Gene Therapy Technique May Help To Prevent Cancer Metastasis

Progress in combating breast cancer has continued to flourish over the past several decades, and scientists are relentlessly developing novel therapies that increase remission and overall survival rates. Yet, controlling the spread of malignant cells from the primary tumor to other sites within the body—commonly known as metastasis—is an area of cancer biology that has stonewalled researchers and is the leading cause of mortality in women with breast cancer.

Investigators from MIT have now developed a new gene therapy technique that is showing promise as a way to prevent breast cancer tumors from metastasizing. In the new study, researchers describe the use of microRNAs (miRNAs)—small noncoding RNA molecules that regulate gene expression—to prevent metastasis.

The MIT team is optimistic that their newly developed therapy could be used alongside chemotherapy to treat early-stage breast cancer tumors before they spread.

“The idea is that if the cancer is diagnosed early enough, then in addition to treating the primary tumor [with chemotherapy], one could also treat with specific miRNAs, to prevent the spread of cancer cells that cause metastasis,” explained senior study investigator Natalie Artzi, Ph.D., assistant professor at Brigham and Women’s Hospital, Harvard Medical School and principal research scientist at the Institute for Medical Engineering and Science at MIT (IMES).

The regulation of gene expression by miRNAs is known to be important in preventing the spread of cancer cells. Previous studies have shown that disruption of this regulation, for example, by genetic variants known as single-nucleotide polymorphisms (SNPs), can have a significant impact on gene expression levels and lead to an increase in the risk of cancer.

To identify the specific miRNAs that play a role in breast cancer progression and could therefore potentially be used to suppress metastasis, the researchers first carried out an extensive bioinformatics analysis. They compared three datasets: one for known SNPs, a second for sites at which miRNAs bind to the genome, and a third for breast cancer-related genes known to be associated with the movement of cells.

The team’s analysis revealed an SNP, known as rs1071738, which influences metastasis. They found that this SNP disrupts binding of two miRNAs, miR-96 and miR-182. This disruption, in turn, prevents the two miRNAs from controlling the expression of a protein called Palladin.

The findings from this study were published recently in Nature Communications in an article entitled “Local MicroRNA Delivery Targets Palladin and Prevents Metastatic Breast Cancer.”

Interestingly, when the researchers carried out in vitro experiments, they found that applying miR-96 and miR-182 decreased the expression of Palladin levels, in turn reducing the ability of breast cancer cells to migrate and invade other tissue.

“Previous research had discussed the role of Palladin in controlling migration and invasion (of cancer cells), but no one had tried to use miRNAs to silence those specific targets and prevent metastasis,” Dr. Artzi noted. “In this way, we were able to pinpoint the critical role of these miRNAs in stopping the spread of breast cancer.”

The researchers subsequently developed a method to deliver engineered miRNAs to breast cancer tumors. They embedded nanoparticles containing the miRNAs into a hydrogel scaffold, which they then implanted into mice. What they found was that this allowed efficient and precise delivery of the miRNAs to a target breast cancer tumor site—resulting in a dramatic reduction in breast cancer metastasis.

“We can locally change the cells to prevent metastasis from occurring,” Dr. Artzi remarked. “We believe local delivery is much more effective (than systemic treatment) because it gives us a much higher effective dose of the cargo, in this case, the two miRNAs and the cisplatin.”

To increase the effectiveness of the treatment even further, the researchers added the chemotherapy drug cisplatin to the nanoparticles. This led to a significant reduction in both the growth of the primary tumor and its metastasis.

“This research offers the potential for combined experimental therapeutics with traditional chemotherapy in cancer metastasis,” commented Julie Teruya-Feldstein, M.D., professor of pathology at Mount Sinai Hospital in New York, who was not involved in the study.

The research team is enthusiastic about their current findings and is looking to further extend their analysis.

“We are very excited about the results so far, and the efficacy seems to be really good. So the next step will be to move on to larger models and then to clinical trials, although there is still a long way to go,” Dr. Artzi concluded.