The metabolism of a tumor cell is different from its normal counterpart cell. Scientists have long suspected that metabolism is connected to tumor progression. Dr. Smith and co-workers designed a proteomics screen based on monitoring the activity of a family of enzymes--serine hydrolyases--involved in metabolism. They used their screen to compare normal prostate cells with prostate cancer cells and discovered that the prostate cancer cells are affected by an increased activity of fatty acid synthase. Fatty acid synthase is the enzyme that converts dietary carbohydrate to fat.
The screen also identified orlistat, marketed by Roche as Xenical
These discoveries, made in vitro, held true when tested in mice. When they administered orlistat to mice bearing prostate tumors, the Smith laboratory discovered that the drug was able to inhibit tumor growth in mice. Further experiments confirmed that orlistat has no effect on normal prostate cells and no apparent side effects in the mice; it acts specifically as fatty acid synthase.
Additional screening of breast cancer and colon cancer cells revealed that fatty acid synthase activity is upregulated in these tumors, as well, presenting the possibility of designing new treatments for these cancers based on inhibiting the enzyme's activity with orlistat or a new drug based on orlistat's inhibitory activity.
Orlistat was originally developed as an inhibitor of pancreatic lipase. Pancreatic lipase is a member of the same enzyme family--the serine hyrdolases--used in Smith's screening. It is involved in processing of fats in the digestive tract, which is how the drug prevents adsorption of dietary fat.
The method developed by Dr. Smith represents a quantum leap in drug discovery. So-called "activity-based" proteomics screening is a new frontier in medical research, based on applying information gleaned from the human genome project. The ability to compile a comprehensive profile of a potential drug's activities, revealing unintended activities along with the intended behaviors targeted by the drug offers a systematic way to simulate how a drug will work, before it is actually tested in animals and humans.
Given the time and cost inherent in developing new treatments, activity-based proteomics screening opens up a new route for finding effective treatments based on monitoring basic cell behaviors, such as metabolism or respiration.
Proteomics screening is an efficient way to determine proof of concept needed before a potential treatment can be refined for clinical trials: in a matter of weeks, Dr. Smith was able to glean the initial discovery that linked excessive fatty acid synthase activity with flawed metabolism in cancer cells, and identified orlistat as its inhibitor.
"This discovery with orlistat has given us a very nice wedge with which we can go in and perturb tumor cells and ask the question, 'What are the active targets, what are the other changes that take place when you inhibit fatty acid synthase?'", says Dr. Smith, "and that will give us really good insights into the mechanism, and we anticipate that's going to reveal a whole swath of additional drug targets along this pathway. This is a big advance in the sense that we have an approved drug--approved for one indication--that has another target and another potential disease indication, prostate cancer."
Dr. Smith is Associate Scientific Director for Technology at The Burnham Institute, where he is also a Associate Professor in the Institute's NCI-designated Cancer Center.
Co-authors contributing to this study include Drs. Steven J. Kridel and Fumiko Axelrod, postdoctoral fellows at The Burnham Institute, and Dr. Natasha Rozenkrantz of Activix Biosciences in La Jolla.
This research was supported by grants from the National Cancer Institute, and the Department of Defense's Prostate Cancer Program.
The Burnham Institute is an independent, nonprofit, public benefit organization dedicated to basic biomedical research principally in the areas of cancer, aging, and the neurosciences. The Institute ranks consistently among the world's most influential research organizations for the impact of its research in analyses conducted annually by the Institute for Scientific Information.