The study focused on disrupting the
inner membrane of mitochondria, the primary producers of energy that fuels cell
functions. Mitochondria are depicted in yellow in the image above of an
osteocarcinoma cell.
Image: Dylan Burnette and Jennifer
Lippincott-Schwartz, NICHD
Researchers are shining a light on
cancer cells’ energy centers – literally – to damage these power sources and
trigger widespread cancer cell death.
In a new study, scientists combined
strategies to deliver energy-disrupting gene therapy using nanoparticles
manufactured to zero in only on cancer cells. Experiments showed the targeted
therapy is effective at shrinking glioblastoma brain tumors and aggressive
breast cancer tumors in mice.
The research team overcame a significant
challenge to break up structures inside these cellular energy centers, called mitochondria, with a technique that induces light-activated electrical currents
inside the cell. They named the technology mLumiOpto.
Lufang Zhou
“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.”
Zhou collaborated on the research with
co-lead author X. Margaret Liu, professor of chemical and biomolecular
engineering at Ohio State, who developed the
particles used to precisely deliver the gene therapy to cancer cells. Zhou and
Liu are also both investigators in The Ohio State University
Comprehensive Cancer Center.
The study appears in the December issue
of the journal Cancer Research.
Mitochondria, the primary producers of
energy that fuels cell functions, have been considered an attractive
anti-cancer therapeutic target for years, but their impermeable inner membrane
complicates these efforts. Zhou’s lab cracked the code five years ago by
figuring out how to exploit the inner membrane’s vulnerability – an electrical
charge differential that keeps its structure intact and functions on
track.
“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 earlier cell studies showed the
mitochondrial inner membrane could be disrupted by a protein that creates
electrical currents, and researchers activated that light-induced protein with
a laser. In this new work, the team created an internal source of light – key
to translating the technology for clinical use.
X. Margaret Liu
The strategy involves delivering genetic
information for two types of molecules: a light-sensitive protein known as
CoChR that can produce positively charged currents, and a
bioluminescence-emitting enzyme. Packed into an altered virus particle and
delivered to cancer cells, the proteins are produced as their genes are
expressed in mitochondria. A follow-up injection of a specific chemical turns
on the enzyme’s light to activate CoChR, which leads to mitochondrial
collapse.
The other half of the battle is ensuring
this therapy does not interfere with normal cells.
Liu’s lab specializes in targeted
anti-cancer therapy development. The foundation for the delivery system in this
work is the well-characterized adeno-associated virus (AAV), a minimally
infectious virus engineered to carry genes and promote their expression for
therapeutic purposes.
The team refined the system to enhance
its cancer specificity by adding a promoter protein to drive up expression of
the CoChR and bioluminescent enzyme only in cancer cells. The researchers also
manufactured the AAV using human cells that encased the gene-packed virus
inside a natural nanocarrier resembling extracellular vesicles that circulate
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.”
Experiments in mouse models showed the
gene therapy strategy significantly reduced the tumor burden compared to
untreated animals in two fast-growing, difficult-to-treat cancers: glioblastoma
brain cancer and triple negative breast cancer. In addition to shrinking the
tumors, the treatment extended survival of mice with glioblastomas.
Animal imaging studies also confirmed
the effects of the gene therapy were limited to cancer tissue and were
undetectable in normal tissue. Results further suggested that attaching the
monoclonal antibody had the added benefit of inducing an immune response
against cancer cells in the tumor microenvironment.
The team is studying additional
potential therapeutic effects of the mLumiOpto in glioblastoma, triple negative
breast cancer and other cancers. Ohio State has submitted a provisional patent
application for the technologies.
This research was supported by the U.S.
Department of Defense and the National Institutes of Health.
Kai Chen of Liu’s lab and Patrick Ernst
of Zhou’s lab were co-first authors of the study. Additional co-authors were
Anusua Sarkar, Seulhee Kim, Yingnan Si, Tanvi Varadkar and Matthew Ringel, all
of Ohio State.
By: Emily Caldwell, Ohio State News
Source: Light-induced
gene therapy disables cancer cells’ energy center
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