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Newswise Bioluminescence, nanoparticles, gene manipulation these sound like the ideas of a science fiction writer, but, in fact, they are components of an exciting new approach to imaging local and metastatic tumors. In preclinical animal models of metastatic prostate cancer, scientists at Virginia Commonwealth University Massey Cancer Center, VCU Institute of Molecular Medicine and Johns Hopkins Medical Institutions have provided proof-of-principle of a new molecular imaging approach that could revolutionize doctors ability to see tumors that have metastasized to other sites in the body, including the bones.

Recently published in the OnlineFirst edition of the journal Cancer Research, a journal of the American Association for Cancer Research, this multiple institution study is the first to develop in vivo (in animal models) a systemically administered, non-invasive, molecular-genetic technique to image bone metastases resulting from prostate cancer. The new method relies on the detection of a gene known as AEG-1, which was originally discovered by the study's co-lead investigator Paul B. Fisher, M.Ph., Ph.D., and has been shown to be expressed in the majority of cancers but not in normal, healthy cells. In preclinical studies, the researchers were able to image bone metastases with greater accuracy than any clinically approved imaging method.

Currently, we do not have a sensitive and specific non-invasive technique to detect bone metastases, so we are very encouraged by the results of this study says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at the VCU School of Medicine and director of the VCU Institute of Molecular Medicine. Additionally, because AEG-1 is expressed in the majority of cancers, this research could potentially lead to earlier detection and treatment of metastases originating from a variety of cancer types.

Imaging the expression of a gene in real time is not an easy task. To do it, the scientists used a promoter called AEG-Prom. A promoter is a set of chemical instructions coded in DNA that initiates activity in a gene. The team combined AEG-Prom with imaging agents consisting of a gene that produces firefly luciferase, the bioluminescent substance that makes fireflies glow, and a gene called HSV1tk, which initiates a chemical reaction when specific radioactive compounds are administered. The team then inserted the combination into tiny nanoparticles that are injected intravenously. When exposed to specific proteins that activate the AEG-Prom, including the c-MYC protein that is elevated in many cancer cells, the AEG-Prom initiates activity in the imaging agent, and the location of cancer cells expressing the imaging agent are made visible using sensitive imaging devices.

"The imaging agents and nanoparticle used in this study have already been tested in unrelated clinical trials. Moving this concept into the clinic to image metastasis in patients is the next logical step in the evolution of this research," says co-lead author Martin G. Pomper, M.D., Ph.D., William R. Brody Professor of Radiology at Johns Hopkins Medical Institutions. "My colleagues and I are working toward this goal, and we look forward to opening a study to deploy this technology as soon as possible."

Fisher and Pomper are pioneering the use of cancer-specific and cancer-selective gene promoters to image cancer. Previous studies in melanoma and breast cancer leveraged another gene originally discovered by Fisher called progression elevated gene-3 (PEG-3) using a promoter known as PEG-Prom. In addition to imaging, this approach could also be used to deliver therapeutic agents, such as targeted therapies, directly to local and distant tumors sites and allow physicians to monitor drug delivery in real time. Separate studies are currently under way to examine the therapeutic potential of this strategy.

Fisher and Pomper collaborated on this research with Siddik Sarkar, Ph.D., postdoctoral research scientist in the Department of Human and Molecular Genetics at the VCU School of Medicine, as well as Akrita Bhatnagar, Ph.D., Yuchuan Wang, Ph.D., Ronnie C. Mease, Ph.D., Matthew Gabrielson, M.D., Polina Sysa, M.D., lL Minn, Ph.D., Gilbert Green, Brian Simmons, Ph.D., and Kathleen Gabrielson, D.V.M., Ph.D., all from Johns Hopkins Medical Institutions.

This study was supported by National Cancer Institute grant CA151838, the Prostate Cancer Foundation, the Patrick C. Walsh Foundation, the National Foundation for Cancer Research and, in part, by VCU Massey Cancer Centers NIH-NCI Cancer Center Support Grant P30 CA016059.

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New Non-Invasive Technique Could Revolutionize the Imaging of Metastatic Cancer

Mutations in the human retinoblastoma protein gene are a leading cause of eye cancer. Now, Michigan State University scientists have turned to fruit fly eyes to unlock the secrets of this important cancer gene.

In a paper featured on the cover of the current issue of the Journal of Biological Chemistry, Michigan State University researchers provide the first detailed examination of a set of mutations similar to those present in the human cancer gene, said Irina Pushel, MSU undergraduate and co-author.

"By systematically evaluating mutations of increasing severity, we now have a model to better predict how we think the protein will react with each mutation," said Pushel, who co-authored the paper with Liang Zhang, lead author and MSU graduate student, and Bill Henry and David Arnosti, MSU molecular biologists. "We're trying to understand the protein, not even in the specific context of cancer, but rather studying how it interacts within the cell, how it interacts with DNA."

The protein, retinoblastoma, would appear to play a key role in everything. When it's healthy, it helps control cell growth and development. If absent, the organism would die. In its abnormal state cells can overgrow, as seen in cancer, or undergo premature death, as in other human diseases.

Since fruit flies are essentially tiny people with wings, in terms of genetics, these model organisms can play a key role in advancing human medicine.

"If we find one of these mutations in a human, then we can predict what will happen with the protein, such as folding incorrectly," Pushel said. "This isn't going to immediately lead to a new drug to treat cancer. However, we have to know how the protein works before we can develop a drug to fix it. Future medicines will be built upon models such as this, though that is years away."

Previous work has shown that a specific part of this protein plays a role in regulating other genes. In this study, the team modified some of the known important parts of this region of retinoblastoma.

Boosting levels of even standard, or wild-type, protein altered fruit flies eyes and wings. However, when levels of the mutated protein began to climb, deformations were consistent and dramatic.

While a cancer treatment based on this finding may be years away, the insight and understanding into cell development and gene regulation is immediate, Pushel said.

"That's the cool thing about basic research; it may not lead directly to the creation of a new drug, but it helps decipher the genetic code, which for each person controls the unique pattern of how they grow and how they develop -- that's amazing," she said. "It will have many impacts, from understanding development to personalized medicine."

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Abnormal properties of cancer protein revealed in fly eyes

Bacteria appear to be having the microbial equivalent of inter-species sex in hospital sinks, swapping chunks of DNA that render them impervious to antibiotics, researchers reported Wednesday.

The findings may help explain the rise in drug-resistant superbugs in hospitals, and they suggest that they may sometimes be breeding on site, as opposed to being carried in by patients.

The team at the National Institutes of Health found carbapenem-resistant Enterobacteriaceae (CRE) that appeared to have exchanged pieces of genetic material called plasmids that gave them resistance to antibiotics. CRE resist most, if not all antibiotics, and they are becoming more common: they are found in about 4 percent of hospitals now and 18 percent of long-term care facilities.

"Over the past decade, there has been a steady and alarming increase in antibiotic-resistant bacteria."

They found the superbugs on patients and in the sinks at the NIH clinical center outside Washington D.C., a large hospital that had a bad outbreak of drug-resistant Klebsiella in 2011 in which 17 patients got badly infected and six died.

They tested all the patients in two wards in 2012 and 2013 - 1,000 in all -- and found 10 patients colonized with CRE. There was clear evidence the germs were getting new plasmids from somewhere. More searching turned them up in sink drains, although theres no direct evidence thats where the patients got them from.

Antibiotic resistance is becoming a huge medical challenge. Antibiotic resistance is caused by resistance genes carried on plasmids, small circles of DNA separate from the chromosomal DNA. Resistance spreads by horizontal gene transfer, in which plasmid genes from a donor bacterial cell spread to a recipient bacterial cell during cell-to-cell contact. When the DNA that is transferred includes antibiotic-resistance genes, the bacterium receiving this DNA becomes antibiotic-resistant too.

It's also not clear where the bacteria are getting the new plasmids, says Julia Segre of the National Human Genome Research Institute, part of NIH.

Bacteria reproduce by splitting in half, but they can also exchange genetic material. This DNA exchange helps them evolve and can help them evolve resistance to antibiotics.

Over the past decade, there has been a steady and alarming increase in antibiotic-resistant bacteria, a trend that poses a serious threat to the U.S. medical system, Segre and colleagues wrote in their report, published in the journal Science Translational Medicine.

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Gene-Swapping Bacteria Are Making New Superbugs