Cancer research published by a team of scientists, including the Bruce Hammock laboratory, University of California, Davis, has been named the Journal of Clinical Investigation's Editor's Pick for the month of July.
Scientists from UC Davis and Harvard Medical School co-authored the paper on how blocking inflammation and/or activating the resolution of inflammation before surgery or chemotherapy can eradicate small tumors and promote long-term survival in experimental animal cancer models.
The paper, “Preoperative Stimulation of Resolution and Inflammation Blockade Eradicates Micrometastases,” available online beginning June 17, combines the expertise of Professor Bruce Hammock and researcher Jun Yang of UC Davis with that of the Harvard Medical School team led by Dipak Panigrahy and Allison Gartung; Professor Vikas Sukhatme from Emory University School of Medicine, Atlanta; and Professor Charles Serhan from Brigham and Women's Hospital/Harvard Medical School.
“During chemotherapy or surgery, dying cancer cells can trigger inflammation and the growth of microscopic cancerous cells,” said Hammock, a distinguished professor who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“We found that preoperative, but not postoperative, administration of the nonsteroidal anti-inflammatory drug ketorolac and/or resolvins, a family of specialized pro-resolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival,” Gartung said. “Moreover, we found that ketorolac and resolvins exhibited synergistic anti-tumor activity and prevented surgery or chemotherapy-induced tumor dormancy escape in our animal models.”
Serhan explained that “Ketorolac unleashed anti-cancer T-cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Pre-operative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses.”
“Collectively, our findings suggest a paradigm shift in clinical approaches to resectable cancers," said Sukhatme. "Simultaneously blocking the ensuing pro-inflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence."
This novel approach of blocking inflammation and/or accelerating the resolution of inflammation before a surgical procedure also holds promise for patients who do not have cancer. “More than 30 percent of healthy individuals harbor microscopic cancers," Panigraphy said. "Non-cancer surgery and anesthesia may promote the growth of existing micro-tumors."
- Dipak Panigrahy, Allison Gartung, Haixia Yang, Molly M. Gilligan, Megan L. Sulciner, Jaimie Chang, Julia Piwowarski, Anna Fishbein, and DulceSoler-Ferran, all with the Cancer Center, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School (HMS);
- Charles N. Serhan from the Center for Experimental Therapeutics and Reperfusion Injury and Department of Anesthesiology, Perioperative and Pain Medicine at Brigham and Women's Hospital, HMS;
- Vikas P. Sukhatme from the Department of Medicine and Center for Affordable Medical Innovation at Emory University School of Medicine;
- Jun Yang and Bruce D. Hammock from the Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center at University of California, Davis;
- Swati S. Bhasin and Manoj Bhasin from the Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, at BIDMC, HMS;
- Diane R. Bielenberg, Birgitta A. Schmidt and Steven J. Staffa from the Vascular Biology Program, Department of Pathology, and Department of Anesthesiology, Critical Care and Pain Medicine at Boston Children's Hospital (BCH), HMS;
- Matthew A. Sparks from the Division of Nephrology, Department of Medicine at Duke University and Durham VA Medical Centers;
- Vidula Sukhatme from GlobalCures Inc.;
- Mark W. Kieran from Division of Pediatric Oncology at Dana-Farber Cancer Center Institute and Department of Pediatric Hematology/Oncology at BCH, HMS; and Sui Huang from the Institute of Systems Biology.
The researchers said the project drew generous support from the National Cancer Institute (Panigrahy and Serhan), Beth Israel Deaconess Medical Center, the Credit Unions Kids at Heart Team (Panigrahy), C.J. Buckley Pediatric Brain Tumor Fund (Kieran), the Kamen Foundation (Kieran), the Joe Andruzzi Foundation (Kieran), National Institute of Environmental Health Science Superfund Research Program (Hammock); National Institute of Environmental Health Science (Hammock), Sheth family (Sukhatme), Stop and Shop Pediatric Brain Tumor Fund (Kieran), Molly's Magic Wand for Pediatric Brain Tumors (Kieran), the Markoff Foundation Art-In-Giving Foundation (Kieran), and Jared Branfman Sunflowers for Life (Kieran).
For 20 years, the Hammock lab has been researching an inhibitor to an enzyme, epoxide hydrolase, which regulates epoxy fatty acids, but the inhibitor drug was not involved in this particular research. However, many other publications and ongoing cancer research projects are. "My research led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis," Hammock said. "The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes.”
Hammock and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, discovered the target enzyme in mammals while they were postgraduate students at UC Berkeley.
Now, newly published research on ovarian cancer, involving an anti-inflammatory compound discovered and developed in the Bruce Hammock lab at the University of California, Davis, and tested at Harvard Medical School on mice models, indicates that the compound not only suppresses inflammation but reduces cancer growth, acting as a “surge protector.”
“We are excited about this research and its potential,” said Hammock, a UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “Chemotherapy and surgery, the mainstays of conventional cancer treatment, can act as double-edged swords. It is tragic that the very treatments used to cure cancer are helping it to survive and grow.”
The research is a “novel approach to suppressing therapy-induced tumor growth and recurrence,” said the 13-member team from Harvard Medical School/Beth Israel Deaconess Medical Center (BIDMC), UC Davis, Institute of Systems Biology of Seattle, and Emory University School of Medicine of Atlanta.
Their paper, “Suppression of Chemotherapy-induced Cytokine/Lipid Mediator Surge and Ovarian Cancer by a Dual Cox-2, sEH Inhibitor,” appears today in the Proceedings of the National Academy of Sciences (PNAS).
“To prevent tumor-recurrence after therapy, it will be critical to neutralize the inherent tumor-promoting activity of therapy-generated debris,” said lead author Allison Gartung of Harvard Medical School/BIDMC. “Our results indicate that a dual COX-2/sEH inhibitor may offer a novel alternative to protect the body from a debris-mediated inflammatory response.”
Gartung said that the study confirmed that chemotherapy-killed ovarian cancer cells “induce surrounding immune cells called macrophages to release a surge of cytokines and lipid mediators that create an optimal environment for tumors to survive and grow.”
The team treated the mice models with a dual lipid pathway inhibitor discovered several years ago in the Hammock lab. It integrates two anti-inflammatory drugs (COX-2 inhibitor and soluble expoxide hydrolase (sEH) inhibitor) into a single molecule with the aim of reducing tumor angiogenesis and metastasis.
Chemist Sung Hee Hwang of the Hammock lab developed the compound, known as PTUPB, for the study. “The dual inhibitor here follows earlier work we did with it, blocking breast and lung tumors in mice,” Hammock said. “PTUPB is already being clinically evaluated for its therapeutic properties in other diseases.” Chemist Jun Yang of the Hammock lab did the mass spectrometry, showing how stabilization of lipid mediators reduces cancer growth and metastasis.
Lead researcher Dipak Panigrahy, a former Harvard physician turned full-time researcher, described chemotherapy and surgery “as our best tools for front-line cancer therapy, but chemotherapy and surgery create cell debris that can stimulate inflammation, angiogenesis, and metastasis. Thus, the very treatment used by oncologists to try to cure cancer is also helping it survive and grow. Overcoming the dilemma of debris-induced tumor progression is critical if we are to prevent tumor recurrence of treatment-resistance tumors which lead to cancer therapy failure.”
The tumor cell debris generates a “cytokine surge” that can result in a perfect storm for cancer progression. “The dual inhibitor acts as a surge protector,” Panigrahy said.
Panigrahy, who led angiogenesis and cancer animal modeling in the laboratory of Judah Folkman, a leading cancer research laboratory, based the debris model on his mother's chemotherapy treatments, and dedicated the research to his mother and “all other women who lost their lives to ovarian cancer.” American Cancer Society statistics show that among women, ovarian cancer ranks fifth in cancer deaths. A woman's risk of ovarian cancer is about 1 in 78; every year more than 14,000 die from the disease.
“Traditional cancer therapy sets up a dilemma,” Panigrahy commented. “Yes, we need to kill cancer cells but the inevitable byproduct of successfully doing so also stimulates tumor regrowth and progression. The more tumor cells you kill, the more inflammation you create, which can inadvertently stimulate the growth of surviving tumor cells. Overcoming the dilemma of debris-induced tumor progression is paramount if we are to prevent tumor recurrence of treatment-resistant tumors – the major reason for failure of cancer therapy. Our studies potentially pave the path for a new strategy for the prevention and treatment of chemotherapy-induced resistance with potential to translate to the clinic. If successful, this approach may also allow us to reduce the toxic activity of current treatment regimens.”
“The collaborative work in this paper not only defines a common problem with current cancer therapy, but it actually offers a potential solution to reduce metastasis and tumor growth following therapy,” said Primo Lara Jr., director of the UC Davis Comprehensive Cancer Center and associate director of Translational Research. “I am pleased that our Center was involved in this exciting project and we hope we can be involved in translating this basic research to the clinic.”
Panigrahy said that non-steroidal anti-inflammatory drugs (NSAIDs), which include aspirin and ibuprofen, reduce pain, fever and inflammation “bit may have severe side effects including stomach and brain bleeding as well as severe cardiovascular and kidney toxicity. They also do not specifically enhance clearing of debris.”
“We are exploring all options to translate PTUPB to cancer patients especially in combination with current cancer therapies such as chemotherapy, radiation, immunotherapy, or surgery which either directly or indirectly may generate tumor cell debris,” Panigrahy said. “Our next step is to investigate whether our findings are consistent with clinical studies involving human cancer.”
The Hammock lab has been researching the sEH inhibitor for 50 years. As a graduate student at UC Berkeley, Hammock co-discovered the sEH inhibitor with fellow graduate student Sarjeet Gill, now a distinguished professor at UC Riverside.
"We have a series of papers largely in PNAS, with the Panigrahy group showing first our soluble epoxide hydrolase inhibitors block tumor growth and metastasis when used with omega3 fish oils or with COX inhibitors and the role for these compounds in regulating a number of mediators of cancer growth," Hammock said.
Multiple grants funded the research. Hammock, the 31-year director of the UC Davis Superfund Program, received funds the National Cancer Institute and the National Institute on Environmental Health Sciences. The Panigrahy laboratory is funded by the Credit Union Kids at Heart Team. Other grants came from the C. J. Buckley Pediatric Brain Tumor Fund, Molly's Magic Wand for Pediatric Brain Tumors, the Markoff Foundation Art-in-Giving Foundation, the Kamen Foundation, Jared Branfman Sunflowers for Life, and the Joe Andruzzi Foundation. An NIH T32-training grant funded Gartung's work.
Allison Gartung completed her doctorate at Wayne State University in 2016 and has since served as a postdoctoral research fellow at Harvard Medical School/BIDMC. Highly honored for her work, she won the highest award for a post-doctoral fellow (Santosh Nigam Award) at the 15th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases, held in 2017 in Puerta Vallarta, Mexico. She served as a guest editor of a special double-issue of 24 invited world-experts in Cancer and Metastasis Reviews on Bioactive Lipids.
Dipak Panigrahy was accepted into medical school at Boston University at age 17. He trained in surgery with Dr. Roger Jenkins, who performed the first liver transplant in New England. Over the past decade, Panigrahy led angiogenesis and cancer animal modeling in the Judah Folkman laboratory. He joined the Beth Israel Deaconess Medical Center in 2013, and in 2014 was appointed assistant professor of pathology, and currently has a laboratory in the Center for Vascular Biology Research. Panigrahy is the expert on the team for preclinical tumor models and examining novel concepts for cancer therapy at the preclinical stage –the diversity of models he has created and worked with is unmatched.
Bruce Hammock, UC Davis distinguished professor, is the world expert and discoverer of the dual COX2-sEH inhibitor. He received his doctorate in entomology/toxicology from UC Berkeley and joined the UC Davis faculty in 1980. 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, and the recipient of scores of awards, including the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics; and the first McGiff Memorial Awardee in Lipid Biochemistry,
Mark Kieran of Bristol-Myers Squibb and Professor Vikas Sukhatme (Dean of Emory School of Medicine), both senior co-authors, are leading world-experts on personalized medicine approaches to support the treatment of cancer patients. Kieran is a leading oncologist with expertise in translating novel therapeutic modalities (beyond chemotherapy/irradiation) into the clinic. Plans for clinical trials involving PTUPB are underway.
Professor Sui Huang, with the Institute for Systems Biology (ISB), is known as the world's leading expert on systems biology and debris-induced tumor growth.
Rand, honored at AACR's meeting April 19 meeting in New Orleans, won the highly competitive international award for her proposal, “Regulation of Cancer Angiogenesis from the Metabolism of Epoxy Omega-6 Fats.”
“We're so proud of her,” said Hammock, distinguished professor of entomology, UC Davis Department of Entomology and Nematology, who holds a joint appointment with the UC Davis Comprehensive Cancer Center.
Rand joined Hammock's biological analytical chemistry lab in 2013 and was a fellow on the Oncogenic Signals and Chromosome Biology T32 Training Grant, Department of Microbiology and Molecular Genetics, directed and administered by Wolf-Dietrich Heyer, professor and chair, Department of Microbiology and Molecular Genetics.
Hammock and co-advisor Kermit Carraway, professor in the Department of Microbiology and Molecular Genetics, co-sponsored her on the grant application.
Rand, who will begin the fellowship in July, was lauded for the relevance of her application to AACR's mission, the belief that it will have a significant impact, and in recognition of her potential as a future leader in the field of angiogenesis research.
“I've always been interested in research that combines chemistry and biology to enhance our understanding of human health,” Rand said, who received her doctorate in chemistry from the University of Toronto, Canada, in 2013.
“My Ph.D research focused on our exposure to fluorinated commercial materials, their resulting metabolism, and how the metabolites might affect our health,” she said. “While my Ph.D training was heavily focused on analytical chemistry and metabolic characterization, I wanted more formal training on the biological and biochemical mechanisms associated with disease.”
Her doctoral advisor, Scott Mabury, a UC Davis graduate, introduced her to Hammock. “In Professor Hammock's lab, I research how bioactive metabolites of epoxy omega-6 fatty acids influence cancer biology, by studying their effect on angiogenesis, tumor growth, and metastasis.”
Hammock and Rand collaborate with Harvard Medical School professor Dipak Panigrahy, former researcher in the Hammock lab and a fellow in Folkman's angiogenesis research lab.
"This is a tremendous honor for both Amy and the Hammock laboratory to be awarded the AACR Judah Folkman grant,” said Panigraphy. “Dr. Folkman was a scientific pioneer who established the field of angiogenesis. Amy's potentially paradigm shifting studies in the Hammock laboratory will carry on the Folkman legacy."
"The late Professor Judah Folkman 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."
"Amy took on one of the most demanding projects in the laboratory in asking how a group of natural compounds regulate angiogenesis," Hammock said. "Based on her work with postdoctoral fellow Bogdan Barnych, they may be able to fine tune angiogenesis to stimulate wound healing when needed but block tumor development in patients."
Sung Hee Hwang, also a postdoctoral fellow in the Hammock laboratory, commented: "It appears that the work that Amy and Bogdan are doing could explain how one of my compounds is able to block tumor growth and metastasis."
Rand also has an active collaboration with with UC Davis biomedical engineer Kathy Ferrara.
Born and educated in Canada, Rand holds two other degrees: a bachelor of arts degree in music a and a bachelor of science degree in chemistry, both awarded by Mount Allison University, New Brunswick, Canada, in 2007.
Judah Folkman (1933-2008), considered the father of angiogenesis research, was a professor at the Harvard Medical School who directed the Children's Hospital Boston Surgical Research Laboratories, now the Vascular Biology Program, and served as the scientific director of the hospital's Vascular Anomalies Center. He is best known for his pioneering research on tumor angiogenesis. Cutting off the blood vessels that feed the tumor can stop cancer tumor growth, he said in his revolutionary work that has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization.
Applicants for the Judah Folkman Fellowship for Angiogenesis Research are postdoctoral or clinical research fellows with a medical degree or a combined M.D./Ph.D. who work in an academic, medical or research institution. They must be in first five years of their postdoctoral training. Proposed research projects are restricted to basic, clinical, translational or epidemiological projects that substantially advance the field of angiogenesis research in cancer.
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.”
"Jack McGiff's generation told us how aspirin worked and provided humanity with a collection of new pharmaceuticals which has greatly improved the health of man and his companion animals," Hammock told his fellow scientists at the March conference. “Jack himself was an inspiring scientist explaining regulation of the renal and cardiovascular systems. He not only founded this international conference but for decades, he has been its inspiration, encouraging collegiality and collaboration while demanding uncompromising science."
“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.”
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.”
Hammock, a decade-long participant at the conference, described WEC “as 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.” This year's conference drew 150 scientists.
Darryl Zeldin, scientific director of the National Institute of Health's National Institute of Environmental Health Sciences (NIH/NIEHS) and Michael Laniado Schwartzman, professor and chair of the Department of Pharmacology at the New York Medical College's School of Medicine, presented Hammock with the award.
"Bruce is credited with the discovery of soluble epoxide hydrolase (sEH) and elucidation of its catalytic mechanisms,” Zeldin said. “He has devoted a good portion of his career to development of sEH inhibitors, one of which has completed a phase II human trial and others are in human trials. He has also been instrumental in development of methods to detect and quantify bioactive lipids in biological samples, methods that are used throughout industry and academia. He has been a leader in the eicosanoid research community, and an outstanding collaborator and colleague."
“I think Jack would have been pleased to know that you were the first awardee,” Schwartzman, a longtime colleague of Jack McGiff told Hammock in an email. “This is a great start to a wonderful WEC tradition.”
Hammock collaborator Dipak Panigrahy, an assistant professor of pathology, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, praised the UC Davis professor for his work and said the prestigious award is particularly fitting.
“Professor Hammock, a member of the National Academy of Science, has led a team of over 40 scientists and students with a multidisciplinary, integrated approach to research focused on insect biology, mammalian enzymology, and analytical chemistry,” Panigrahy said, noting that Hammock has produced more than a thousand publications on a wide range of topics in entomology, biochemistry, analytical and environmental chemistry in high quality journals, and that his laboratory has generated more than 50 patents.
About Bruce Hammock
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 historical research funding base is diverse and includes long terms grants from NIH, USDA, Department of Defense, UC Mosquito Research Program and many private and research foundation contracts and grants,” Panigrahy pointed out.
“Dr. Hammock pioneered the first class of pharmaceuticals to directly address the cytochrome P450 (CYP) epoxygenase pathway of arachidonic acid metabolism,” Panigraphy related. “These soluble epoxide hydrolase (sEH) inhibitors are powerful pharmacological tools to raise the levels of epoxyeicosatrienoic acids or EETs. They are being evaluated in clinical trials for cardiovascular diseases and are being considered for long-term use in diabetes, stroke, cerebral ischemia, dyslipidemia, pain, immunological conditions, eye diseases, neurological diseases, renal disease, organ damage, vascular remodeling, atherosclerosis, ischemia-reperfusion, lung disease (chronic obstructive pulmonary diseases-COPD), graft stenosis, cancer, and other medical conditions.”
“In addition, Dr. Hammock's laboratory has demonstrated that omega 3 epoxides are more potent than EETs in many assays,” Panigraphy said. “Importantly, Dr, Hammock's studies are providing insight into the outcome of dramatically increasing omega 3 lipids in the U.S. diet.”
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, ~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 the Kenneth A. Spencer Award in Agricultural Chemistry, NIEHS Merit Award, Alexander von Humboldt Award, George and Judy Marcus Senior Fellow from the American Asthma Foundation, the Bernard Brodie Award in Drug Metabolism from the American Society for Pharmacology and Experimental Therapeutics, and the University of Michigan William E. H. Lands Lecturer in Biochemistry and Nutrition. He was also a visiting professor at the Beth Israel Deaconess Medical Center, Harvard University.
In addition to his directorship of the Superfund program, Hammock serves on the board of the National Accelerator Mass Spectrometry Facility, Lawrence National Laboratory. He is a fellow of the Entomological Society of America (ESA) and recipient of the ESA's Recognition Award for Insect Physiology, Biochemistry and Toxicology. The UC Davis Academic Senate honored him with its Distinguished Teaching Award for Graduate and Professional Teaching, and the Distinguished Research Faculty Award.
About Jack McGiff
John "Jack" McGiff (1927-2013), an internationally known cardiovascular and renal researcher, and distinguished pharmacologist, founded WEC in 1998. McGiff and John Vane (1982 Nobel laureate) worked together in the early 1970s to determine much of what is known about the mechanism of action of aspirin on renal function and blood pressure. McGiff went on independently to publish more than 250 papers on the role of eicosanoids and prostaglandins in health and disease.
Born John Charles “Jack” McGiff in August of 1927, he died in February 2013 at age 85 at his home in Patchogue, N.Y. He received his bachelor's degree from Georgetown University, Washington, D.C., and his medical degree from the Columbia College of Physicians and Surgeons, Cooperstown, N.Y. A veteran of the Marine Corps in the Korean War, he shined in a medical and research career that included chief of cardiology at St. Louis University; professor and chair of the Department of Pharmacology at the University of Tennessee Center for the Health Sciences in Memphis; and professor and chair (1979 to 2010) of the Department of Pharmacology at New York Medical College, Department of Pharmacology at New York Medical College, Valhalla. During his career, McGiff held a grant from the National Institutes of Health for 28 years.
The Eicosanoid Research Association, Inc. based in Peekskill, N.Y., sponsors the annual conference to promote scientific research and education in the field. The conferences are always held in March in Baltimore and serve as an interactive forum for the “exchange of ideas and learning of exciting new developments in the field of eicosanoids with a focus on cancer, inflammation, and cardiovascular disease,” a spokesperson said. Junior and senior researchers present their work, much of it unpublished. Eicosanoids are compounds involved in cellular activity and are derived from polyunsaturated fatty acids.
The study is especially significant because of the desperate shortage of livers among thousands of very ill patients, said lead researcher Dipak Panigrahy of Harvard Medical School, in work published online in the July 29th edition of Proceedings of the National Academy of Sciences (PNAS).
According to the American Liver Foundation website, 1,848 patients died in 2005 while waiting for a donated liver to become available. “Currently, about 17,000 adults and children have been medically approved for liver transplants and are waiting for donated livers to become available. The waiting list grows every year.”
The researchers found that a natural substance in blood vessels stimulates organ and tissue regeneration.
The 28-member team discovered that “systemic administration of EETs significantly increased liver and lung regeneration by 23 percent to 46 percent when compared to control mice post partial liver resection,” Panigrahy said.
“This can be very useful in transplant both for the donor and the recipient in getting full function back with liver transplant,” said researcher and co-author Bruce Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Comprehensive Cancer Center.
In addition to liver transplants, “the research could lead to the success of other organ transplants and speed the recovery of both the patient and the donor,” Hammock said. It could also be a boon for other wound-healing procedures “where tissue repair and growth are crucial.”
“We are planning to evaluate EETs and soluble epoxide hydrolase (sEH) inhibitors in humans who need tissue regeneration such as organ regeneration and wound healing,” Panigraphy said. “We are working to evaluate soluble epoxide hydrolase inhibitors in humans by surgeons.” The surgeons include Mark Puder, Boston Children’s Hospital, lung regeneration; and Roger Jenkins of the Lahey Clinic, Boston, who performed New England's first successful liver transplant in July 1983. In addition, they plan to work with other clinicians for testing EETs in stimulating wound healing in diabetic and nondiabetic patients.
Panigrahy, noting the chronic shortage of livers for transplant, said that liver surgeons “urgently need novel ways to regenerate livers. With Bruce (Hammock) we are working with Dr. Roger Jenkins, who performed New England's first successful liver transplant in July 1983.”
The research, titled “Epoxyeicosanoids Promote Organ and Tissue Regeneration” and accomplished with animal models, showed acceleration of liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Vascularization deals with blood vessel formation in abnormal tissue or in abnormal positions.
“There is a soluble epoxide hydrolase with investigational new drug status with the FDA that stabilizes these natural regulators and we could use them for compassionate trials in this area,” Hammock said. “One possible trial, with Mark Puder at Harvard, is for correcting a condition that blocks growth of lungs in newborns. We have a chance to dramatically increase the number of these babies that survive.”
“We are working on this fatal disease of newborns termed diaphramic hernia,” added Panigrahy. “So far this is all in experimental animals but we are planning to test if increasing EETs can be successful in encouraging poorly developed lungs of newborns to grow."
In their abstract, they wrote: “…we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.
Among the co-researchers are Jun Yang and Bora Inceoglu of the Hammock lab.
“We are very excited about these findings,” Inceoglu said. “Traditionally wound repair and healing is an area where we clearly lack efficacious drugs. This work demonstrates that there are natural processes one can augment and promote to accelerate wound healing. This is a hopeful moment for many patients suffering from serious conditions that can be helped with these new drugs."
Said Yang: “The finding here implies the modulation of EETs in vivo might help wound healing especially for the organ transplant patients. In the study, the result based on liver transplant patients supports this argument, which is very exciting and provides the basis for the translation to the clinic."
Hammock, who directs the NIEHS Superfund Research Program on the UC Davis campus, received financial support from Superfund Program and from NIH grants. He also receives financial backing as a George and Judy Marcus Senior Fellow of the American Asthma Foundation.
Other funding sources supporting the 28-member team were the National Cancer Institute Grant, the Stop and Shop Pediatric Brain Tumor Fund, the C. J. Buckley Pediatric Brain Tumor Fund, the Joshua Ryan Rappaport Fellowship, the Children’s Hospital Boston Surgical Foundation and the Vascular Biology Program, a Howard Hughes Medical Institute Research Fellowship, and the Intramural Research Program of NIH.
Panigrahy cautioned that the work is a work in progress. “Further studies are needed to carefully evaluate the benefits as well as the risks in the clinical modulation of these lipid mediators,” said Panigrahy. “EETs are a substance that can potentially link wound healing and cancer. Stimulating of EETs promotes wound healing. We have shown the ability of EET antagonists to inhibit tumor growth and metastasis. These results could pave the way for a new strategy for the prevention and treatment of metastatic disease — that is, inhibition of EET bioactivity. Specific EET antagonists, inhibitors of endothelial CYP epoxygenases, or the overexpression of EET-metabolizing enzymes may represent new strategies for the treatment of angiogenic diseases, including cancer.”