siRNA-toting nanoparticles inhibit breast cancer metastasis

May 12, 2015, Case Western Reserve University
breast cancer
Mammograms showing a normal breast (left) and a breast with cancer (right). Credit: Public Domain

Researchers at Case Western Reserve University combined finely crafted nanoparticles with one of nature's potent disrupters to prevent the spread of triple-negative breast cancer in mouse models.

The highly aggressive cancer subtype is difficult to manage and, currently, the FDA has no approved targeted treatments. But striking results from a new study, published in the journal Cancer Research make the researchers optimistic they have a potential game-changer for triple negative cancer and more.

"There are multiple targets within a cell," said William Schiemann, professor of oncology at the Case Western Reserve School of Medicine and the Case Comprehensive Cancer Center, and a leader of the research. "With this technology, we can target any gene or any location, for other cancers, more diseases—potentially even immunology-based diseases."

Regular injections of nanoparticles carrying siRNA silenced the gene that regulates expression of the protein β3 integrin. Expression of β3 integrin in the cell-development process called the endothelial-mesenchymal transition (EMT), is essential for the cancer to spread from its primary tumor.

Nearly 15 percent of breast cancers in the United States are triple negative, and the subtype is most prevalent among African-American women in their 20s and 30s

According to the National Cancer Institute, the five-year survival rate for women whose cancer is discovered early and contained to a is 98 percent. But, the survival rate for those diagnosed with distant metastases plummets to less than 25 percent.

To try to tackle metastasis, Schiemann teamed with Zheng-Rong Lu, the M. Frank and Margaret Domiter Rudy Professor of Biomedical Engineering at Case Western Reserve, Jenny Parvani, now a postdoctoral investigator, PhD student Maneesh Gujrati and undergraduate student Margaret Mack.

Lu's lab has been developing lipid-based nanoparticles to deliver medicines to specific targets in the body for a decade. Lipids include fats and oils, but these organic molecules are also building blocks in cell structures and functions.

Schieman's lab investigates ways to manipulate the EMT process. He suggested they target the β3 integrin gene with siRNA, short for small interfering RNA or silencing RNA.

The nanoparticle, which Lu labeled ECO, navigates a number of roadblocks. It crosses the blood-brain barrier, which is key to effective therapy. Metastatic cells from this type of cancer often lodge in the brain.

ECO withstands degradation and remains cloaked from the body's immune system while circulating in the blood. ECO induces endosomes to wrap and transport it inside a cancer cell. The particle's makeup prevents entrapment in the endosomal membrane and digestion by enzyme-packed lysosomes.

The are coated with RGD peptide that draws them to the gene that controls expression of β3 integrin. When attached to the gene, TGF-β, the nanoparticle releases siRNA, which jams the machinery.

The study adds to growing evidence that a lack of β3 integrin stops production of migrating cancer cells.

In this study, five mice with a mouse version of were injected with particles every five days for 14 weeks. Compared to control mice, the treated mice's tumors shrunk significantly, but more importantly, the treatment significantly inhibited metastasis.

Five mice with human triple-negative received the same treatment, which produced the same results.

"The results were really, really surprising," Lu said.

"I was shocked, actually," Schiemann said. "We can do most anything invitro in the lab, but to do this in the live body of a mouse is a huge hurdle to clear."

Four weeks after treatment was stopped, the treated mice remained tumor free while continued to grow in untreated controls.

No significant difference in body weight across treatment groups and controls were found, indicating low toxicity of the treatments.

The researchers are further testing whether the delivery system is safe and seeking grants for dosing experiments and other steps toward clinical trials.

"We're also looking at different genes, different therapies and more delivery platforms," Lu said.

Explore further: Even low-androgen triple-negative breast cancer responds to anti-androgen therapy

Related Stories

Even low-androgen triple-negative breast cancer responds to anti-androgen therapy

February 24, 2015
A University of Colorado Cancer Center study published today in the journal Molecular Cancer Therapeutics shows that only about 1 percent of triple-negative breast cancer cells in a tumor must be "androgen-receptor-positive" ...

Molecular signature for outcomes of triple negative breast cancer

April 13, 2015
Compared to other types of breast cancer, triple negative breast cancers are often more aggressive and have fewer treatment options. In a new study published in the journal Proceedings of the National Academy of Sciences ...

Triple negative breast cancer in African-American women has distinct difference

April 22, 2015
What makes triple negative breast cancer more lethal in African American women than White women or women of European descent? A new study reveals specific genetic alterations that appears to impact their prognosis and ultimately ...

Toxic mushroom-based drug may help battle colorectal cancer

April 22, 2015
For some time, cancer scientists have considered the toxin, alpha-amanatin derived from "death cap" mushrooms, as a possible cancer treatment. However, due to its penchant for causing liver toxicity, its potential as an effective ...

Novel breast cancer gene found

January 9, 2015
A new study identifies a gene that is especially active in aggressive subtypes of breast cancer. The research suggests that an overactive BCL11A gene drives triple-negative breast cancer development and progression.

Integrin cell adhesion receptors are risky cancer drug targets

February 11, 2014
A possible cancer treatment strategy might in fact lead to increased metastasis in some cases. This finding from a team of LACDR researchers led by Erik Danen made the cover of the February 11 edition of Science Signaling.

Recommended for you

Daily low-dose aspirin may be weapon against ovarian cancer

July 20, 2018
(HealthDay)— One low-dose aspirin a day could help women avoid ovarian cancer or boost their survival should it develop, two new studies suggest.

Discovery of kidney cancer driver could lead to new treatment strategy

July 19, 2018
University of North Carolina Lineberger Comprehensive Cancer Center scientists have uncovered a potential therapeutic target for kidney cancers that have a common genetic change. Scientists have known this genetic change ...

Sunscreen reduces melanoma risk by 40 per cent in young people

July 19, 2018
A world-first study led by University of Sydney has found that Australians aged 18-40 years who were regular users of sunscreen in childhood reduced their risk of developing melanoma by 40 percent, compared to those who rarely ...

Analysis of prostate tumors reveals clues to cancer's aggressiveness

July 19, 2018
Using genetic sequencing, scientists have revealed the complete DNA makeup of more than 100 aggressive prostate tumors, pinpointing important genetic errors these deadly tumors have in common. The study lays the foundation ...

Complementary medicine for cancer can decrease survival

July 19, 2018
People who received complementary therapy for curable cancers were more likely to refuse at least one component of their conventional cancer treatment, and were more likely to die as a result, according to researchers from ...

Overcoming resistance to a standard chemotherapy drug

July 19, 2018
Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works. Researchers at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.