Several Clinical Trials Are Underway at Memorial Sloan-Kettering to Examine the Effectiveness of Natural Products in Killing Cancer Cells
From antibiotics to painkillers to cancer drugs, many molecules found in nature have proven to be remedies for human disease. At Memorial Sloan-Kettering, a handful of drugs now in clinical trials have been derived from sources ranging from microorganisms to plants to marine creatures. The theory behind the development of drugs from natural products is that these molecules inherently have some kind of biological function, and that function can be enhanced and exploited to develop effective treatments for patients.
From the earliest days of traditional medicine, plants have been used to treat ailments and ease suffering caused by disease. The pharmaceutical industry had its origins in the late 19th century when it began to manufacture medications such as aspirin and morphine, which were initially found in nature. Two of the earliest successful cancer drugs, vinblastine and vincristine -- both conceived in the 1950s to treat leukemia and still used today -- were developed from molecules isolated from the Madagascar periwinkle. This prompted the National Cancer Institute in 1960 to initiate a large-scale project to collect samples from plants and marine organisms all over the world and test them for antitumor activity. Today, more than 60 percent of all cancer drugs are derived from or inspired by compounds found in nature.
"Some of the best cancer drugs on the market today originally came from plants," said Memorial Sloan-Kettering Cancer Center medical oncologist Gary K. Schwartz, citing paclitaxel (Taxol®) -- which is used to treat tumors including breast, ovarian, and non-small cell lung cancers -- and irinotecan (Camptosar®) --- which is used primarily to treat colorectal cancer -- as two examples. "The reason that plants or animals create these compounds could be as a protective mechanism of evolution -- a response to some kind of noxious stimuli, such as bacteria or viruses. In nature, these molecules kill foreign substances, and in the same way they can kill cancer," he said.
"We believe natural products have evolved because they are the right size and shape to bind large biomolecules such as proteins and nucleic acids," said Memorial Sloan-Kettering Cancer Center chemist Samuel J. Danishefsky, who is a leader in the field of natural product synthesis. "In addition, by definition they have shown their ability to be viable inside living species. These are two important milestones that provide an immediate advantage over other potential drug candidates."
For the past several years, much of Dr. Danishefsky's work has focused on the synthesis of a class of drugs called the epothilones. Epothilones come from the bacterium Sorangium cellulosum, which was originally isolated from soil found on riverbanks in Africa. The epothilones use the same mechanism that paclitaxel and its semisynthetic variant docetaxel (Taxotere®) do to block the formation of the mitotic spindle, which is an essential part of cell division. However, in the test tube and in mouse models of cancer, the epothilones appear to be less toxic to healthy cells than some other drugs and have the ability to destroy tumors that have developed resistance to paclitaxel and other drugs.
Dr. Danishefsky was the first to synthesize the key epothilones in the laboratory and has since created more than 100 analogs -- molecules that are similar but have different chemical groups attached. One epothilone analog that appears particularly promising in preclinical research is Fludelone, which has been studied for its effectiveness in killing cancer cells, including breast, ovarian, colon, prostate, leukemia, and multiple myeloma. Clinical trials for Fludelone have not begun, but the Center has been involved with early trials of two other epothilone drugs.
Pharmacologist Ting-Chao Chou has collaborated closely with Dr. Danishefsky in evaluating many of the epothilone analogs. "Instead of randomly screening a huge number of molecules for activity, we choose to learn from Mother Nature," Dr. Chou said. "We are using the information we collect in the laboratory to design better compounds and to develop better therapeutic strategies for treating cancer."
Another natural-product drug developed at Memorial Sloan-Kettering Cancer Center is 17-AAG, a derivative of the antibiotic geldanamycin, isolated from the microorganism Streptomyces hygroscopicus. A "targeted therapy," 17-AAG inhibits heat-shock protein 90 (HSP90), which plays an important role in cell growth and survival. Neal Rosen, a medical oncologist and researcher in the Molecular Pharmacology and Chemistry Program, has been studying the drug for the past decade. In several research projects, led by David B. Solit, who was then a research fellow and is now an assistant attending physician at Memorial Sloan-Kettering Cancer Center, members of Dr. Rosen's laboratory did much of the preclinical work demonstrating that the drug was safe in animal models and effective at killing a number of tumors, including those with mutations in the genes HER2/neu, BCR-ABL, or BRAF. In 1997, Memorial Sloan-Kettering Cancer Center structural biologist Nikola P. Pavletich published a paper revealing the structure of the HSP90 protein and showing how geldanamycin binds to it.
