Sunday, September 15, 2013

Radioactive Bacteria Against Metastatic Pancreatic Cancer

In spite of the recent successful development for anti-cancer treatment in multiple directions, no significant improvement in therapy of pancreatic cancer has been reported over the last 25 years, underscoring the urgent need for new alternative therapies.

Researchers at Albert Einstein College of Medicine of Yeshiva University have developed a therapy for pancreatic cancer that uses Listeria bacteria to selectively infect tumor cells and deliver radioisotopes into them. The experimental treatment dramatically decreased the number of metastases (cancers that have spread to other parts of the body) in a mouse model of highly aggressive pancreatic cancer without harming healthy tissue. 

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"We're encouraged that we've been able to achieve a 90 percent reduction in metastases in our first round of experiments," said co-senior author Claudia Gravekamp, Ph.D., associate professor of microbiology & immunology at Einstein who studies new approaches to treating metastatic cancer. "With further improvements, our approach has the potential to start a new era in the treatment of metastatic pancreatic cancer."

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Pancreatic cancer is among the deadliest of cancers, with a five-year survival rate of only 4 percent. The National Cancer Institute predicts that this year, 45,220 new cases of pancreatic cancer will be diagnosed and 38,460 people will die from the disease. Pancreatic cancer confined to the pancreas can be treated through surgery. But early pancreatic cancer is difficult to detect, since it rarely causes noticeable signs or symptoms. Most pancreatic cancer cases are diagnosed only after the cancer has spread (metastasized), typically resulting in jaundice, pain, weight loss and fatigue. But there is no cure for metastatic pancreatic cancer, and treatment focuses mainly on improving quality of life.

Several years ago, scientists observed that an attenuated (weakened) form of Listeria monocytogenes can infect cancer cells, but not normal cells. In a 2009 study, Dr. Gravekamp discovered the reason: The tumor microenvironment suppresses the body's immune response, allowing Listeria to survive inside the tumors. By contrast, the weakened bacteria are rapidly eliminated in normal tissues. (Listeria in its wild form causes foodborne illnesses, particularly in immunocompromised people.)

Scientists later showed that Listeria could be harnessed to carry an anti-cancer drug to tumor cells in laboratory cultures, but this concept was never tested in an animal model. These findings prompted Dr. Gravekamp to investigate Listeria-tumor interactions and how Listeria could be used to attack cancer cells.

The idea of attaching radioisotopes (commonly used in cancer therapy) to Listeria was suggested by Ekaterina Dadachova, Ph.D., professor of radiology and of microbiology & immunology at Einstein and the paper's co-senior author. Dr. Dadachova, who is also the Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research, is a pioneer in developing radioimmunotherapies -- patented treatments in which radioisotopes are attached to antibodies to selectively target cells including cancer cells, microbes or cells infected with HIV. When the antibodies bind to antigens that are unique to the cells being targeted, the radioisotopes emit radiation that selectively kills the cells.

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Working together, Drs. Gravekamp and Dadachova coupled a radioactive isotope called rhenium to the weakened Listeria bacteria. "We chose rhenium because it emits beta particles, which are very effective in treating cancer," said Dr. Dadachova. "Also, rhenium has a half-life of 17 hours, so it is cleared from the body relatively quickly, minimizing damage to healthy tissue."

Mice with metastatic pancreatic cancer were given intra-abdominal injections of the radioactive Listeria once a day for seven days, followed by a seven-day "rest" period and four additional daily injections of the radioactive bacteria. After 21 days, the scientists counted the number of metastases in the mice. The treatment had reduced the metastases by 90 percent compared with untreated controls. In addition, the radioactive Listeria had concentrated in metastases and to a lesser extent in primary tumors but not in healthy tissues, and the treated mice did not appear to suffer any ill effects.

The treatment may have the potential for clearing an even higher percentage of metastases. "We stopped the experiment at 21 days because that's when the control mice start dying," said Dr. Dadachova. "Our next step is to assess whether the treatment affects the animals' survival."

As said, the scientists found that this treatment reduced the number of metastases by 90% compared to control mice injected with saline. It also reduced primary tumor weight by an average of 64% compared to saline controls.

Metastases had radioactivity levels 4- to 15-fold higher than all organs except the liver and kidneys. Levels in livers and kidneys were comparable to those in metastases. However, the radioactivity didn’t appear to damage or alter the organs’ functions. The normal cells in these tissues may not be as vulnerable to radioactive damage as those in tumors because they don’t divide as quickly. Neither the bacteria nor radioactivity were detected in any normal or tumor tissue a week after the last treatment.

"At this point, we can say that we have a therapy that is very effective for reducing metastasis in mice," Dr. Gravekamp noted. "Our goal is to clear 100 percent of the metastases, because every cancer cell that stays behind can potentially form new tumors." The researchers expect the treatment could be improved by fine-tuning the treatment schedule, using higher doses of radiation, or by piggybacking additional anti-cancer agents onto the bacteria. Einstein has filed a patent application related to this research that is currently available for licensing to partners interested in further developing and commercializing this technology.

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Unexplained effects

But Elizabeth Jaffee, an oncologist at Johns Hopkins University in Baltimore, Maryland, who has used non-radioactive Listeria in human trials for advanced cancers, including pancreatic cancer, says that some of the observations in the paper are hard to explain, particularly how weakened Listeria gets into metastases and why it's ineffective against the primary tumor.

Other researchers worry that healthy organs may receive excessive amounts of radiation. James Abbruzzese, an oncologist at the University of Texas MD Anderson Cancer Center in Houston, says that the levels of radiation reported in the liver and other organs were disturbingly high, and that he would have liked clearer data that the radiation is being delivered specifically to tumors.

Estimating dose levels between animals and humans is not always straightforward, but Dadachova counters that, according to her calculations, the radiation levels are below what is considered the safety threshold for humans, and that patients with pancreatic cancer tend to be less prone to radiation sickness because they have not usually received chemotherapy beforehand.

Joseph Herman, a radiation oncologist at Johns Hopkins, says that he would have liked to have seen results for other tumor types. And although the study found no signs of tissue damage one week after high-dose treatment of radioactive Listeria, Herman thinks that the effects of radiation might take longer to show up.

Still, Herman says, the approach might present an option where few exist. “The benefit is that it's a way of killing cancer cells in a cancer where therapy has not been very effective,” he says. “It's exciting, but it needs to be further validated.”

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