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September 8, 1999

SNAPSHOT OF NEW DRUG IN ACTION MARKS A MAJOR ADVANCE BY MEMORIAL SLOAN-KETTERING RESEARCHERS

NEW YORK, September 9, 1999 - Memorial Sloan-Kettering Cancer Center (MSKCC) scientists have achieved a major milestone in a line of research that has spanned a quarter-century: the first-ever molecular "snapshot" of a new drug interacting with its cellular target. The picture shows how a novel cytodifferentiation agent, discovered by MSKCC researchers, closely fits into an enzyme and affects how it regulates cells. By visualizing how the drug, called SAHA, nestles into the active site of the enzyme and subtly alters its structure, the picture will enable investigators to make more potent and more specifically targeted versions of these drugs. The first clinical trial of SAHA is planned to begin this fall at Memorial Sloan-Kettering in patients with advanced cancers. Studies at MSKCC in laboratory models suggest that SAHA may have a broad role in treating cancers of the breast, lung, prostate, and other organs.

The work, published in the September 9th issue of the journal Nature, identifies the structure of the molecular target of these cytodifferentiation agents, chemical agents which can induce cancer cells to mature and die like normal cells. The concept of cytodifferentiation therapy as an approach to treating cancer has been pioneered by Center President Dr. Paul A. Marks, Sloan-Kettering Institute Chairman Dr. Richard A. Rifkind, Dr. Ronald Breslow of Columbia University, and their colleagues.

The work with SAHA holds the potential for applying cytodifferentiation agents across a broad range of cancers. The identification of the molecular target of such drugs provides a more detailed understanding of how cancer develops and suggests more specific ways to interfere with that process. "It's a new therapeutic approach to cancer," Dr. Marks said. - more - What exactly does histone deacetylase do in cells, and how does SAHA interfere with it? Histones are proteins in the nuclei of cells; the histones provide a core around which the long chains of DNA are wrapped. For a gene in a DNA chain to be turned on, or "expressed," the DNA chain must be unwrapped from the histone core. Histone deacetylase keeps the DNA and histones tightly wrapped. So when SAHA inhibits histone deacetylase, it allows the DNA to unwrap, making genes accessible to the cellular switches that turn them on.

The pictures in the recent Nature paper were produced in the laboratory of structural biologist Dr. Nikola P. Pavletich by postdoctoral investigator Dr. Michael S. Finnin. Using the technique of x-ray crystallography, they show the critical parts of the structure of SAHA, trichostatin A, and an analogue of human histone deacetylase (a lookalike counterpart enzyme from bacteria). The pictures also show precisely how both SAHA and trichostatin A hinder the enzyme's activity.

The enzyme has a narrow, deep pocket, at the bottom of which is the active site - the atoms where SAHA and trichostatin A bind. The critical parts of SAHA and trichostatin A are the binding end, which is made up of a substance called hydroxamic acid, and a long narrow chain of atoms that allows the hydroxamic acid to reach all the way to the bottom of the pocket. The combination produces a snug fit, like a lock and key.

"Now that we know what these inhibitors look like, and how they fit and work, we already have ideas about how to improve them, and can do this faster," Dr. Pavletich said. For example, the SAHA molecule could be modified to make its long chain fit better in the enzyme's pocket, or to make the drug dissolve more readily so that it will stay longer in the blood. "This demonstrates the power of structural biology," Dr. Pavletich said. "If you can see the structure, that can be extremely powerful in the development of a drug."

Dr. Finnin noted that histone deacetylase normally interacts with a very large complex of - more - proteins that may regulate it. Each part of the complex may perform a specific task to help the enzyme work. "The next step in this research," Dr. Finnin said, "is to dissect this complex to understand its function."

"There are a slew of biological problems that remain to be solved," added Dr. Rifkind. "We don't know, for instance, why SAHA influences the activities of only certain genes, and why SAHA is so selective for cancer cells. But we can say that SAHA is a very promising potential drug. And this latest work provides a clear pathway for the development of these agents as substances that can be used to help patients."

The planned clinical trial of SAHA - under the direction of Dr. William Kevin Kelly and Dr. Howard I. Scher, of the Genitourinary Oncology Service, and Dr. David R. Spriggs, of the Developmental Chemotherapy Service - is expected to start this fall. It is a Phase I trial, designed primarily to determine the drug's safety as a cancer treatment and to begin to understand its effects on different types of cancer, including those of the prostate, breast, and lung.

Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to patient care, research, and education in cancer. Throughout its long, distinguished history, the Center has played a leadership role in defining the standards of care for patients with cancer. In 1999, Memorial Sloan-Kettering was named the nation's best cancer center for the seventh consecutive year by U.S. Â鶹´«Ã½ & World Report.

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Memorial Sloan-Kettering press releases can be found online at: http://www.mskcc.org/document/prmenu/htm

Background About This Research The authors of the Nature paper are: Drs. Michael S. Finnin, Jill R. Donigian, Alona Cohen, Victoria M. Richon, Richard A. Rifkind, Paul A. Marks, Ronald Breslow, and Nikola P. Pavletich. Various groups at Memorial Sloan-Kettering and their colleagues have also contributed to the work leading up to the clinical trial of SAHA. These collaborating investigators include: Drs. David B. Agus, Carlos Cordon-Cardo, Richard D. Glick, William Kevin Kelly, Michael P. LaQuaglia, Joseph Michaeli, Pier Paolo Pandolfi, Neal Rosen, Francis M. Sirotnak, David R. Spriggs, Leonard Cohen of the American Health Foundation, and others.

The research described in the Nature paper has been funded by the National Cancer Institute, the Howard Hughes Medical Institute, the DeWitt Wallace Fund for MSKCC, the Japan Foundation for the Promotion of Cancer Research, and the Samuel and May Rudin Foundation. The clinical trial of SAHA at MSKCC will be supported by the National Institutes of Health, The Burke Foundation, CaPCURE, and the PepsiCo Foundation.