Newly Approved Cancer Drug Based on 30 Years of Research

"It's enormously satisfying for my collaborators, our talented students and fellows, and me that our research on the control of cancer cell growth has led to the development of this new approach to treating cancer and, ultimately, to our discovery of SAHA," said Dr. Marks.

SAHA is the prototype of a family of small synthetic molecules that target and inhibit histone deacetylases (HDACs), enzymes that are known to silence certain genes that allow tumor cells to proliferate when left unchecked. SAHA is more than just an alternative to established anticancer agents; it is a novel targeted anticancer drug that is selective in its effects on cancer cells. It is first among this new class of targeted anticancer drugs called HDAC inhibitors to be approved by the FDA.

SAHA acts in part by selectively altering the expression of genes and the activity of proteins that control cell growth and death -- proteins that are abnormal in many different cancers. It blocks the enzymes, HDACs, that remove the acetyl group (a set of small chemical fragments) from those proteins, which results in changes in their structure and thwarts the abnormal function. This can cause the death of cancer cells, but not normal cells, which are as much as ten times more resistant to these effects than are cancer cells.

An important milestone in vorinostat's history occurred in 1999, when Dr. Marks and his colleagues reported in the journal Nature the molecular structure of the active site of an HDAC and demonstrated how SAHA blocks its activity. The images, produced in the laboratory of Memorial Sloan-Kettering structural biologist Nikola P. Pavletich using x-ray crystallography, showed precisely how SAHA snugly nestles into the pocket of the targeted enzyme, altering its structure and affecting the way it regulates the introduction of the acetyl group into proteins that control gene expression, cell growth, and cell death. [PubMed Abstract]

HDAC keeps long chains of DNA tightly wrapped around a core of histone proteins in the nuclei of cells. When SAHA inhibits HDAC, it allows the DNA to unwrap, permitting the genes in the DNA chain to receive cellular signals that express them, or turn them on, which can stop the growth and development of cancer cells.

"The molecular snapshots we created provided a clear pathway for the development of other molecules like vorinostat," said Dr. Marks.

Vorinostat has shown significant anticancer activity in both hematologic and solid tumors in clinical trials directed by physician-investigators at Memorial Sloan-Kettering, led by medical oncologists W. Kevin Kelly and Howard I. Scher. The drug was approved by the FDA for CTCL, a rare, slow-growing cancer of infection-fighting T cells that affects the skin as well as internal organs.

Memorial Sloan-Kettering researchers continue to study vorinostat in the lab and in patients. Currently, there are more than 35 clinical trials evaluating the safety and effectiveness of vorinostat as a single agent or in combination with other treatments, including radiotherapy, in patients with a wide spectrum of cancer types. Clinical trials at Memorial Sloan-Kettering are evaluating the effectiveness of the drug in patients with advanced prostate cancer and glioma (a type of brain tumor).

It is not clear why some patients with a particular type of cancer respond to HDAC inhibitors and others do not, Dr. Marks explained, and this is a major area of ongoing research in his laboratory. "The present goal of our work is to discover markers in tumor cells that might identify which patients are most likely to respond to vorinostat," he said. "We are also investigating the basis of the resistance of normal cells and the sensitivity of cancer cells to HDAC inhibitors, which may provide new insights as to how to better use these drugs."