Novel gene-silencing nanoparticles shown to inhibit Ewing's sarcoma

A novel delivery system that transports gene silencing nanoparticles into tumor cells has been shown to inhibit Ewing's sarcoma in an animal model of the disease.
In this classic "Trojan horse" approach, a protein called transferrin that normally delivers iron into cells is modified to also smuggle into tumor cells siRNA (short interfering RNA) encased in nano-sized sugar polymers. The siRNA was designed to target a specific growth-promoting gene called EWS-FLI1 that's active only in Ewing's sarcoma tumors.

Once inside these cells, the genetic machinery of the tumor cells are effectively silenced or shut down, preventing further growth.

"This is the first study to show that systemic administration of siRNA can inhibit disseminated tumor growth," said Siwen Hu, a postdoctoral fellow at Children's Hospital of Los Angeles and the University of Southern California, and one of the study's lead investigators.

"We conclude that this novel delivery system is a powerful and simple method to induce gene silencing, with the potential to move to clinical trials," said Hu, who presented the results at the 96th Annual Meeting here of the American Association for Cancer Research.

In recent years, scientists have been intrigued by the potential of siRNA to block the activity of genes that promote the growth of tumors. Harnessing the power of this new technology, however, has proved daunting for a variety of reasons, including the ability to deliver these bits of genetic material in high concentrations to specific tumor sites, while avoiding degradation.

To overcome these hurdles, the scientists employed a sugar-containing polymer invented by chemical engineers at the California Institute of Technology. For this experiment, the polymer binds to and condenses the engineered siRNA into nanoparticles that, in effect, form a protective shield around their precious genetic cargo. These nanoparticles, in turn, are attached to transferrin, a protein that typically carries iron molecules through the bloodstream until it meets up with a transferrin receptor on the surface of another cell. The transferrin binds tightly to a receptor on the cell's surface, where it is drawn inside and surrounded by a small vesicle. The vessels are acidified, causing the nanoparticles to release its contents – the siRNA.

"Since transferrin receptors are upregulated in tumor cells, this delivery system will home in on tumor cells, leaving normal cells in tact," Hu said.

To test their new delivery system, the scientists targeted tumor cells from the patients of Ewing's sarcoma, a rare and often deadly bone cancer that generally strikes young adults. Despite aggressive therapy, about 40 percent of patients with Ewing's family tumors and 95 percent with metastases die as a result of their disease.

Scientists now recognize that Ewing's sarcoma results when two chromosomes break and trade their genetic content in what's technically called a "translocation," activating the oncogene EWS-FLI1 which triggers the tumor growth characteristic for this cancer.

In their experiment, siRNA was delivered to this growth-promoting region of the tumor cell, effectively reducing cell replication by 80 percent.

The scientists then tried their novel technology in laboratory mice grafted with human Ewing's sarcoma tumors. Following three consecutive days of treatment, the scientists observed strong, but transient, inhibition of tumor growth.

However, when used over longer durations (twice-weekly injections up to four weeks), the results were striking.

"Long-term treatments with this delivery system markedly inhibited tumor growth, with little or no tumor growth in many animals," said Hu.

Future experiments will combine the novel delivery system with small molecular anti-tumor agents, with hopes of creating a new and effective way to treat Ewing's sarcoma and other tumors in the clinic.

"Clinically, Ewing's patients are treated with combination of chemotherapeutic agents, but despite aggressive treatments, the patient outcomes are poor," said Hu.

"The delivery system we're developing can shield the drugs from degradation before reaching the target sites, while delivering siRNA for more specificity and potency so as to lower the required dose for efficacy."

The study was a collaborative effort between the laboratory of Timothy J. Triche, at Children's Hospital of Los Angeles; and the laboratory of Mark E. Davis, at the Caltech. Also participating in the study were Jeremy D. Heidel and Derek W. Barlett, both at Caltech.

Support for this research came from the Las Madrinas endowment in Molecular Genetics and Molecular Pathology at the Children's Hospital of Los Angeles, the Whitaker Foundation, with the National Science Foundation funding part of the work at Caltech.

Source: American Association for Cancer Research

Related stories:

Argonne wins four R&D 100 Awards
Advances in technology ranging from help for victims of Parkinson's disease and epilepsy to more efficient combustion in industrial furnaces are likely with award-winning research at the U.S. Department of Energy's Argonne National Laboratory and its partners.
Argonne's research accomplishments have won four of the prestigious R&D 100 Awards, given to the world's top 100 scientific and technological innovations. This is the second year in a row that Argonne has won four R&D 100 Awards.
Forsyth scientists trigger cancer-like response from embryonic stem cells
Scientists from The Forsyth Institute, working with collaborators at Tufts and Tuebingen Universities, have discovered a new control over embryonic stem cells' behavior. The researchers disrupted a natural bioelectrical mechanism within frog embryonic stem cells and trigged a cancer-like response, including increased cell growth, change in cell shape, and invasion of the major body organs. This research shows that electrical signals are a powerful control mechanism that can be used to modulate cell behavior.
Doctors warn patients of HPV link to oral cancer
Ten years ago, most of Dr. Brian Nussenbaum's oral cancer patients were men over 60 who used tobacco and drank heavily. Today, his patients with oral cancer look different. And so does the risky behavior that seems to be leading to their cancer.
Scientists develop new cancer-killing compound from salad plant
(PhysOrg.com) -- Researchers at the University of Washington have updated a traditional Chinese medicine to create a compound that is more than 1,200 times more specific in killing certain kinds of cancer cells than currently available drugs, heralding the possibility of a more effective chemotherapy drug with minimal side effects.
Researcher Looks For Better Way to Kill Cancer Cells
Physics Professor Diandra Leslie-Pelecky brought more with her when she arrived at UT Dallas than expertise in nanotechnology and shiny behemoth lab equipment. She brought an award for $84,000 from the National Institutes of Health via the Cleveland Clinic.
A link between mitochondria and tumor formation in stem cells
Researchers report on a previously unknown relationship between stem cell potency and the metabolic rate of their mitochondria –a cell's energy makers. Stem cells with more active mitochondria also have a greater capacity to differentiate and are more likely to form tumors.
New findings may improve treatment of inherited breast cancer
Scientists have identified some of the elusive downstream molecules that play a critical role in the development and progression of familial breast cancer. The research, published by Cell Press in the October 10th issue of the journal Molecular Cell, also identifies a compound found in grapes and red wine as an excellent candidate for treatment of some forms of breast cancer.
Research team solves structure of 'beneficial' virus
The 3-D structure of the virus, known as Seneca Valley Virus-001, reveals that it is unlike any other known member of the Picornaviridae viral family, and confirms its recent designation as a separate genus "Senecavirus." The new study reveals that the virus's outer protein shell looks like a craggy golf ball -- one with uneven divets and raised spikes—and the RNA strand beneath it is arranged in a round mesh rather like a whiffleball.

News discussion:

Nanotechnology news