Scientists are focusing on the energy centers of cancer cells – in a literal sense – to damage these power sources and induce widespread death in cancer cells. In a recent study, researchers combined methods to administer gene therapy that disrupts energy using nanoparticles designed to specifically target only cancer cells.
Tests indicated that the targeted treatment is successful at reducing glioblastoma brain tumors and aggressive breast cancer tumors in mice.
The research team addressed a major hurdle by utilizing a cutting-edge technique to dismantle mitochondria – the energy centers of the cell – through a method that creates light-activated electrical currents within the cell. They named this innovative technology mLumiOpto.
“We disrupt the membrane so mitochondria cannot work functionally to produce energy or work as a signaling hub. This causes programmed cell death followed by DNA damage – our investigations showed these two mechanisms are involved and kill the cancer cells,” said co-lead author Lufang Zhou, professor of biomedical engineering and surgery at The Ohio State University. “This is how the technology works by design.”
Mitochondria play a crucial role as the powerhouses of cells, generating the energy necessary for cellular functions. For years, they have been seen as a promising target for anti-cancer therapies, yet their impermeable inner membrane has posed significant challenges.
Five years ago, Zhou’s lab discovered a way to take advantage of a vulnerability in the inner membrane—an electrical charge difference that maintains its structure and ensures its proper functionality.
“Previous attempts to use a pharmaceutical reagent against mitochondria-targeted specific pathways of activity in cancer cells,” he said. “Our approach targets mitochondria directly, using external genes to activate a process that kills cells. That’s an advantage, and we’ve shown we can get a very good result in killing different types of cancer cells.”
Zhou’s previous cell experiments demonstrated that a protein capable of generating electric currents could cause a disruption in the mitochondrial inner membrane, and researchers utilized a laser to activate this light-sensitive protein. In this latest research, the team developed an internal light source, which is crucial for adapting the technology for clinical applications.
The approach involves introducing genetic material for two types of molecules: a light-sensitive protein called CoChR that generates positively charged currents and an enzyme that emits bioluminescence. These components are encapsulated in a modified viral particle and delivered to cancer cells, leading to the production of the proteins as their genes are expressed within the mitochondria.
A subsequent injection of a specific chemical activates the enzyme’s light, which in turn triggers CoChR, resulting in the collapse of the mitochondria. Another important aspect of this treatment is to make sure it does not affect healthy cells. Liu’s laboratory focuses on the development of targeted therapies for cancer.
The basis for the delivery mechanism in this study is the well-researched adeno-associated virus (AAV), which is a minimally infectious virus designed to transport genes and facilitate their expression for therapeutic applications.
To improve the system’s specificity for cancer, the team introduced a promoter protein that increases the expression of the CoChR and bioluminescent enzyme exclusively in cancer cells. Additionally, the researchers developed the AAV using human cells, encapsulating the gene-packed virus in a natural nanocarrier that mimics extracellular vesicles, which are commonly found in human blood and biological fluids.
“This construction assures stability in the human body because this particle comes from a human cell line,” Liu said.
Finally, the researchers developed and attached to the delivery particle a monoclonal antibody designed to seek out receptors on cancer cell surfaces.
“This monoclonal antibody can identify a specific receptor, so it finds cancer cells and delivers our therapeutic genes. We used multiple tools to confirm this effect,” she said. “After constructing AAVs with a cancer-specific promoter and a cancer-targeting nanoparticle, we found this therapy is very powerful to treat multiple cancers.”
Research conducted on mouse models demonstrated that the gene therapy approach significantly decreased tumor size when compared to untreated animals in two fast-growing, difficult-to-treat cancers: glioblastoma brain cancer and triple negative breast cancer. Besides reducing tumor size, the treatment also prolonged the survival of mice afflicted with glioblastomas.
Imaging studies of the animals further verified that the gene therapy’s effects were confined to cancerous tissue and were not observable in normal tissues. The findings also implied that linking the monoclonal antibody provided the additional advantage of generating an immune response targeting cancer cells within the tumor microenvironment.
The research team is exploring further potential therapeutic impacts of mLumiOpto for glioblastoma, triple-negative breast cancer, and other cancers. A provisional patent application for the technologies has been submitted by Ohio State.
Journal reference:
- Kai Chen, Patrick Ernst, Anusua Sarkar, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D. Ringel, Xiaoguang “Margaret” Liu, Lufang Zhou. mLumiOpto Is a Mitochondrial-Targeted Gene Therapy for Treating Cancer. Cancer Research, 2024; DOI: 10.1158/0008-5472.CAN-24-0984
