Earlier research by the Judah Folkman laboratory of Harvard Medical School showed that cutting off blood vessels that feed a cancerous tumor can stop its growth.
The seven-member research team—five from the Bruce Hammock laboratory of UC Davis—“characterized a novel lipid signaling molecule that can change fundamental biological processes involved in our health and disease,” said lead author and researcher Amy Rand. “We've found that a novel product derived from the metabolism of omega-6 fatty acids stimulates angiogenesis, which may contribute to enhanced tumor growth by providing tumors with oxygen and nutrients.”
“As a highly regulated process, angiogenesis is critical for wound healing and development, but many diseases result in unregulated angiogenesis, including cancer,” explained Rand, a postdoctoral fellow in the lab of Bruce Hammock, a distinguished professor who holds a joint appointment with UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “We may be able to control angiogenesis to stimulate wound healing when necessary, but also block tumor growth in patients. Diseases that rely on angiogenesis may be able to be treated in part by changes in dietary lipid exposure or by controlling levels of these metabolites through enzyme inhibitors that block their formation.”
The research, published April 10 in the Proceedings of the Natural Academy of Sciences (PNAS), explains, in part, why inhibiting the soluble epoxide hydrolase (sEH) in some systems is angiogenic whereas combining sEH inhibition with the inhibition of cyclooxygenase (COX) enzymes is dramatically antiangiogenic, which in turn may suppress tumor growth.
“There's uncertainty regarding the link between unsaturated fats and cancer, due to ongoing conflicts between scientific studies and insufficient data,” Rand said. “Because of this, there is a major gap in our understanding of how these essential dietary fats affect our health. We used tools to detect and characterize unknown metabolites from omega-6 unsaturated fats and determined their effect on angiogenesis, to address at least a small part of this uncertainty by focusing on how these fats contribute to cancer tumor growth.”
Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, said the research, titled “Cyclooxygenase-Derived Proangiogenic Metabolites of Epoxyeicosatrienoic Acids
Holds long term hope for cancer patients and those afflicted with heart, eye and other diseases. The team also included Christophe Morisseau, Bogdan Barnych, and Kin Sing Stephen Lee all of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center; Tomas Cajka of the UC Davis Genome Center; and Dipak Panigraphy of Harvard Medical School. Lee is now an assistant professor at Michigan State University.
“Pro and anti-angiogenic therapy can potentially help millions of people worldwide in various diseases such as heart, ulcers, eye and cancer as first demonstrated by Dr. Judah Folkman and his colleagues,” said Panigraphy, formerly of the Hammock lab and now with the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, and the school's Department of Pathology.
“While the COX and sEH pathways can be targeted with drugs, their interaction is poorly understood,” Panigraphy said. “These studies by Rand et al demonstrate for the first time new specific mechanisms whereby targeting the sEH pathway can be both pro- and anti-angiogenic and has the potential to help patients with devastating diseases such as in the eye and cancer where blocking angiogenesis is desired.”
Rand, who received her doctorate in chemistry from the University of Toronto, Canada, in 2013, the same year she joined Hammock's biological analytical chemistry lab, said she's “always been interested in research that combines chemistry and biology to enhance our understanding of human health.”
Future work? “We aim to understand the direct involvement of these omega-6 fatty acid metabolites with cancer tumor growth and metastasis.”
Rand last year received the $100,000 Judah Folkman Fellowship for Angiogenesis Research from the American Association for Cancer Research. She won the highly competitive international award for her proposal, “Regulation of Cancer Angiogenesis from the Metabolism of Epoxy Omega-6 Fats.” Rand joined Hammock's biological analytical chemistry lab in 2013 and was a fellow on the Oncogenic Signals and Chromosome Biology T32 Training Grant, UC Davis Department of Microbiology and Molecular Genetics.
The late Judah Folkman (1933-2008), a Harvard Medical School professor considered the father of angiogenesis research, “is best known for pioneering the concept of blocking angiogenesis (the development of blood vessels) to control cancer growth," Hammock said. "This concept has resulted in a number of anti-cancer drugs and has had a major impact on cancer treatment. Of course, blood vessel development is also critical for survival."
Folkman discovered that cutting off the blood vessels that feed the tumor can stop cancer tumor growth. His revolutionary work has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization. Inhibitors of the sEH pathway are moving toward human trials to control neuropathic pain, but if combined with nonsteroidal anti-inflammatory drugs can block tumor growth by blocking angiogenesis. So Dr. Sung Hee Hwang combined inhibitors of both pathways into one molecule which is being investigated in cancer models at the UC Davis Cancer Center by Dr. Paul Henderson and Northwestern University Medical School by Dr. Guang-yu Yang.
Hammock directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
This work was supported by NIEHS and the NIEHS Superfund Program; and two of Rand's grants: the Oncogenic Signals and Chromosome Biology T32 Training Grant, NIH/NIEHS; and her 2016 AACR Judah Folkman Fellowship for Angiogenesis Research.
Researchers at the Huazhong University of Science and Technology, Wuhan China, used the drug developed at UC Davis to show that the neurofibrillary pathology of an Alzheimer's disease-related protein could be dramatically reduced. Their work was published in December in the Journal of Huazhong University of Science and Technology.
“They further demonstrated the mechanism of action of the UC Davis drug in blocking the oxidative stress-driven phosphorylation events associated with Alzheimer's disease,” Hammock said. The UC Davis drug stabilizes natural anti-inflammatory mediators by inhibiting an enzyme called soluble epoxide hydrolase (sEH) discovered at UC Davis and recently spotlighted in the Proceedings of the National Academy of Sciences and the National Institutes of Health's PubMed.
“I was thrilled to see this paper on tau phosphorylation from Huazhong University shows that our drug could block a key event and a key enzyme called GSK-3 beta thought critical in the development of Alzheimer's disease,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“We were planning to do this study, but having another laboratory do it with our compound was even better,” he said. “Since our publication last year in PNAS that showed UC Davis soluble epoxide hydrolase inhibitors both prevented and reversed depression, we have been excited about trying to block the development of Alzheimer's disease.”
The PNAS paper, “Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress,” was co-authored by a 13-member research team led by Hammock and Kenji Hashimoto of Chiba University Center's Division of Clinical Neuroscience, Japan. They found that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression and several other disorders of the central nervous system. Co-authors of the paper included Hammock lab researchers Christophe Morisseau, Jun Yang and Karen Wagner.
Hammock credited several UC Davis colleagues for their work leading to the publications. Research from the labs of Liang Zhang and Qing Li at the University of Hawaii--Qing is a former UC Davis doctoral student--pointed out some of the mechanisms involved in cognitive decline which associate professor Aldrin Gomes of the UC Davis Department of Neurobiology, Physiology and Behavior and Fawaz Haj of the UC Davis Department of Nutrition “have shown to be blocked by the natural metabolites stabilized by the UC Davis drugs,” Hammock said.
One of the Hammock lab drugs is moving toward human clinical trials for neuropathic pain through a Davis-based company, EicOsis, LLC, and the financial support of the Blueprint Program through NIH's National Institute of Neurological Disorders and Stroke. Hammock founded the company to develop inhibitors to the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of fatty acids, to treat unmet medical needs in human and animals.
“The clinical back-up candidate at EicOsis penetrates the blood brain barrier and should be a perfect compound to test if this class of chemistry can prevent cognitive decline and Alzheimer's disease,” Hammock said.
The National Institute of Environmental Health Sciences, National Institutes of Health, funded the research.
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
“We think that this research will lead to a very positive outcome to improve the lives of cystic fibrosis patients,” said co-author Bruce Hammock, distinguished professor in the UC Davis Department of Entomology and Nematology who holds a joint appointment with the UC Davis Comprehensive Cancer Center.
The research, published in the current edition of the Proceedings of the National Academy of Sciences, links a newly discovered class of bacterial enzymes to battling cystic fibrosis, a progressive, genetic disease characterized by persistent lung infections and inability to breathe normally.
Senior author Jennifer Bomberger of the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine explained that the opportunistic bacterium, Pseudomonas aeruginosa, outcompetes other microorganisms in a cystic fibrosis patient's lungs and establishes a stronghold.
In analyzing secretions drawn from the lungs of cystic fibrosis patients at the Children's Hospital of Pittsburgh, the scientists discovered that the bacterium perpetuates inflammation by secreting an enzyme called Cif that sabotages the body's ability to make a key molecule called a "pro-resolving lipid mediator" and stop the inflammatory response it started.
The scientific discovery could lead to new therapies that would interrupt or correct the bacterial sabotage, Hammock and Bomberger said.
“This paper is the outcome of an exciting and interdisciplinary project,” said Hammock, who directs the UC Davis Superfund Program financed by the National Institutes of Health's National Institute of Environmental Health Sciences (NIH-NIEHS).
“It started several years ago with the NIEHS Superfund Program funding both a group at Dartmouth and at UC Davis. A very productive and exciting collaboration resulted in looking at how to mitigate the effects of environmental chemicals on human health. Our collaborative work led to this joint publication which yields exciting hope for cystic fibrosis patients.”
Bomberger continues to work on the biology of the system while the Dartmouth and Davis groups have developed inhibitors of the action of CIF to stabilize pro-resolving mediators, reduce inflammation, and control periodic flare ups of bacterial infections.
"It will be key to devise a way to remove P. aeruginosa's ability to capitalize on the body's natural inflammatory response, without eliminating that response," said Bomberger. "Inflammation is happening for a reason—to clear infection. We just need it to temper the response when it is not effectively doing its job or is no longer needed."
Other co-authors of the paper include Hammock lab members Christophe Morisseau and Jun Yang, both from the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center. .Institutions involved in the study also included the Harvard School of Medicine.
Water warriors Bruce Hammock, distinguished professor of entomology with a joint appointment with the UC Davis Comprehensive Cancer Center, and research scientist Christophe Morisseau of the Hammock lab proved to be “The Splash Brothers,” much like basketball superstars Steph Curry and Klay Thompson of the Golden State Warriors.
But they did it with water balloons, not with a basketball.
It was all part of the 13th annual Hammock Lab Water Balloon Battle, dubbed “Balloon Battle at Briggs” last Friday afternoon. The 40 participants, including professors, researchers, graduate students, staff, students and family members, tossed 3000 water balloons in 15 minutes on the thirsty Briggs Hall lawn, as the temperature soared to 97 degrees. As the supply dwindled, they dumped the remaining water from the buckets on each other.
A highlight: “Splash Sister” Alifia Merchant of the Hammock lab, who just received her master's degree in agriculture and environmental chemistry, managed to sneak up on Hammock and drench him.
Hammock launched the annual event in 2003 as a form of camaraderie and as a means of rewarding the lab members for their hard work. The international Hammock lab includes 7 researchers, 9 postdoctorates, 3 graduate students, 10 visiting scholars, 3 staff and 1 undergrad. They represent Barbados, Canada, China, France, Germany, Hong Kong, India, Japan, Korea, Sweden, Thailand, Turkey, United States, Ukraine and Uruguay.
Among those participating was Aldrin Gomes, associate professor in the Department of Physiology and Membrane Biology, and his lab.
When UC Davis police officer Stephen Jerguson passed by on foot, he was invited to join in on the fun. Seven-year-old Jasmine Morisseau, daughter of Christophe Morisseau, handed him a water balloon for safe-keeping as he watched the fun-in-the-sun event from the sidelines. At the end of the battle, he handed it back to her. He then joined the group in cleaning up the balloon remnants.
Hammock, a member of the National Academy of Sciences and a fellow of the National Academy of Inventors, directs the campuswide 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 National Institutes of Health 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 more than 300 postdoctorates.
The “Balloon Battle at Briggs” was canceled last year due to the severity of the California drought.
In 2014, the water warriors took drought-conservation precautions as they did this year.
“We devised a filling station out of drip line and valves so we could fill the balloons outside and also turn off the water when not in use,” said Hammock lab program manager Cindy McReynolds. “Water conservation was a big topic surrounding the (2014) event, so we also used it as an opportunity to discuss ways we have changed our daily routines to conserve water."
As an extra bonus, the annual battle provides a little water for the thirsty Briggs Hall lawn, which is used by campus wildlife, including ducks, turkeys, squirrels, birds, butterflies and bees.
The research, published March 14 in the journal Proceedings of the National Academy of Sciences, involves studies of an inhibitor of soluble epoxide hydrolase in rodents. Soluble epoxide hydrolase, or sEH, is emerging as a therapeutic target that acts on a number of inflammatory or inflammation-linked diseases.
“The research in animal models of depression suggests that sEH plays a key role in modulating inflammation, which is involved in depression,” said Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Comprehensive Cancer Center. “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.”
Researchers from Hammock's laboratory, collaborating with depression expert Kenji Hashimoto and colleagues at the Chiba University Center for Forensic Mental Health, Japan, examined the role of the potent sEH inhibitor known as TPPU, in a rodent model of depression, “social defeat.”
They found that TPPU displayed rapid effects in both inflammation and social defeat-stress models of depression. Expression of sEH protein was higher in key brain regions of chronically stressed mice was higher than in control mice, they found.
“Most drugs for psychiatric diseases target how neurons communicate; here we are targeting the wellness and environment of the neurons,” said UC Davis researcher Christophe Morisseau.
Said UC Davis researcher Karen Wagner: “The rapid antidepressant action of the sEH inhibitor in these murine models of depression is truly noteworthy because current antidepressants used in humans and animal models take weeks to have full effects.”
The researchers also discovered that postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, showed a higher expression of sEH than controls.
The researchers found that pretreatment with TPPU prevented the onset of depression-like behaviors in mice after induced inflammation or repeated social-defeat stress. Mice lacking the sEH gene did not show depression-like behavior after repeated social-defeat stress.
“All these findings suggest that sEH plays a key role in the pathophysiology of depression and that epoxyfatty acids, and their mimics as well as sEH inhibitors, are potential therapeutic or prophylactic drugs for depression,” Hashimoto said.
Robert E. Hales, distinguished professor of clinical psychiatry and the Joe P. Tupin Endowed Chair of the Department of Psychiatry and Behavioral Sciences at UC Davis School of Medicine, said new medication treatment approaches are needed to treat depression. Hales, who was not involved in the research, said the new paper represents “an important and novel approach to treating depression.”
“With lifetime prevalence rates of major depressive disorder being in the range of 16 percent and with nearly two-thirds of patients failing to respond to pharmacologic treatments, there is a pressing need to discover new medication treatment approaches,” Hales said. “Their findings lend support to the potential use of TPPU, a sEH inhibitor, as a new therapeutic medication to prevent and treat depression.”
Other authors on the paper are: Qian Ren, Min Ma, Tamaki Ishima, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong, and Mei Han, Chiba University; and Jun Yang at UC Davis.
Morisseau, Yang and Wagner are inventors on University of California patents related to soluble epoxide hydrolase. Some of these patents have been licensed by EicOsis Human Health, a Davis company founded by Hammock to develop pharmaceuticals to alleviate neuropathic and inflammatory pain.
The research was funded by Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan to Kenji Hashimoto, (#24116006), and a Research Fellowship for Young Scientists of the Japan Society for the Promotion of Science (Tokyo, Japan) to Qian Ren.
Partial support was provided by the National Institute of Environmental Health Sciences (NIEHS) R01 ES002710, NIEHS Superfund Research Program grant P42 ES004699, and NIH U24 DK097154 West Coast Comprehensive Metabolomics Center.
Hammock and Professor Bruce German, UC Davis recently received a National Institutes of Health grant in collaboration with Pei-an Shih, UC San Diego Department of Psychiatry, to investigate the role of bioactive lipids in a related psychiatric disorder, anorexia nervosa.