New findings by a multi-institution research team led by the University of Maryland Fischell Department of Bioengineering outline a targeted therapeutic strategy.
to treat triple-negative breast cancer (TNBC) – a potential first for this less common, but particularly aggressive form of breast cancer.
Most breast cancers are fueled by the hormone estrogen, the hormone progesterone, or an excess of a protein called HER2 that in normal amounts actually helps control cell growth. There are specific breast cancer treatments that work by targeting each of these three factors.
However, about 10 to 20 percent of breast cancers are not fueled by any of these three factors and are thus designated as triple-negative breast cancer. There currently are no targeted therapies for triple-negative breast cancer. However, this new UMD-led research proposes a treatment strategy for this type of cancer that is centered on nanotechnology-based precision-targeting of a gene known as POLR2A.
A paper by the group—which in addition to the University of Maryland includes researchers from Ohio State University, Indiana University and the University of Science and Technology of China—is published today in Nature Nanotechnology.
Triple-negative breast cancer (TNBC) does not respond to modern hormonal therapies nor to medicines that target HER2 protein receptors. Thus, most TNBC patients are limited to chemotherapy as their only systemic treatment option.
“Due to the lack of a targeted therapy option, TNBC patients often face a poorer prognosis compared with patients of other types of breast cancer,” said BIOE Professor Xiaoming (Shawn) He, corresponding author of the paper. “While we have seen dramatic advancements in breast cancer treatment in recent decades, TNBC patients are typically treated with conventional chemotherapy that is often associated with adverse side effects, drug resistance, and even cancer relapse or recurrence. Therefore, it is of urgent need to develop targeted treatments for TNBC.”
All cancers originate as the result of changes that have occurred within the genes of a cell or group of cells. In the case of triple-negative breast cancer, a gene known as TP53 is most frequently deleted or mutated.
But, TP53 is critical. It provides instructions for making a protein called p53 that helps prevent the development of tumors by stopping cells with mutated or damaged DNA from growing and dividing uncontrollably. Although many researchers have considered techniques to restore p53 activity, no such therapy has been translated into the clinic, owing to the complexity of p53 signaling.
Recognizing this, Professor He and his research team have instead focused efforts on POLR2A – a gene that is essential for cells to survive, and is a genetic neighbor of TP53. The group chose this route because alterations in genes tend to be large regional events in the body. Most cancers that lead to the loss of a particular tumor suppressor gene (likeTP53), also lead to the partial loss of nearby genes such as POLR2A.
Although cancer cells can survive a partial loss of POLR2A, they become weakened and vulnerable to POLR2A inhibition. Knowing this, He and his research team hypothesized that targeted inhibition of POLR2A could potentially kill TNBC cells while sparing normal cells.
To explore this option, the team looked to RNA interference (RNAi) with small interfering RNA (siRNA), a biological process by which RNA molecules inhibit gene expression or translation. This process can be used to precisely target virtually any genes – including those that may contribute to cancer growth.
The challenge, however, is that siRNA is extremely unstable in blood and in endosomes and lysosomes, the digestive system of cells. To overcome these obstacles, the research group designed “nano-bomb” particles that they could use to protect POLR2A siRNA in blood circulation and carry the siRNA into the targeted tumor for cells to “eat.” The particles then generate CO2 gas to break open endosomes and lysosomes to ensure timely release of siRNA to inhibit POLR2A.
The group believes that their findings offer hope that one day a nanotechnology-based precision-targeting strategy could be used to fight TNBC and many other types of cancer.
In addition to his BIOE appointment, He is a faculty member of the University of Maryland’s Robert E. Fischell Institute for Biomedical Devices, as well as the University of Maryland’s Marlene and Stewart Greenebaum Comprehensive Cancer Center.
Along with He, the following contributed to the Nature Nanotechnology paper: co-first authors Jiangsheng Xu (BIOE; The Ohio State University/OSU), Yunhua Liu (Indiana University), and Yujing Li (Indiana University); co-authors Hai Wang (BIOE; OSU), Samantha Stewart (BIOE), Kevin Van der Jeught (Indiana University), Pranay Agarwal (OSU), Yuntian Zhang (BIOE; University of Science and Technology of China/USTC), Sheng Liu (Indiana University), Gang Zhao (USTC), and Jun Wan (Indiana University); and co-corresponding author Xiongbin Lu (Indiana University).