New York, N.Y., January 23, 1998 - Memorial Sloan-Kettering Cancer Center (MSKCC) researchers delving into the fundamental mechanisms underlying one form of leukemia have learned how to interfere with the genetic changes that lead to this potentially fatal type of cancer. In laboratory studies, the investigators identified a combination of drugs that turn on proteins called transcription factors, which may be turned off in leukemia. The drug duo induces leukemia cells to mature and behave like normal, healthy blood cells. This finding, the first evidence supporting a new approach called "transcription therapy," may have broad implications for improving the treatment of other types of cancer that arise as a result of faulty gene transcription. The study was published in the February 1998 issue of the scientific journal Nature Genetics.
"This is exciting because we are taking our knowledge of how genes are regulated and using it to design an effective, targeted approach to treating cancer," said Dr. Pier Paolo Pandolfi, the geneticist who led the study. "We were able to show that this treatment was effective in mice, and we are planning to evaluate it soon in patients."
Specifically, Dr. Pandolfi and his team studied the molecular genetics underlying acute promyelocytic leukemia (APL), a type of leukemia that afflicts 2,000 to 3,000 Americans each year and has an especially abrupt onset. Five years ago, MSKCC investigators led by Dr. Raymond P. Warrell, Jr. showed that a drug called retinoic acid (RA) could be used to treat many patients with APL by inducing their cancer cells to mature, or differentiate, into healthy white blood cells. Differentiation therapy is an especially intriguing treatment approach, since it doesn't kill cells, but rather prompts them to "grow up" and behave normally.
Yet some APL patients remain resistant to RA treatment. Scientists looking at what determines which patients respond to RA and which ones don't have identified a genetic difference between the two groups. APL patients who do well on RA treatment have leukemia that results from the fusion of two genes called PML and RAR-alpha (PML-RAR ), while the leukemia of patients who are resistant to RA is caused by a fusion of the genes PLZF and RAR-alpha (PLZF-RAR ).
To study these minute genetic differences further, Dr. Pandolfi and his colleagues developed two groups of mice: One group harbored the PML-RAR gene fusion, while a second group had the PLZF-RAR gene fusion. Both groups of mice developed APL similar to that seen in humans. In normal cells, certain proteins called transcription factors -- such as RAR -- turn on the expression of other genes with specific functions, such as controlling cell growth and maturation. Using advanced analytical techniques, Dr. Pandolfi's group showed that unlike RAR , proteins produced by the PML-RAR and PLZF-RAR gene fusions turned off, or "repressed," the expression of the cell's genes that normally prompt a cell to mature into a healthy, functioning white blood cell. Because these genes were turned off, the cells didn't mature, and leukemia developed. Moreover, the investigators found that PML-RAR and PLZF-RAR were acting as transcription repressors because of their ability to interact with other proteins. In PML- RAR , these interactions were broken apart by RA, while in PLZF-RAR they were insensitive to RA, explaining why retinoic acid works in some APL patients but not others.
Armed with this new knowledge, the MSKCC researchers set out to find ways to undo this chain of events. They knew that genetic material in a chromosome is tightly held together by proteins called histones. However, histones prevent individual gene expression. Previous studies of histones have shown that transcription repressors may work by favoring the placement of histones onto specific genes, thus masking their genetic material and turning them off. The scientists turned to a drug called Trichostatin A, one of a family of drugs called histone deacetylase inhibitors. These drugs prevent histones from doing their job, thus favoring gene expression and possibly antagonizing the activity of transcription repressors such as PML-RAR and PLZF-RAR . The drug combination worked well in the mice resistant to retinoic acid alone (those with the PLZF-RAR gene fusion), and was even more effective in mice already sensitive to retinoic acid (those with the PML-RAR gene fusion). Indeed, the leukemia cells matured to become normal white blood cells. Moreover, the drugs produced no adverse side effects.
"This study is critically important for two reasons," said Dr. Warrell, the pioneer of retinoic acid for APL. "Narrowly, it explains why patients with APL may develop resistance to retinoic acid, and provides a therapy which can potentiate the response to retinoic acid as well as prevent or overcome the loss of response to this drug. More broadly, it opens up an exciting new pathway for the treatment of many types of cancers."
One such cancer might be non-Hodgkin's lymphoma, a disease that strikes far more patients than APL: More than 50,000 people in the United States are diagnosed with non-Hodgkin's lymphoma each year. Mutations in a gene called BCL-6 make up the most frequent genetic alteration in non-Hodgkin's lymphoma. Alterations in BCL-6 -- which belongs to the same family of genes as PLZF -- turn on this transcription repressor, leading to lymphoma. "We plan to take our new findings with APL and apply them to design transcription therapy for patients with non-Hodgkin's lymphoma," said Dr. Pandolfi, who is currently planning such a clinical trial. Researchers intend to evaluate Trichostatin A as well as a similar drug called sodium phenylbutyrate.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Throughout its long, distinguished history, the Center has played a leadership role in defining the standard of care for patients with cancer. In 1997, Memorial Sloan-Kettering was named the nation's best cancer center for the fifth consecutive year by U.S. News & World Report.
Journal
Nature Genetics