Using bacteria to ferry radioisotopes commonly used in cancer therapy directly into pancreatic cancer cells in mice, researchers in the US were able dramatically to reduce the number of secondary tumors that arise when the cancer spreads to other parts of the body (metastases).
Claudia Gravekamp and colleagues at Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, write about their successful experiment in a paper that was published this week in the print issue of the Proceedings of the National Academy of Sciences.
Gravekamp, co-senior author of the paper, is an associate professor of microbiology and immunology at Einstein and studies new approaches to treating metastatic cancer.
She says she and her colleagues were greatly encouraged when they achieved a 90% reduction in secondary tumors or metastases in their first round of experiments.
Gravekamp says in a statement:
“At this point, we can say that we have a therapy that is very effective for reducing metastasis in mice.”
Plus they managed to achieve this success in mice with highly aggressive pancreatic cancer without harming healthy tissue.
“With further improvements, our approach has the potential to start a new era in the treatment of metastatic pancreatic cancer,” says Gravekamp.
Pancreatic cancer is one of the deadliest cancers, with fewer than 4% of people surviving more than five years after diagnosis.
In the US, estimates from the National Cancer Institute suggest this year just over 45,200 people will discover they have pancreatic cancer and around 38,500 will die from it.
Pancreatic cancer is not easy to detect early because it takes a long time for noticeable symptoms to emerge, so by the time most patients undergo diagnosis, the cancer has already spread to other parts of the body.
However, one recently published study suggests it may be possible to detect pancreatic cancer early using an approach called metabolomic analysis to evaluate levels of only four metabolites.
If pancreatic cancer is detected before it has spread, then it can be treated with surgery, but once it has spread or metastasized, the chances of successful treatment are not good.
Patients with metastasized pancreatic cancer typically have jaundice, pain, weight loss, and fatigue. There is no cure once it has reached this stage, and treatments are given mainly to improve quality of life.
The idea for this study started several years earlier when scientists noticed that a weakened lab form of the bacterium Listeria monocytogenes can infect cancer cells but not healthy normal cells. (The wild form of the bacterium is the one that causes listeriosis, a potentially serious food-borne disease, especially in people with weakened immune systems.)
Then in 2009, Gravekamp discovered why Listeria infects cancer cells and not healthy ones. The environment around the tumor suppresses the immune system which is then too weak to defend against the bacterium, allowing it to survive inside the cancer cells of the tumor. In normal tissue it doesn’t get to live long enough for this to happen.
After this discovery, scientists experimenting with bacteria as carriers of anti-cancer agents, showed using lab cultures that Listeria could be adapted to carry anti-cancer drugs into tumor cells. But they never tested it in animals.
It was co-senior author Ekaterina Dadachova, professor of radiology and of microbiology and immunology at Einstein, who had the idea to see if Listeria could carry radioisotopes (commonly used in cancer therapy) into the tumor cells.
Dadachova is a pioneer in developing radioimmunotherapies, where radioisotopes are attached to antibodies that select particular cells, such as disease bacteria, cancer cells, or cells infected with HIV. When the antibodies bind with their target they release their radioactive payloads which blast and kill the target cells with radiation.
For this latest study, Gravekamp, Dadachova and colleagues attached the radioactive isotope rhenium to the weakened Listeria.
Dadachova says they chose rhenium because it emits beta particles, which are particularly good at treating cancer.
Another reason they chose rhenium is it has a half-life of 17 hours, so quite soon becomes harmless, causing minimum damage to healthy cells.
The team worked with two groups of mice that had metastatic pancreatic cancer. They gave both groups abdominal injections once a day for 7 days. In one group the injections contained the radioactive Listeria, in the other group they contained saline (the controls).
After 21 days the researchers counted the secondary tumors in the mice and found 90% fewer in the radioactive Listeria group compared to the saline-treated controls.
They also found the radioactive bacteria reduced primary tumor weight by an average of 64% compared with the saline-treated controls.
When they examined the cancerous and healthy tissue, the team found higher concentrations of Listeria in the secondary tumors, and to a lesser extent in the primary tumors, but not in normal healthy tissue.
They also report that the mice that received the radioactive bacteria did not show any harmful side effects.
Gravekamp says their goal is to clear 100% of the secondary tumors. Every cancer cell that is left alive is a potential source of new secondary tumors, so the only way to be sure is to kill all of them.
Dadachova says they had to stop the experiment at 21 days because the control mice were dying. They now need to find out what effect the treatment has on animals’ survival.
The team thinks it can improve the treatment by fine-tuning the dosing schedule, using higher doses of radiation, or even by adding more payload to the bacteria in the form of other anti-cancer drugs.
Meanwhile at other research centers, scientists are also working on approaches to use backpacking bacteria to carry minute doses of “nano-medicines”.
Written by Catharine Paddock PhD