New Cancer Switch Discovered By Duke Medical Center Pharmacologists

April 29, 1996

DURHAM, N.C. -- A new way that cancers may be triggered in the body -- through damage to a molecular "safety key" that normally holds cell growth in check -- has been reported by Duke University Medical Center pharmacologists.

The discovery, reported in the Nov. 1 issue of Genes & Development, is one of three different advances described by the scientists in October and November, all of which point toward new ways to interfere with the malignant machinery of cancer cells to kill them.

In a second paper in the October issue of Molecular and Cellular Biology, the scientists reported new understanding of how cancer cells acquire the ability to avoid the natural death, called "apoptosis," that normal cells experience. Such capability allows cancer cells to survive chemotherapy treatments that would kill normal cells. Reporting the findings are assistant professor of pharmacology Ann Marie Pendergast, and graduate students David Cortez and Lisa Kadlec.

In a third paper in the Nov. 21 Proceedings of the National Academy of Sciences, Mikhail Gishizky of SUGEN Inc. along with Pendergast and Cortez reported success in halting the growth of leukemia cells by jamming their growth machinery. The researchers said they believe that such "molecular sabotage" could become a useful treatment for a variety of cancers.

The research by Pendergast and her colleagues was supported by the National Cancer Institute and the National Institutes of Health. Pendergast is a Whitehead Scholar and a scholar of the Leukemia Society of America. She is also a member of the Duke Comprehensive Cancer Center, which is supported by the National Cancer Institute. Cortez is a graduate student in the department of molecular cancer biology.

The researchers made their discoveries studying an abnormal gene called BCR-ABL, which produces two forms of leukemia -- chronic myelogenous leukemia and acute lymphoblastic leukemia. The BCR-ABL gene forms when a genetic mistake occurs in bone marrow cells destined to become white blood cells. In the usual genetic mixing and matching within the dividing cell, bits of two chromosomes are snipped off and rejoined to one another. In the process, a piece of the gene called BCR is restitched to a large gene called cABL, or "cellular" ABL. The protein produced by the cABL gene is a "tyrosine kinase," a type of enzyme found throughout the cell. The cABL enzyme is normally a well-behaved part of the cell-growth machinery.

However, the stitched-together BCR-ABL outlaw protein turns itself on, sending the cell proliferating out of control.

In earlier work, Pendergast and her colleagues found that the outlaw BCR-ABL protein plugs into an adaptor protein called GRB-2 to switch on a chain of other enzymes that eventually activates the cancer gene, or oncogene, called ras, which launches uncontrolled growth.

In the Proceedings paper, Gishizky, Cortez and Pendergast reported discovering that a purposely "damaged" form of GRB-2 could suppress activation of ras and reverse the cancerous growth of human leukemia cells in test tubes.

"These results suggest that inhibition of GRB-2 interactions may provide a useful therapeutic target for treatment of [chronic myelogenous leukemia] as well as other tyrosine kinase-associated human cancers such as breast, ovarian, glioma, squamous cell carcinoma and leukemia," the scientists wrote. According to Gishizky, SUGEN has already produced a short protein segment, or peptide, that mimics GRB-2 but jams the cell-growth machinery. The peptide is now being distributed by SUGEN for testing on tumors taken from humans, he said.

In the October Molecular and Cellular Biology paper, Cortez, Pendergast and graduate student Lisa Kadlec also reported the results of producing slightly altered, or mutated, versions of the BCR-ABL gene. Their aim was to better understand the multitude of ways it switches on cell-growth, as well as blocks apoptosis. The ability of cancer cells to avoid apoptosis makes them resistant to cancer-killing drugs, which is a major cause of death among cancer patients.

The scientists discovered that some mutant BCR-ABL genes eliminated both the cancer-causing and anti-apoptosis capabilities of the cells. However, they found one mutant that did activate the oncogene ras and did block apoptosis, but did not cause the cells to become cancerous, or "transformed."

"This finding offers us two lessons," Pendergast said. "One is that there are multiple pathways to activate ras. And the other is that we can separate the pathways for anti-apoptotic and transforming activity. Ras appears to be necessary, but not sufficient for the transforming activity of BCR-ABL." According to Pendergast, the discovery offers the possibility of cancer treatments that eliminate drug-resistance by selectively rendering tumor cells vulnerable to normal cell death when treated with anti-cancer drugs.

In the paper in Genes and Development, Pendergast and postdoctoral fellow Zonghan Dai reported a new way that both normal cell growth and cancer can be switched on in the cell. They discovered a "safety key" molecule that fits into the normal cABL enzyme to keep it turned off. The protein molecule, called Abi-2, has structural features that allow it to fit parts of cABL like a key fits a lock.

"This is the first time we've been able to open a window on what activates normal cABL," said Pendergast. "People have been looking for this molecule, or a molecule with these characteristics, for over a decade."

In their experiments, Dai and Pendergast discovered that if they truncate the segments of Abi-2 that fit cABL, then cABL becomes cancer-causing.

In a companion paper in Genes and Development, Steven Goff of Columbia University has reported discovering a similar molecule, which he called Abi-1, in brain tissue.

"We believe that these molecules represent a major undiscovered way that chemical signals are transmitted from tyrosine kinases into the cell's nucleus," said Pendergast. The Abi proteins may be a previously unknown mechanism for producing cancer, said Pendergast, not by direct damage to a cancer gene, but by damage to a "safety key" that is its partner.

Duke University Medical Center

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