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Columbia scientists develop cancer terminator viruses

Results advance quest for viral-based therapies for cancer

Researchers at Columbia University Medical Center continue to make strides in their work to develop the next generation of effective viral-based therapies for cancer. Two papers about promising research with genetically engineered viruses studied in mice, published today in the journals Cancer Research and the Proceedings of the National Academy of Sciences (PNAS), bring us significantly closer to this objective and the start of clinical trials with these viral-based therapies in cancer patients.

Both papers were led by Paul B. Fisher, M.Ph., Ph.D., professor of clinical pathology and the Michael and Stella Chernow Urological Cancer Research Scientist at Columbia University College of Physicians and Surgeons.

In the Cancer Research paper, the researchers discuss the development of a "terminator" virus, which was administered to mice with pancreatic cancers at both primary and distant sites (akin to metastases). As predicted, when the virus was injected directly into the primary tumor, the virus destroyed not only the primary tumor, but also distant tumors. While the infection caused by the virus was sufficient to kill the primary tumor, a second weapon added to the virus �V interferon-gamma (IFN-��) �V eliminated the metastases. IFN-�� elicited an anti-tumor immune response against the distant metastatic cancer cells.

In the PNAS paper, Dr. Fisher and the team describe the production of a virus conceptually similar to the "terminator" virus, which selectively replicates and kills breast cancer cells in mice. Human breast tumor xenografts were established on both sides of immune-deficient mice. Results found that treating the tumors on just one side of the animal with very few injections of this modified virus not only cured the injected tumors, but also resulted in the destruction of the tumors on the opposite side of the animal. Instead of carrying IFN-�� as the other v irus did, this virus carried a gene called mda-7/IL-24, a novel gene identified and cloned in Dr. Fisher's laboratory, which is selectively toxic to cancer cells and is now in phase II clinical trials as a cancer gene therapeutic.

"We are extremely excited about these results and the prospect of one day using a form of the cancer terminator virus in human clinical trials," said Dr. Fisher, the study's senior author. "While the results of these trials need to be investigated further and replicated in future trials, we believe that viral-based therapies will someday soon be a standard part of the cancer armamentarium."

About the "Terminator" Viruses

The "terminator" viruses have the potential to become effective treatments for a wide range of tumors - such as ovarian, pancreatic, breast, brain (glioma), prostate, skin (melanoma) and colon cancer - because the virus is constructed to exploit a characteristic of all solid cancers. However, clinical trials are necessary before such treatments can be approved by the U.S. Food and Drug Administration and available for patients.

These publications are a continuation of research published in the Jan. 25, 2005 issue of PNAS, where the same research team, also led by Dr. Fisher, incorporated gene therapy into a specially designed non-replicating virus to overcome one of the major hurdles of gene therapy: its tendency to kill normal cells in the process of eradicating cancer cells. The virus eradicated prostate cancer cells in the lab and in animals, while leaving normal cells unscathed.

The present cancer "terminator" viruses represent the next generation of therapeutic viruses that permit replication uniquely in cancer cells with simultaneous production of immune modulating and toxic genes. These viruses effectively eliminate primary tumors and distant tumors (metastases) without harming normal cells or tissues.

Dr. Fisher's cancer research team includes Columbia Un iversity Medical Center investigators: Drs. Zao-zhong Su (research scientist), Devanand Sarkar (associate research scientist), Nicolaq Vozhilla (pathology technician), Eun Sook Park (pathology technician) and Pankaj Gupta (associate research scientist). Two scientists from Virginia Commonwealth University in Richmond, Va. are also involved in the research: Mr. Aaron Randolph (graduate student) and Dr. Kristoffer Valerie (professor).


Source:Columbia University Medical Center

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