The Burnham Institute’s Jeffrey Smith, PhD, has discovered that orlistat, commonly prescribed as an anti-obesity drug, has a positive side-effect: it inhibits cancer growth. Dr. Smith made this discovery using an activity-based proteomics screening technique developed in his laboratory that makes it possible to identify active targets and simultaneously screen for their inhibitors. These results are published in the March 15th edition of Cancer Research.
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™, as an inhibitor of fatty acid synthase.
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. Further experiments confirmed that orlistat has no effect on normal prostate cells and no apparent side effects in the mice; it acts specifically on 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.
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 good insights into the mechanism, which we anticipate will 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 and 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.