COLUMBUS, Ohio -- Researchers may be close to developing an additional weapon for treating a type of rapidly growing, fatal brain tumor that often afflicts AIDS patients.
The new approach, reported in the latest issue of the journal Blood, focuses on activating a protein receptor that stimulates cells to commit suicide.
These specific tumors -- primary central nervous system lymphomas (PCNSL) -- have now been shown by the researchers to express the receptor (called FAS) and to undergo cell death when that receptor is triggered.
Since the brain itself does not appear to express this receptor, researchers may be able to trigger the receptor on the tumor cells without damaging nearby normal brain tissue. These lymphomas are now almost universally untreatable and can kill a patient within two to four months after the condition is diagnosed.
These brain tumors almost always contain Epstein-Barr virus, a virus that normally remains dormant in most normal people, held at bay by healthy lymphocytes called T-cells. But when the immune system is damaged, or the number of T-cells has dropped substantially -- as is the case with AIDS patients -- the virus activates, presumably leading to the brain lymphoma.
Robert Baiocchi, a third-year medical student at Ohio State University, and Michael Caligiuri, co-director of the division of hematology and oncology and associate director for clinical cancer research for the university’s Comprehensive Cancer Center, led the work.
They examined tissue taken from eight different AIDS patients who had died from these lymphomas. They discovered that all the tumors expressed FAS at very high levels.
FAS is common in the rest of the body, especially the liver, but the normal brain appears to be free of FAS. Caligiuri said that finding FAS in the brain tumors was an advantage. The blood-brain barrier generally prohibits the passage of compounds from the brain into the circulatory system.
“The brain is a chemotherapy sanctuary. This means we may be able to administer anti-FAS medicines within the brain that could stimulate the brain tumors to self-destruct, without harming normal brain or without traveling to other parts of the body that normally produce FAS,” he said.
To test their ideas, Caligiuri and Baiocchi turned to laboratory animals known as SCID (severe combined immune deficient) mice. These mice lack functional immune systems of their own. Because of that, researchers can put normal human cells inside the animals. After about three months, the animals develop actual human lymphomas with the Epstein-Barr virus that strikingly resemble the brain lymphomas seen in some patients with AIDS. In the mice, however, the tumors appear in the lymph nodes. In humans, the lymphomas appear in the brain.
The researchers were then able to use anti-FAS compounds to trigger FAS which begin killing the human tumor that had developed in the SCID mouse.
Baiocchi and Caligiuri next examined three fresh brain tumors from patients with AIDS and PCNSL and were also able to show that when the tumors received anti-FAS therapy, those tumor cells died. Furthermore, the cell death begun by the anti-FAS treatment was improved by adding radiation. Currently, radiation is the only standard treatment available for PCNSL tumors. The researchers saw improved tumor cell death when the immune stimulant interleukin 2 was used.
The next step, Caligiuri said, is to grow these same tumors in the brains of rats that have deficient immune systems, and then test if the animals’ blood-brain barriers isolate the treatment and protect the animals’ other organs.
“Our dream would be to give the brain gene therapy which would cause it to express what’s called FAS ligand, an anti-FAS molecule that binds to FAS and triggers specific cell death,” Caligiuri said, which in turn would have the possibility of destroying existing tumors.
The research is supported by a grant from the National Cancer Institute.
Baiocchi and Caligiuri began this work while at Roswell Park Cancer Institute in Buffalo, NY, but completed their work at Ohio State. Working with them there were Vijay P. Khatri, Matthew J. Lindemann, Mary E. Ross, Anthony J. Caprio, Thomas V. Caprio, Robert Fenstermaker and Zale P. Bernstein, all from Roswell Park. Guiliana Papoff and Giovina Ruberti, both researchers at the Institute of Cell Biology in Rome, Italy, were part of the research team.
Journal
Blood