Scientists report on promising new approaches to induce cancer cell suicide

November 20, 2003

In cancer, the normal process by which cells die is defective. Researchers are reporting today on three new approaches to activate cancer cells' ability to commit suicide. In one set of studies, scientists employed a series of molecular and gene therapy tricks to convert an angiogenic protein used by tumors to promote their growth into a cancer cell killer. In separate study, scientists used a fragment of genetic material to disable a protein used by many tumor types as an "off switch" to prevent cell death, triggering cancer cell suicide. A third study focused on a novel inhibitor to improve responses to central nervous system tumor therapy. The findings were presented today at the International Conference on Molecular Targets and Cancer Therapeutics organized by the American Association of Cancer Research (AACR), National Cancer Institute (NCI) and European Organisation for Research and Treatment of Cancer (EORTC) in Boston.

Antisense inhibition of survivin expression as a cancer therapeutic: Abstract 324

Scientists have inhibited cancer in mice using a synthetic fragment of genetic material to block production of a protein that many tumor types use to survive. Researchers at Eli Lilly and Company reported the studies of the compound, LY2181308, which is directed against a molecular target called survivin.

Survivin belongs to a family of proteins, called Inhibitor of Apoptosis Proteins, which play a key role in the regulation of apoptosis and cell division. The protein is expressed in a majority of human cancers but not in normal adult tissues, making it a potential target for cancer therapies. LY2181308 is an anti-sense oligonucleotide that potently downregulated survivin expression in human cancer cells derived from lung, colon, breast, prostate, ovary, cervix, skin and brain.

"We believe that the use of antisense molecules against targets such as survivin are a viable option for the treatment and management of cancer patients, either as a single agent or in combination with chemotherapeutic agents," said Bharvin Patel, Ph.D., of Eli Lilly, and lead investigator of the study.

In the mouse studies, the researchers tested LY2181308 against survivin in xenograft tumor model using human melanoma cells implanted under the skin. Intravenous administration of the survivin antisense molecule LY2181308 to tumor-bearing nude mice significantly inhibited tumor growth compared to animals treated with saline or mis-match control oligonucleotide. Furthermore, they demonstrated that this anti-tumor activity was associated with significant inhibition of survivin expression in these xenograft tumors. Other studies are currently assessing the activity of LY2181308 and chemotherapeutic agents in the cancer model.

Killing cancer cells and endothelial cells with a VEGF-triggered cell death receptor: Abstract 407

Scientists today presented new research on inducing cancer cell suicide. Tumors stimulate new blood vessel growth in order to acquire oxygen and nutrients, a process called tumor angiogenesis, by secreting an angiogenic growth factor called VEGF. Researchers from the University of California, San Francisco today presented a novel treatment approach using the tumor's own weapon against itself by forcing VEGF to act as a cell death factor instead of a growth factor.

VEGF normally works by attaching to the extracellular region of VEGF receptor 2, which activates the intracellular region of the receptor to send growth signals. The research team created an artificial VEGF receptor, called R2Fas, in which the intracellular region of VEGF receptor 2 was replaced with a part of the Fas death receptor, which can trigger a process of cellular suicide termed apoptosis.

Blood vessel cells in culture normally grow when exposed to VEGF. When the R2Fas receptor was expressed in blood vessel cells, the cells were instead rapidly killed by VEGF, showing that VEGF acted as a death factor instead of a growth factor. When the R2Fas receptor was expressed in cancer cells in culture that over-express VEGF, the R2Fas receptor caused the cells to die by apoptosis.

"The ability of the R2Fas receptor to switch the function of VEGF from a growth factor to a death factor may allow a new approach to anti-angiogenesis by simultaneously targeting both the VEGF-producing cancer cells and the tumor blood vessels," said Tim Quinn, M.D., assistant professor at the University of California, San Francisco Pediatrics Department. "Animal studies in which R2Fas will be expressed in tumors and tumor blood vessels will determine the feasibility of this approach."

ZD6474, a vascular endothelial growth factor reception 2 (VEGFR-2) inhibitor, inhibits growth of multiple primary central nervous system tumor types: Abstract 709

Researchers have shown that a new and experimental drug - ZD6474 -- strongly inhibited the growth of three deadly brain tumors in animals. In the study, conducted at Duke University Medical Center, ZD6474 inhibited the growth of three types of human tumors grown in mice -- glioblastoma, medulloblastoma, and ependymoma - a remarkable finding, given that brain tumors are very distinct in their biologic makeup.

"Despite our best efforts in the laboratory and the clinic, the survival rate for glioblastoma - the most common and lethal brain tumor -- hasn't changed in ten years," said Jeremy Rich, M.D., assistant professor in the Brain Tumor Center at Duke. "This new drug candidate has demonstrated great promise in treating human tumors that were grown in mice, and we feel these results are indicative of how the drug may act in humans."

Mice that received ZD6474 showed a 10- to 25-day delay in growth in all of the tumors compared to control mice. The drug worked by blocking tumor angiogenesis, the process by which tumor cells grow new blood vessels. Specifically, ZD6474 blocked activation of the receptor for vascular endothelial growth factor (VEGF). VEGF is a protein that malignant cells secrete in order to grow and maintain their blood vessels. When the VEGF receptor is not activated, the tumor's blood supply is diminished and the tumor shrinks and slows its spread.

Secondarily, ZD6474 prevented activation of the EGF (epidermal growth factor) receptor, another protein that cells use to grow new blood vessels, to resist dying, and to invade other cells. Additionally, ZD6474 showed promise in treating tumors that had genetically manipulated themselves to resist the effects of toxic chemotherapy.
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Founded in 1907, the American Association for Cancer Research is a professional society of more than 21,000 laboratory, translational, and clinical scientists engaged in cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. This work is carried out through five major peer-reviewed scientific journals and high-quality scientific programs focusing on the latest developments in all areas of cancer research.

The National Cancer Institute, founded in 1971, is the principal United States government agency charged with coordinating the National Cancer Program. It facilitates international cooperation in clinical trials involving U.S. and foreign collaborating institutions.

The European Organisation for Research and Treatment of Cancer was organized in 1962 to conduct, develop, coordinate and stimulate laboratory and clinical research in Europe, and to improve the management of cancer and related problems by increasing the survival and quality of life for patients.

American Association for Cancer Research

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