- Author: Kathy Keatley Garvey
The Hammock lab and the Guodong Zhang lab at the University of Massachusetts published exciting research today (April 30) in the Proceedings of the National Academy of Sciences that involves hope for patients with obesity-enhanced colon cancer.
Their research showed that inhibiting an enzyme, soluble epoxide hydrolase--discovered in the Hammock lab--may reduce the risk of obesity-enhanced colon cancer and may offer a therapeutic target to block and treat colonic inflammation.
Co-first authors Weicang Wang and Jianan Zhang of the Zhang lab, and Jun Yang of the Hammock lab/UC Davis Comprehensive Cancer Center, noted that 30 percent of Americans are obese, and these individuals have a 30 to 60 percent higher risk of developing colon cancer. It is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Colon inflammation is an early symptom of cancer.
“But to date, the mechanisms by which obesity increases cancer risks are not well understood, and there are few effective strategies to prevent obesity-enhanced colon cancer," said Zhang, a former postdoctoral researcher in the Hammock lab and now an assistant professor of food science at UMass where he focuses his research on prevention of colonic inflammation (inflammatory bowel disease) and colon cancer. "Our study showed that soluble epoxide hydrolase and its metabolites are over-expressed in colon of obese mice. In addition, we found that pharmacological inhibition or genetic deletion of soluble epoxide hydrolase (sEH) abolishes obesity-induced inflammation and activation of pro-tumorigenic pathways in colon. These results showed that sEH is an essential enzyme involved in obesity-enhanced colonic inflammation and potentially colon cancer, and pharmacological inhibitors of sEH could be novel agents for prevention of these diseases.”
In the study, the 18-member team investigated the roles of sEH in obesity-induced colonic inflammation, which included using two different sEH inhibitors and a knockout mouse genetically modified not to produce sEH. Results proved similar in all cases.
They further conducted another study in both lean and obese mice with experimentally induced colon inflammation and used molecular analyses to follow a pathway called Wnt. About 90 percent of sporadic colorectal cancers have activating mutations within the Wnt pathway. The team found that obesity increases activation of Wnt signaling in the colon, but it can be abolished by the two different inhibitors and the knockout.
“The sEH inhibitor blocked obesity-induced colon inflammation,” said Hammock. “This worked even for mice on high fat diets.”
“Colon inflammation is highly associated with a variety of diseases and the inflammation often progresses to colon cancer,” Hammock said. “Weicang Wang, Guodong Zhang and co-workers have done a meticulous job investigating the biologically active fats including fatty acid diols that are associated with the inflammation. By blocking the production of these diols they were able to block the inflammation.”
“The study was an exciting discovery from lipidomics technique,” said co-first author Jun Yang. “The consistent results from pharmacologic inhibition and genetic knockout (KO) as well as the signaling pathway mechanistic studies all support sEH as a potential treatment for obesity-induced colon inflammation."
Co-author Jun-Yan Liu is already collecting human samples to extend the study, and Hammock pointed out that they hope that the soluble epoxide hydrolase inhibitor will be in human clinical trials this year.
This work, titled “Lipidomic Profiling Reveals Soluble Epoxide Hydrolase as a Therapeutic Target of Obesity-Induced Colonic Inflammation,” drew grant support from the USDA's National Institute for Food and Agriculture; National Institutes of Health's National Institute of Environmental Health Sciences (NIH/NIEHS); NIEHS Superfund Research Program, and the National Natural Science Foundation of China.
The five UC Davis researchers—Bruce Hammock, Jun Yang, Jia Sun, and Sung Hee Hwang and Debin Wan—are all with the Hammock lab/UC Davis Comprehensive Cancer Center.
The UMass researchers, in addition to those listed above: Yuxin Wang, Wiepeng Qi, Haixia Yang, and Professor Yeonhwa Park, Department of Food Science, Katherine Sanidad, Food Science and Molecular and Cellular Biology Graduate Program, and Professor Daeyoung Kim of the Department of Mathematics and Statistics.
Hammock, a member of the National Academy of Sciences and the National Academy of Inventors, directs two major UC Davis programs; the Superfund Program financed by the National Institute of Environmental Health's National Institute of Environmental Health Sciences (NIH-NIEHS); and the NIH Biotechnology Training Program. He began his career reseaching insect pests but switched to human health issues.
To date, the Hammock laboratory has published almost 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, and pain and inflammation.
For many years Gill and Hammock were alone in studying this enzyme but today its importance is well recognized in mammalian biology, with more than 17,000 peer-reviewed papers in the area. Hammock credits the NIEHS for supporting research in this area since the 1970s.
A Davis-based company, EicOsis, has received a large grant from the U.S. National Institutes of Health to move inhibitors to the clinic to treat diabetic neuropathic pain. “We are developing a non-opiate analgesic to treat the chronic pain often associated with diabetes and hope to be in human trials over the next 12 months,” said William Schmidt, vice president of clinical development at EicOsis.
- Author: Kathy Keatley Garvey
He's an entomologist, trained to find ways to control insect pests, but now he aims to help humans with medical issues, including diabetes, high blood pressure and depression.
Bruce Hammock, distinguished professor of entomology at UC Davis, has just received the international John C. McGiff Memorial Award for his pioneering contributions to eicosanoid research.
The average person on the street probably has no clue what eicosanoids are. Well, as Hammock explains: "Eicosanoids are a particular class of fats that, rather than being nutritional or structural, are regulatory. They regulate blood pressure, childbirth, pain, inflammation, tissue repair and other biologies. By mass, more than 75 percent of the world's medications work on the eicosanoid pathway. These include such familiar drugs as aspirin, Advil, Ibuprofin and Motrin."
Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, received the award during the International Winder Eicosanoid (WEC) Conference, March 13-16 in Baltimore, Md. He delivered the McGiff Memorial Lecture on “Epoxide Hydrolase Inhibitors as Biochemical Probes and Drug Candidates.”
“The current drugs that alter the eicosanoid pathways block the formation of drugs that block natural fats that increase hypertension, increase pain and increase inflammation,” Hammock explained. “We have been working on a third branch of the pathway that reduces blood pressure, inflammation and pain. By blocking the degradation of these natural molecules we block harmful biologies. These new drugs are promising for control of diabetes, hypertension and other diseases. We are working to move some of these compounds that work outside of the brain to the clinic for both man and companion animals to control inflammatory and chronic pain.”
"However, we found that some of our compounds reach the brain where they can reduce complications from stroke and convulsions, including those from epilepsy. Based on these brain-penetrating compounds, Kenji Hashimoto's lab at the Chiba University Center for Forensic Mental Health, Japan, found that they are promising for depression, bipolar disorders and some other central nervous system effects. These compounds have proven valuable to numerous investigators to understand disease biology and are being followed by several drug companies.”
Using the newly discovered chemical in the Hammock lab, the UC Davis and Hashimoto researchers drew international attention on March 14 for their publication in the Proceedings of the National Academy of Sciences (PNAS). The result could be a new, innovative tool to control depression, a severe and chronic disease that affects 350 million persons worldwide, they said.
“The research in animal models of depression suggests that sEH plays a key role in modulating inflammation, which is involved in depression,” according to the UC Davis-issued news release. “Inhibitors of sEH protect natural lipids in the brain that reduce inflammation, and neuropathic pain. Thus, these inhibitors could be potential therapeutic drugs for depression.”
WEC is a group of scientists who have high standards of research, but freely collaborate and exchange reagents and ideas. It represents science at its best. "Never would we have made the advances we have at Davis without this friendship and collaboration of scientists from around the world,” Hammock said. This year's conference drew 150 scientists.
Bruce Hammock, who received his doctorate in entomology/toxicology from UC Berkeley in 1973, joined the UC Davis entomology faculty in 1980. With Sarjeet Gill (now at UC Riverside) he discovered that the enzyme, soluble epoxide hydrolase (sEH), degrades fatty acid epoxides and plays an important role in human diseases. He and his lab have developed inhibitors of sEH that are anti-inflammatory, anti-hypertensive, analgesic and organ-protective. Recently he founded the company, Eicosis LLC, to target diabetic neuropathic pain. The company just received two large federal grants for translational drug development and aims to move one of the sEH inhibitors to human clinical trials.
The Hammock lab is the 30-year home of the UC Davis/NIEHS Superfund Research and Training Program, an interdisciplinary program funded by the National Institute of Environmental Sciences (NIEHS) that has brought in almost $60 million to the UC Davis campus. The Hammock lab is also the home of the NIH Training Grant in Biomolecular Technology. The lab alumni, totaling more than 100 graduates, hold positions of distinction in academia, industry and government as well as over 300 postdoctorals.
The UC Davis distinguished professor has authored or co-authored more than 1020 peer-reviewed publications, many in top journals. This includes 500 related to epoxide hydrolase, 80 related to esterase and amidase, more than 260 related to immunoassay, and 240 related to insect biology.
Hammock is a fellow of the National Academy of Inventors (NAI), which honors academic invention and encourages translations of inventions to benefit society. He is a member of the National Academy of Sciences (NAS) and the recipient of numerous other awards, including major teaching awards at UC Davis.
And yes, he's an entomologist. He's a fellow of the Entomological Society of America (ESA) and recipient of the ESA's Recognition Award for Insect Physiology, Biochemistry and Toxicology.
Bruce Hammock: from six-legged insect pests to two-legged Homo sapiens.