cancer cell. The goal of this CPRIT-supported project is to identify and test new types of treatments that interfere with this process and thereby prevent the growth of yolk sac tumors – without the side effects of current treatments.

Individual Investigator Research Awards for Computational Biology: Dr. Nick Grishin and Dr. Yuh Min Chook

The goal of this research is to efficiently find proteins that are being carried out of the nucleus of a cell into its cytoplasm (i.e., “exported”) by an exporter protein called CRM1. This research will develop a computer program that, taking a protein sequence as input, predicts whether this protein is exported by CRM1, and evaluates the energy of binding between the candidate cargo protein and CRM1.

The major challenge is to design a mathematical formula to compute this energy accurately. To devise the formula, Drs. Grishin and Chook will use amino acid sequences of known cargo proteins and 3-D structures of complexes between CRM1 and its cargoes (obtained by the Chook Lab). The values of parameters in the formula will be optimized to distinguish between proteins that bind to CRM1 and those that do not. Using this program, the researchers will identify proteins that are predicted to bind CRM1. The team will validate cancer-relevant predictions experimentally by making these proteins and measuring their binding to CRM1. The program can also be used to design CRM1 inhibitors.

The CRM1 cargo-prediction program will allow oncologists and cancer biologists to predict candidate cargoes for further testing, and to determine which proteins are key for cancer progression and cancer cell death when treated with anti-CRM1 drugs.

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