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.
The drug candidate, known as EC5026, targets a novel pathway to block the underlying cause of certain types of pain. Described by EicOsis as a “novel, non-opioid and oral therapy for neuropathic and inflammatory pain,” it is an inhibitor to the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids. UC Davis recently licensed certain patents supporting the underlying technology exclusively to EicOsis.
Clinical trials are expected to begin this summer. “The clinical trials would be the world's first clinical evaluation of sEH for pain,” said William Schmidt, EicOsis vice president of clinical development, who has focused his entire professional career on developing novel pain medicines. “I am thrilled that we have a drug candidate lacking the side effects of both opioids and non-steroidal anti-inflammatory drugs that can potentially produce lead to an entirely new way to treat chronic pain.”
“Chronic pain is an enormous emotional and economic burden for more than 100 million people in the United States alone,” said Hammock, a UC Davis a distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. He co-founded EicOsis in December 2011 to alleviate pain in humans and companion animals. “The extreme and poorly treated pain that I observed as a medical officer working in a burn clinic in the Army, is a major driver for me to translate my research to help patients with severe pain.”
National statistics show that as many as eight out of every 10 American adults suffer from chronic pain; three out of four patients consider their therapies for pain ineffective; and as many as a third of the opioid-prescribed patients misuse them.
Every day, more than 130 people in the United States die from opioid overdose, according to the National Institute of Drug Abuse. The Centers for Disease Control and Prevention estimates that the total economic burden of prescription opioid misuse alone in the United States is $78.5 billion a year. That includes the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.
“This completes the fundraising for Phase 1 of the clinical development program of this novel pain therapeutic,” said Hammock. “We are particularly pleased that the support came from Open Philanthropy with its history of both financially successful and socially important investments.”
Dushyant Pathak, UC Davis associate vice chancellor for Research and executive director of Venture Catalyst, lauded the achievement. “We are very pleased to see the achievement of this important business milestone by EicOsis,” Pathak said. “It's especially heartening to see the entrepreneurial persistence of Bruce Hammock being recognized by Open Philanthropy.”
Open Philanthropy identifies outstanding investment opportunities and makes grants based on importance, need, and tractability, according to the organization's scientific advisors Chris Somerville and Heather Youngs. They said Open Philanthropy selected the Davis project because the EicOsis drug “may reduce suffering from chronic pain conditions which are severe in both developed and developing nations.”
On its website, http://www.eicosis.com, EicOsis depicts itself as “a privately held company developing a first-in-class therapy of a once daily, oral treatment for neuropathic and inflammatory pain in humans and companion animals.”
“Our orally active compounds stabilize natural regulatory mediators in the body that reduce endoplasmic reticulum stress, which, in turn, appears to cause a variety of chronic diseases,” said EicOsis neurobiologist Karen Wagner. “The EicOsis compounds represent a new mechanism of action that both resolves inflammation and reduces pain.”
EicOsis (pronounced eye-cosis), derives its name from eicosanoid, “the major backbone of chemical mediators in the arachidonate cascade,” said Cindy McReynolds, an EicOsis project manager and a doctoral student in pharmacology and toxicology at UC Davis. “It symbolizes the epoxide group in chemistry, which is key to the anti-inflammatory chemical mediators and where the biochemical target called soluble epoxide hydrolase works.”
The National Institutes of Health (NIH) Blueprint for Neuroscience Research (Blueprint) awarded EicOsis a $4 million grant to advance compounds through Phase 1 clinical trials for diabetic neuropathic pain. A goal of the Blueprint Neurotherapeutics Network is to discover, develop and generate novel compounds that will ultimately be commercialized and benefit humankind.
In addition, EicOsis received support from the NIH's National Institute of Neurological Disorders and Stroke (NINDS), and the support of two small business programs affiliated with the National Institute of Environmental Sciences: the Small Business Innovation Research (SBIR) and the Small Business Technology Transfer (STTR).
“We are fortunate to receive all this support in the development of our oral medication for pain treatment through human Phase 1a trials, and now Open Philanthropy through human Phase 1b trials and beyond,” said Alan Buckpitt, a UC Davis retired professor of veterinary pharmacology and toxicology, and a principal investigator on the grants.
Nationally recognized for his achievements, 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 scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics.
Hammock, a member of the UC Davis faculty since 1980, received his doctorate in entomology and toxicology from UC Berkeley. He traces the history of his enzyme research to 1969 during his graduate student days in the John Casida laboratory. Hammock was researching insect developmental biology and green insecticides when he and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, discovered the target enzyme in mammals that regulates epoxy fatty acids.
“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.”
“Basically, I began by trying to figure out how a key enzyme, epoxide hydrolase, degrades a caterpillar's juvenile hormone, leading to metamorphosis from the larval stage to the adult insect,” Hammock. He asked himself these questions: “Does the enzyme occur in plants? Does it occur in mammals?" It does, and particularly as a soluble epoxide hydrolase in mammals.
"It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock, marveling that “this all began by asking how caterpillars turn into butterflies.”
An enzyme inhibitor developed in the UC Davis laboratory of Bruce Hammock and tested in mice by a team of international researchers shows promise that it could lead to a drug to prevent or reduce the disabilities associated with the neurodevelopmental disorders of autism and schizophrenia.
“We discovered that soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Inhibiting that enzyme stops the inflammation and the development of autism-like and schizophrenia-like symptoms in animal models,” said collaborator Kenji Hashimoto, a professor with the Chiba University Center for Forensic Mental Health, Japan. The scientists found higher levels of sEH in a key region of the brain—the prefrontal cortex of juvenile offspring-- after maternal immune activation (MIA).
“Mothers who have MIA, which results from severe stress in that region of the brain, have an increased occurrence of neurodevelopment disorders in their offspring,” Hashimoto explained. “In our study, the sEH enzyme increased dramatically in a key brain region of mice pups from mothers with MIA.”
The research, published today (March 18) in the Proceedings of the National Academy of Sciences (PNAS), is the work of 14 researchers from Chiba University Center for Forensic Mental Health; the Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, in Wako, Saitama, Japan; and the Hammock laboratory.
Research in Mice Pups
By inhibiting sEH, the researchers reversed cognitive and social interaction deficiencies in the mice pups. They hypothesize that this is due to increasing natural chemicals, which prevent brain inflammation. In people, this could reduce the disabilities associated with autism, such as anxiety, gastrointestinal disturbances and epilepsy.
“The same chemical and biochemical markers behaved as predicted in human stem cells,” said Hammock, a distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
Earlier studies have indicated a genetic disposition to the disorders. The team also studied postmortem brain samples from autism patients that confirmed the alterations.
“In the case of both autism and schizophrenia, the epidemiology suggests that both genetics and environment are contributing factors,” said neuroscientist and associate professor Amy Ramsey of the Department of Pharmacology and Toxicology, University of Toronto, who was not involved in the study. “In both cases, maternal infection is a risk factor that might tip the scales for a fetus with a genetic vulnerability. This study is important because it shows that their drug can effectively prevent some of the negative outcomes that occur with prenatal infections. While there are many studies that must be done to ensure its safe use in pregnant women, it could mitigate the neurological impacts of infection during pregnancy.”
Neuroscientist Lawrence David, professor and chair of the School of Public Health, University of Albany, N.Y., who was not involved in the research, said that the study might lead to “an important therapeutic intervention for neurodevelopment disorders.”
Might Be Important Therapeutic Invervention
“There is increasing evidence that maternal immune activation activities (MIA) during fetal development can lead to aberrant neurobehaviors, including autistic-like activities,” said Lawrence, who studies neuroimmunology and immunotoxicology. The study “suggests that enzymatic control of fatty acid metabolism is implicated in neuroinflammation associated with schizophrenia and autism spectrum disorders. The expression of Ephx2 giving rise to soluble epoxide hydrolase (sEH) influences production of fatty acid metabolites, which elevate inflammation in the experimental model of mice after MIA; the sEH inhibitor TPPU (N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea) was postnatally used to improved behaviors. Analysis of cadaver brains from individuals with ASD also expressed increased sEH. Fatty acid metabolites have been known to affect fetal development, especially that of the brain; therefore, TPPU might be an important therapeutic intervention for neurodevelopmental disorders.”
Molecular bioscientist Isaac Pessah of the UC Davis School of Veterinary Medicine, distinguished professor and associate dean of research and graduate education in the Department of Molecular Biosciences, described the findings as “significant” and called for more detailed and expanded studies.
“There is mounting evidence that inappropriate maternal immune responses during pregnancy to infection contributes elevated risk to autism spectrum disorder, at least in a fraction of cases,” Pessah said. “The most significant findings reported here is that a commonly used mouse model of immune-triggered behavioral deficits mimicking some of the core symptoms in autistic children can be suppressed by inhibiting a novel biochemical target, soluble epoxide hydrolase; a target not previously explored as a target for therapeutic intervention to treat ASDs. These findings provide a rational basis for more detailed and expanded studies in mice carrying mutations implicated in ASDs to determine whether the therapeutic benefits of soluble epoxide hydrolase inhibitor(s) observed in this study are more generalizable.”
Autism in the United States
The Center for Disease Control and Prevention (CDC) estimates that 1 in 68 children in the United States have autism, commonly diagnosed around age 3. It is four times more common in boys than girls. CDC defines autism spectrum disorder as a “developmental disability that can cause significant social, communication and behavioral challenges.” The disorder impairs the ability to communicate and interact.
Approximately 3.5 million people or 1.2 percent of the population in the United States are diagnosed with schizophrenia, one of the leading causes of disability, according to the Schizophrenia and Related Disorders Alliance of America (SARDAA). Scores more go unreported. Approximately three-quarters of persons with schizophrenia develop the illness between 16 and 25 years of age. Statistics also show that between one-third and one half of all homeless adults have schizophrenia, and 50 percent of people diagnosed have received no treatment. Among the symptoms: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and obsessive-compulsive disorders, such as hoarding, according to SARDAA.
Promising Prophylactic or Theraputic Target
In their research paper, titled “Key Role of Soluble Epoxide Hydrolase in the Neurodevelopmental Disorders of Offspring After Maternal Immune Activation,” the scientists described sEH as “a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.”
First author Min Ma and second Qian Ren of the Hashimoto lab conducted the animal and biochemical work, while chemists Jun Yang and Sung Hee Hwang of the Hammock lab performed the chemistry and analytical chemistry. Takeo Yoshikawa, a team leader with the RIKEN's Molecular Psychiatry Laboratory, performed measurements of gene expression in the neurospheres from iPSC (induced pluripotent stem cells) from schizophrenia patients and postmortem brain samples from autism patients.
Hashimoto described the international collaboration as “exciting and productive.” This is their third PNAS paper in a series leading to endoplasmic reticulum stress. “We report discovery of a biochemical axis that leads to multiple neurological disorders, including depression, Parkinson's disease, schizophrenia, autism spectrum disorders and similar diseases,” he said.
First Human Trials
William Schmidt, vice president of clinical development at EicOsis, a Davis-based company developing inhibitors to sEH to treat unmet medical needs in humans and companion animals, said the company is developing a first-in-class therapy for neuropathic and inflammatory pain. “EicOsis is in the process of finalizing our first human trials on the inhibitors of the soluble epoxide hydrolase, originally reported from UC Davis,” Schmidt said. “We are targeting the compounds as opioid replacements to treat peripheral neuropathic pain. It is exciting that the same compound series may be used to prevent or treat diseases of the central nervous system.”
Several grants from the National Institutes of Health, awarded to Hammock, supported the research. Hammock praised the many collaborators and students he has worked with on the project. “This work illustrates the value of research universities in bringing together the diverse talent needed to address complex problems,” Hammock said. “It also illustrates the value of fundamental science. This autism research can be traced directly to the fundamental question of how caterpillars turn into butterflies.”
Now working solely on research to benefit humankind, Hammock began his career in insect science at UC Berkeley where he investigated how epoxide hydrolase degrades a caterpillar's juvenile hormone. The process leads to metamorphosis from the larval stage to the adult insect. Hammock then wondered "Does the enzyme occur in plants? Does it occur in mammals?"
It does, and particularly as a soluble epoxide hydrolase in mammals.
"Science is full of surprises," said Hammock, who founded EicOsis to help human patients conquer pain without opioids. "We need to remember that the concept, the clinical target, and even the chemical structure, came from asking how caterpillars turn into butterflies."
ABSTRACT, PNAS Paper, "Key Role of Soluble Epoxide Hydrolase in the Neurodevelopmental Disorders of Offspring After Maternal Immune Activation"
“Maternal infection during pregnancy increases the risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy-fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, the expression of sEH (or EPHX2) mRNA in iPSC-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in the postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment of TPPU (a potent sEH inhibitor) into juvenile offspring from P28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV)-immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV-immunoreactivity in the mPFC of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH would represent a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.”
Related Research Published in PNAS
- Soluble Epoxide Hydrolase Plays a Key Role in the Pathogenesis of Parkinson's Disease
- Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress
Born Jan. 30, 1951 in Hong Kong and fondly known as “Amazing Grace,” she received her doctorate at UC Davis in 1983 with major professor Hammock, now a UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
Her husband of 41 years, Davy Jones, a longtime professor in the UK Department of Toxicology and Cancer Biology, received his doctorate from UC Davis, studying with major professor Jeffrey Granett of the then Department of Entomology.
Hammock described Grace Jones as a hard-working scientist with “amazing skill and creative insight.”
“Following her research at Texas A&M University, Grace joined my lab in the 1970s at UC Riverside and then finished her PhD at Davis in 1983,” recalled Hammock, a member of the UC Riverside faculty from 1975 to 1980, when he accepted a joint-faculty appointment in toxicology and entomology at UC Davis.
“She asked how juvenile hormone regulated the development of moth larvae that are serious agricultural pests,” Hammock said. “She also found two parasites, one of which sped up host larval development and the other of which slowed host larval development. She found that both parasitoids were manipulating the host insect endocrine system to their benefit. Endocrine regulation of insect development was a theme of Grace's whole career which she pursued with amazing skill, hard work and creative insight.”
Longtime friend and colleague Lynn Riddiford, emerita professor of biology at the University of Washington, Seattle, who worked with Grace Jones on a National Science Foundation grant, praised her as “a creative and imaginative scientist.”
“Her research focused on the action of juvenile hormone (JH), a key hormone regulating metamorphosis in insects,” Riddiford said. “Early on Grace studied the molecular mechanisms involved in the regulation by JH of several proteins in the cabbage looper, Trichoplusia ni—the JH-inducible JH esterase that breaks down JH and several JH-suppressible hemolymph storage proteins. Her work was always careful and thorough and contributed significantly to the field.”
Riddiford said that “Grace became intrigued by the idea that Ultraspiracle (USP), the heterodimeric partner of the ecdysone receptor (EcR), might be the long-sought JH receptor. She pursued this line of research with rigor, and later found that USP bound methyl farnesoate, the immediate precursor of JH, with the high affinity typical for hormone receptors. Furthermore, she showed that the methyl farnesoate-USP complex was critical for the larval-pupal transformation in Drosophila. Even though her initial idea that USP was the JH receptor proved wrong, her work stimulated the field and resulted in a deeper understanding of the factors controlling metamorphosis in Drosophila.”
Riddiford added: “Grace will be especially remembered for her amazing drive and determination to forge ahead with her science and to continue to make significant contributions despite the disabilities engendered by her stroke.” (See research publications)
Keith Wing, Hammock's second doctoral student who went on to become a senior research associate at Rohm and Haas and DuPont, and is now a consultant, remembered her as “a cheerful, hard-working colleague and friend, and wife of Dr. Davy Jones, University of Kentucky. A few of us spent many a late night studying juvenile hormone esterase and binding proteins at UC Riverside and Davis in lepidopteran larvae, trying to help the lab piece together the story of how JH metabolism and transport helped to regulate insect metamorphosis.”
“We shared everything and always helped each other out,” Wing said. “Grace went on to focus on this in much greater detail, including exploration into insect hormone receptors and regulation. She was an incredibly dedicated researcher who contributed a lot to the field."
Grace Jones received her bachelor's degree in biology in 1973 from Belmont (N.C.) Abbey College, and her master's degree in biology in 1974 from Jacksonville (Ala.) State University. She did post graduate research at Texas A&M in insect physiology and endocrinology before joining the Hammock lab in UC Riverside (1979-80). After receiving her doctorate in 1983 from UC Davis, she headed to Harvard University's Medical School as a visiting scholar in the Department of Cell Biology and Department of Pathology, working there from 1989 to 2000. Her career then included visiting scientist at Massachusetts Institute of Technology's Department of Biology and a visiting professor at Baylor College of Medicine, where she specialized in stem cell research.
The UC Davis alumnus joined the UK Department of Entomology in 1984 as an assistant research professor, studying insect biochemistry and molecular biology. She was promoted to associate research professor in 1990, and then switched to UK's School of Biological Sciences, becoming an assistant professor of molecular and cellular biology in 1991; an associate professor in 1993; and a full professor in 1999.
"Dr. Jones was a superb, internationally recognized scientist, even as her health declined over the past 18 years, but she continued to work on teaching and research throughout," wrote UK Department of Biology chair Vincent Cassone on a web page memoralizing her. "Over the course of her research career, Dr. Jones had received millions of grant dollars for her important studies from the National Institutes of Health and National Science Foundation, and published more than 100 research articles in prestigious journals such as the Proceedings of the National Academy of Sciences, USA, Journal of Biological Chemistry, and Molecular and Cellular Endocrinology. She and Davy also received a patent in 2007 for a method to identify drugs that interact with insect nuclear receptors, which could be used for biological control of pest species."
"Over the years, students have expressed great admiration and love for Professor Jones in letters and emails, and eminent scientists have expressed their high regard for her work," Cassone wrote. "A Grace Jones Memorial Fund for Family Support has been set up. Donations can be sent to the UK College of Health Science c/o Loralyn Cecil, 900 South Limestone 124E, Lexington, KY 40508 or online at https://karrn.org/. Her infectious smile will be missed in the halls of Biology, as she had her daily walks, arm in arm, color-coordinated with her husband, Davy, a testament to devotion and love."
Davy Jones notified his wife's friends and colleagues, including Hammock, of her death with an email, “Butterfly has flown on.” He attached a photo of Grace and a blue morpho butterfly.
She died in his arms, as this song, “Amazing Grace,” played softly in the room, he wrote.
“UC Riverside, UC Davis and the field lost a wonderful colleague and we have all lost a dear friend,” Hammock told him.
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.