Scientists at City of Hope and UCLA stop tumor growth with nanoparticles

July 28, 2015 | by Chase Doyle

 

Carlotta Glackin lab Scientists in the lab of Carlotta Glackin, second from right, have taken the first step in developing a potential new therapy for some of the deadliest cancers. Even more remarkable, they’ve done so with a novel, nondrug delivery approach.

 

Scientists at City of Hope and UCLA have become the first to inhibit the expression of a protein, called TWIST that promotes tumor invasion and metastasis when activated by cancer cells. As such, they’ve taken the first step in developing a potential new therapy for some of the deadliest cancers, including ovarian cancer and melanoma.

 

Carlotta Glackin Researcher Carlotta Glackin is known as the "mother of TWIST," for her role in isolating the gene responsible for the protein's production.

 

Perhaps even more remarkable, they’ve done so with a novel, nondrug delivery approach.

Using extremely small particles, called nanoparticles, of coated silica, the researchers successfully delivered a nucleic acid known as small interfering RNA (siRNA) into tumor cells of mice. The result was a dampening of TWIST’s action – and a dramatic reduction in tumor size.

“Not only did we reduce the size of the tumors,” said Carlotta Glackin, Ph.D., associate professor of neurosciences at City of Hope, “but we also inhibited angiogenesis, which is the formation of blood vessels inside the tumor … And we didn’t even use a drug.{C}

Glackin, the so-called “mother of Twist,” first isolated the gene responsible for its production in 1990 during her postdoctoral studies at Caltech and has been working with the protein ever since. Having originally studied its function in normal development – TWIST regulates genes involved in embryo formation and initiates the growth of the skeleton – Glackin was encouraged by colleagues at City of Hope to explore its role in cancer.  What she found, in just about every cancer examined, was TWIST driving the disease’s deadliest features – tumor growth, metastasis, recurrence and drug resistance.

Discovery of protein's role was just the beginning

Although identifying TWIST’s pathological function was a major step forward, shutting off the protein in cancer cells proved a different challenge altogether.

“TWIST is a transcription factor,” Glackin explained, “which means it acts on genes inside the nucleus … Most therapies, however, only target the outside membrane of the cell. Since TWIST is on the inside of the cell, we needed to find a way to get the therapeutics inside the cell for them to work.”

 

Jeffrey Zink of UCLA Jeffrey Zink of the California NanoSystems Institute and Jonsson Comprehensive Cancer Center at UCLA was a co-leader of the study.

 

The researchers’ solution was a nanoparticle delivery system developed by Jeffrey Zink, Ph.D., in collaboration with Fuyu Tamanoi, Ph.D., both from the California NanoSystems Institute and Jonsson Comprehensive Cancer Center at UCLA. That delivery system relies on nanoparticles coated with a highly-charged layer of polymer, specifically polyethyleneimine. This surface layer enables binding and protecting siRNA from degradation. When injected into the bloodstream, those particles, due to their small size, escape the blood stream and enter the tumor tissue, where they become trapped. There, the siRNA inhibits the cells’ expression of TWIST.

According to results of the eight-week study, weekly intravenous injections of the siRNA-nanoparticle combination decreased tumor size in mice, shutting down not only the TWIST gene but other genes involved in cancer progression.

The treatment also led to an unexpected effect on blood vessel growth around the tumors.

“We knew that turning off TWIST inhibited angiogenesis,” said Glackin, “but we didn’t know that it would prevent the whole process from starting in the first place … The results were very, very surprising to me.”

Because TWIST plays a significant role in resistance to chemotherapy, its inhibition also creates cells that are more susceptible to traditional therapies. The addition of chemotherapy to the nanoparticle treatment could thus result in more pronounced tumor reduction.

“The interesting part about the anti-TWIST therapy,” Glackin said, “is that it takes tumor cells that are drug-resistant and makes them sensitive to that drug again. I see it being used in conjunction with therapies to keep the tumors sensitized to the therapy as long as possible. I also see it as a therapy that will reduce the existence of metastasis ... If we used this therapy and combined it with the drug, we would have gotten rid of the tumors completely.”

 

Fuyu Tamanoi Fuyu Tamanoi of the California NanoSystems Institute and Jonsson Comprehensive Cancer Center at UCLA was a co-leader of the study.

 

Next step: Testing against ovarian cancer

The next step for researchers at City of Hope and UCLA is to combine the therapy with cancer-drug molecules in the same nanoparticles using breast models and start testing this treatment regimen on ovarian cancer.

“We want to do it for ovarian cancer because it’s the most drug-resistant of all cancers and often is diagnosed late,” said Glackin. “If this therapy works in ovarian cancer, I think that will be our first trial.”

Glackin stressed that this research could not have been accomplished without the contributions of her colleagues.

“Every single component was vital,” she concluded. “This collaboration was truly meant to be.”

Jeffrey Zink and Fuyu Tamanoi, both members of the California NanoSystems Institute and Jonsson Comprehensive Cancer Center at UCLA, were co-leaders of the study with Glackin. Other authors included City of Hope graduate students James Finlay and Cai Roberts, and UCLA graduate student Juyao Dong.

The study was published online in the journal Nanomedicine: Nanotechnology, Biology, and Medicine.

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Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant numbers P30CA33572 and CA133697. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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