- Author: Kathy Keatley Garvey
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.
- Author: Kathy Keatley Garvey
The research, published in the current edition of the Proceedings of the National Academy of Sciences, shows that bioactive products from a major family of enzymes discovered in the UC Davis lab of Bruce Hammock, reduced the eye disease severity in an animal model with neovascular AMD. The compounds regulated inflammatory immune cells both locally—in the retina--and systemically.
Previous research has largely ignored the role of immune cells, “which likely are a major contributor in this pathologic process,” said corresponding author Kip Connor, a vision scientist at the Massachusetts Eye and Ear Infirmary and an assistant professor of ophthalmology at Harvard Medical School.
The chronic, progressive disease affects as many as 11 million Americans but that number is expected to double by 2020, said Connor, one of the nine international experts in lipid biology and AMD involved in the study. Globally, some 196 million are projected to get AMD by 2020. The risk of getting AMD increases from 2 percent for those ages 50-59, to nearly 30 percent for those over the age of 75, according to the Bright Focus Foundation, which helped fund the research.
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, expressed hope that the team “that Dr. Connor's laboratory will find a solution to this devastating human health problems."
The study, based in Connor's laboratory at Harvard, “shows how rapidly fundamental knowledge of physiology and regulatory biology can be translated to practical solutions for a major type of blindness,” Hammock said. “I was at Harvard several years ago and saw a poster outside a laboratory on AMD. This resulted in me meeting Eiichi Hasegawa, a doctorial fellow in the Connor lab, and through him, Kip, which has led to a long-term collaboration.”
“I also see the compounds that I made moving to human clinical trials with the hope of treating pain and inflammatory diseases such as AMD,” Hammock added.
“In patients with advanced AMD, abnormal blood vessels start to develop from underneath the light-sensing layer of the eye in a process known as choroidal neovascularization (CNV),” Connor explained. “Such cases, termed neovascular or “wet” AMD, account for 10 to 15 percent of AMD cases,develop abruptly, and rapidly lead to substantial vision loss.”
“Although we do not fully understand how and why AMD develops, identifying additional mechanisms that regulate abnormal blood vessel growth in the eye beyond what we currently know could open up a range of possibilities for new research and treatments for AMD,” Connor noted.
The team demonstrated that “specific bioactive products from the cytochrome P450 (CYP) pathway, a major family of enzymes, can influence CNV and vascular leakage by changing how immune cells are recruited to areas of disease and injury,” lead author Eiichi Hasegawa said. “Specifically, we isolated and characterized two key mediators of disease resolution generated from the CYP pathway: 17,18-epoxyeicosatetraenoic acid (EEQ) and 19,20-epoxydocosapentaenoic acid (EDP). “
“Our study offers new insights into bioactive lipid metabolites as regulators of systemic inflammatory immune cells and mediators in CNV resolution,” Connor said, noting that current treatments for AMD do not fully address the underlying causes of this disease. “Given the high prevalence and progressive nature of neovascular eye disease, the ability to stabilize bioactive lipids that mitigate or halt disease is of great and increasing therapeutic significance. It is our hope that emerging technologies and future studies will expand on our work and ultimately lead to safe, targeted, and cost-effective therapies that markedly improve visual outcomes and quality of life for patients suffering from these debilitating ocular diseases.”
Said co-author Kin Sing Stephen "Sing" Lee, who worked on the initial enzyme project as a postdoctoral researcher in the Hammock lab at UC Davis, and is now an assistant professor of pharmacology and toxicology at Michigan State University: “It was so exciting at UC Davis to be involved with basic research on inflammation but also see the compounds that I made moving to human clinical trials with the hope of treating pain and inflammatory diseases such as AMD. It was also a thrill to develop collaborations with scientists throughout the world like Eiichi Hasegawa and Kip Connor
In addition to Connor, Hammock, Lee and Hasegawa, co-authors of the publication, “Cytochrome P450 Monooxygenase Lipid Metabolites are Significant Second Messengers in the Resolution of Choroidal Neovascularization" include Saori Inafuku, Lama Mulki, M.D., Yoko Okunuki, M.D., Ph.D., Ryoji Yanai, M.D., Ph.D., Kaylee E. Smith, Clifford B. Kim, Garrett Klokman, Deeba Husain, M.D., and Joan W. Miller, M.D., of Massachusetts Eye and Ear/Harvard Medical School, as well as Diane R. Bielenberg, Ph.D., of Boston Children's Hospital/Harvard Medical School, Narender Puli, Ph.D., and John R. Falck, Ph.D., of the University of Texas Southwestern, Wolf-Hagen Schunck, Ph.D., of the Max Delbruch Center for Molecular Medicine in Germany, Matthew L. Edin, Ph.D., and Darryl Zeldin, M.D., of the National Institutes of Health's National Institute of Environmental Health Sciences (NIH/NIEHS).
The research was supported in part by the NIH NIEHS, Research to Prevent Blindness, Massachusetts Lion Eye Research Fund, BrightFocus Foundation, Harvard Department of Opthalmology and Massachusetts Eye and Ear Infirmary; the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad; the Robert A. Welch Foundation, and by a scholar award and a medical student fellowship grant. (Follow the Connor lab on Twitter @ConnorLab and the Bruce Hammock lab on Facebook at https://www.facebook.com/hammocklab/)